Molekulare Medizin: Grundlagen, Pathomechanismen, Krankheitsbilder 9783110150971, 3110150972 [PDF]

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TX

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4

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OctamerHistonkern 10 nm

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UPS v5$16.5,37,21

TATA TFIID

TFIID TATA TFIIA TFIIB TFIID TFIIA

TFIIB

TATA POL II TFIIF

Mediator/ SRB

POL II

TFIID TFIIA

TFIIF

TFIIB

TATA TFIIE TFIIH

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POL II

TFIID TFIIA

TFIIF

TFIIB

TATA

TFIIE TFIIH

A

RN

POL II

TFIID TATA

PP

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TFIIB

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TFIIF

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U2AF GUC CAUUCA I I I I I I I I I C A G GU A A G U Exon 1

5´

AUGAU I I I I I UACUA

IAI

G I C

Py

CAGG Exon 2

Verzweigungspunkt + U5, U4/U6

G A C 1 on Ex

UACUA C II A G AU UGA

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UACUA C II A G AU UGA

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CAGG Exon 2

CAG

CAG G Exon 1 Exon 2

Assemblierung des Spleißosoms

Schritt 1 = Ausbildung der Lassostruktur = 1. Transesterifizierung

Schritt 2 = Zusammenspleißen des Exons, Freisetzung des Lariats = 2. Transesterifizierung

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6>85(.2',(5(1'(1 v5,3/(776 (,1( (,*(1( 7tpc (;,67,(5(1N :(,/ )@5 ',( j7 %(=@*/,&+ '(6 '5,77(1 p8./(27,'6 %(67(+(1 '$5) J',(6 ,67 (,1 i581' )@5 '(1 :2%%/(KP h@5 -('( 7tpc *,%7 (6 (,1 =8O *(+?5,*(6 g1=*7P f,(6(5 m203/(; %(:(*7 6,&+ ,1 UAOt,&+781* JNN6&$11,1*DDKN 80 0,77(/6 e2'21Bc17,&2'21 k17(5$.7,21 '$6 cwi k1,7,$7,216.2'21 =8 ,'(17,7=,(5(1P p$&+ (5)2/*7(5 g5.(1181* %,1'(7 6,&+ 1$&+ h5(,O 6(7=81* 921 (khT 81' (khU ,0 VP u&+5,77 ',( *52M( 5,%2620$/( w17(5(,1+(,7 JXRuKN :$6 =85 x(592//67>1',*81* '(6 =85 r527(,16+,*(1 ZRu t,%26206 )@+57P

UPV e*7 $8&+ ',( c1=$+/ %(7(,/,*7(5 o2/(.@/( t(&+O 181*\ p(%(1 '(5 =8 75$16/$7,(5(1'(1 0tpc :(5'(1 7tpcOo2/(.@/( 81' 5tpc J$/6 d(67$1'7(,/ '(5 t,%2620(1K 62:,( (,1( x,(/=$+/ 5,%2620$/(5 r527(,1( 81' v5$16O /$7,216,1,7,$7,216O %=:P O(/21*$7,216)$.725(1 %(1?7,*7P r5,1=,3,(// />M7 6,&+ ',( v5$16O /$7,21 :,( $8&+ ',( v5$16.5,37,21 ,1 '5(, r+$6(1 817(57(,/(1\ k1,7,$7,21Og/21*$7,21O v(50,1$7,21P l('( ',(6(5 r+$6(1 %(1?7,*7 *(621'(57( Jr527(,1OKh$.725(1 81' cvr %=:P ivr $/6 g1(5*,(75>*(5P

RMSMQMS s2!.3,!4)/.3).)4)!4)/. w17(5 ',(6(0 d(*5,5 )$M7 0$1 ',( x25*>1*( =86$00(1N ',( '85&+/$8)(1 :(5'(1N %(925 ',( (,*(17/,&+( r527(,168)7 %(, $//(1 (8.$5,1,7,$7,216.203/(;(6 J%(67(+(1' 1(%(1 '(5 VRu 5,%2620$/(1 w17(5(,1+(,7 $86 '(5 o(7+,215(1 g,6(163,(*(/1 921 ktrOS 2'(5 ktrOT Jktr 3 ,521 5(*8/$725< 3527(,1K *(%81'(1 :,5'P f(5 ktgBktr m203/(; $0 WAOg1'( %/2&.,(57 ',( v5$16/$7,216,1,7,$7,21N :(,/ '(5 (khVh m203/(; 1,&+7 0(+5 '(1 VUu r5>,1,7,$7,216.203/(; 5(.587,(5(1 .$11 J6,(+( c%%P UPUTKP h2/*O /,&+ ,67 ,1 (,6(1'(7=,(17(1 |(//(1 ',( u5( r527(,165(1 0tpc6 %(1?7,*(1 ',( d(7(,/,*81* ',(6(6 h$.7256 $1 '(5 k1,7,$7,21 81' .?11(1 '(6+$/% 1,&+7 0(+5 75$16/$7,(57 :(5'(1P r2/,29,586 0tpc .$11 +,1*(*(1 6(,1( v5$16/$7,21 81$%+>1*,* 921 (khVh ,1,7,,(5(1 81' %(+(556&+7 )2/*/,&+ ',( =(/O /8/>5( v5$16/$7,216.$3$=,7>7P

RMSMQMT s2!.3,!4)/.3%,/.'!4)/. 5.$ L4%2-).!4)/. u2%$/' '$6 ZRu t,%2620 $0 k1,7,$7,216&2'21 %(5(,767(+7N .$11 ',( r527(,16+5(1' 6,&+ ,0 25(1(1 n(6(5$67(5 .(,1( u723&2'216 %(71'(1N :(,67 ',( 0tpc u(48(1= ,1 '(0 80 (,1 %=:P =:(, p8./(27,'( 9(56&+2%(1(1 t$67(5 0(,67 0(+5(5( u723&2'216 $8) J6,(+( c%%P UPUWKP offenes Leseraster

5´… AUG AUAACGAGGGCUA GCG… 3´ Me t I l e T h r A r gA l aS e r .…

+1 frameshift

+1 St op

+2 frameshift

+1 +2A s pAs nG l uG l yStop

c%%P UPUW NNh5$0(6+,)7DD o87$7,21(1 )@+5(1 2)7 =80 c%%58&+ '(5 r527(,16=,6,216.21752//(1 )@+5(1 '$=8N '$M %(, '(5 v5$16/$7,21 g1(5*,( ,1 h250 921 =:(, o2/(.@/(1 ivr 352 r(37,'%,1'81* 9(5O %5$8&+7 :,5'N 2%:2+/ ',( c86%,/'81* (,1(5 r(37,'%,1'81* $1 6,&+ (,1 (;(5*21,6&+(5 r52=(66 ,67P

normales Protein

M e t …………… Glu

Lys

Pro …………… St op

normale mRNA

A U G…………… GAG CUU AAG

CCU …………… U A A

5´ UTR

Leu

Offenes Leseraster

verändertes Protein

M e t …………… Va l

Leu

Lys

Pro …………… St op

missense Mutation

A U G…………… GUG CUU AAG

CCU …………… U A A

5´ UTR

3´ UTR

An 3´ UTR

verkürztes Protein

M e t …………… Glu

nonsense Mutation

A U G…………… GAG CUU UAG

Leu St op CCU …………… UAAA

5´ UTR

An 3´ UTR

verändertes Protein

M e t ……………A r g A l a St op

frameshift Mutation

A U G…………… CGA GCU U A A GCC U…………… …UA 5´ UTR

An

An 3´ UTR

c%%P UPUY g5(.7( 921 r81.7087$7,21(1 ,0 25(1(1 n(6(5$67(5 (,1(5 0tpcP g,1( 7.7,9( 1250$/( 0tpc u(48(1= :85'( *(:>+/7N 80 ',( g5(.7( 921 0,66(16(N 1216(16( 81' )5$O 0(6+,)7 o87$7,21(1 =8 9(5'(87/,&+(1P f(5 r)(,/ :(,67 $8) '$6 381.7087,(57( p8./(27,' +,1N ',( 9O)?50,*( m/$00(5 .(11=(,&+1(7 '$6 v5,3/(770867(5 '(6 -(:(,/,*(1 v5$16.5,37(6P

UPV e1'(57 '$6 e2'21 )@5 (,1( %(67,007( c0,126>85( ,1 (,1 $1'(5(6P h2/*/,&+ :,5' $1 ',(6(5 u7(//( (,1( )$/6&+( c0,126>85( ,16 :$&+6(1'( r52O 7(,1 (,1*(%$87P o$1 635,&+7 +,(5 921 (,1(5 NN0,66(16( 087$7,21DDP g,1( 0,66(16( o87$7,21 /,(*7 %(,63,(/6:(,6( '(5 u,&+(/=(//(5.5$1.81* =8 i581'(N %(, '(5 (,1 x$/,1 JiwiK $167$77 (,1(5 i/87$0,16>85( JiciK $/6 6(&+67( c0,126>85( ,1 ',( tOi/2O %,1.(77( (,1*(%$87 :,5' 81' '(6+$/% (,1 3$7+2/2*,6&+ 9(5>1'(57(6 j>02*/2%,1 685(O.2',(5(1'(6 v5,3/(77 ,1 (,1 u723&2'21 80P f,( h2/*( ,67 (,1 3$7+2/2*,6&+ 9(5.@5=7(6 r527(,1N '$6 6(/%67 ,167$%,/ 6(,1 .$11P g,1 d(,63,(/ +,(5O )@5 %,(7(1 (,1,*( h250(1 '(5 tOv+$/$66>0,( J6,(+( $8&+ m$3P WPSPSKN %(, '(1(1 9(5O 6&+,('(1( '(5 ,16*(6$07 SVX e2'216 ,1 (,1 u723&2'21 JwciK 087,(57 6(,1 .?11(1P f(5 '5,77( o87$7,216785(1N %,6 '$6 t,%2620 $8) (,1 u723&2'21 ,1 ',(6(0 )$/6&+(1 n(6(5$67(5 75,57P f,( h2/*( ,67 (,1 0(,67 9(5.@5=7(6 J6(/7(1 -('2&+ $8&+ 9(5/>1*(57(6K r527(,1 0,7 (,1(0 )$/6&+(1 u&+:$1=(1'( Je$5%2;5( h81.7,21(1 (5+(%/,&+ 67?5(1 .?117(P f85&+ NN1216(16(O0(',$7(' '(&$7 %(67(+(1 .?11(1 Jv$%(//( UPWKP v$%P UPW u7$%,/,7>7 9(56&+,('(1(5 0tpc6 t(*8/$7253527(,1 A &2',(5(1'( 0tpc6 L=P dP o{eN hquN ioOeuhb

SW 0,1 A SZR 0,1

j$86+$/781*63527(,1 A &2',(5(1'( 0tpc6 L=P dP icrfjN h(55,7,1N c&7,1b

T + A /SR +

u(+5 67$%,/( 0tpc6 L=P dP sOi/2%,1N tOi/2%,1b

/TV +

UPV e1O ',*( d('$5) $1 '(1 r52'8.7(1 '(5 NN+286(.((3,1* *(1(6DD 35277,(57 '$*(*(1 ,0 u,11( =(//8/>5(5 ~.2120,( 921 /$1*/(%,*(1 0tpc v5$16.5,37(1P f85&+ :(/&+( o(5.0$/( 817(56&+(,'(1 6,&+ /$1*/(%,*( 921 .85=/(%,*(1 0tpc6a f$6 u(48(1=027,9 cwwwc 71'(7 6,&+ 0(+5)$&+ :,('(5+2/7 ,1 '(5 UA 1,&+7O75$16O /$7,(57(1 t(*,21 '(5 0tpc6 (,1,*(5 q1.2*(1( 81' =(//8/>5(5 y$&+67806)$.725(1P f,(6( cwwwcO5(,&+(1 u(48(1=(1 9(50,77(/1 ',( 3+5(1 g,6(1+20?267$6( (,1(56(,76 '85&+ '$6 d,1'(1 @%(56&+@66,*(1 ,175$=(//8/>5(1 g,6(16 $1 h(55,7,1P c1O '(5(56(,76 :,5' ',( g,6(1$8)1$+0( @%(5 ',( t(*8/$7,21 '(5 |$+/ 921 v5$16)(55,1O 5(=(3725(1 $8) '(5 |(//0(0%5$1 .21752//,(57P k0 UA 1,&+7O75$16/$7,(57(1 g1'( '(5 7)5 0tpc %(71'(1 6,&+N (%(162 :,( $0 WAOg1'( '(5 h(55,7,1 0tpc6N ,521O5(6321O 6,9( (/(0(176 JktgKN ',( 921 ktr *(%81'(1 :(5'(1 .?11(1 81' '$0,7 ',( 7)5 0tpc 67$%,/,6,(5(1P f,( ktr d,1'81* $1 ',( ktg6 '(5 7)5 0tpc ,67 $%+>1*,* 920 =(/O /8/>5(1 g,6(163,(*(/ 81' ,67 %(, g,6(10$1*(/ (5+?+7 Jc%%P UPUVKP w0*(.(+57 )@+57 +2+(6 =(//8/>5(6 g,6(1$1*(%27 =8 9(50,1'(57(5 c5,1,7>7 '(6 ktr )@5 ',( ktg6 81' '$0,7 =8 5$6&+(5(0 c%%$8 '(5 81*(6&+@7=7(1 v5$16)(55,15(=(3725 0tpcP f,(6( t(*8/$7,21 ,67 ,0 u,11( '(5 g,6(1+20?267$6( 6,1192//N '$ 921 '(5 u2//.21=(175$7,21 $%:(,&+(1'( g,6(163,(*(/ =8 *(*(1/>87*(1 x(5>1'(581*(1 '(5 g,6(1$8)1$+0( )@+O 5(1P y,( ',(6(6 m$3,7(/ *(=(,*7 +$7N ,67 '(5 y(* 920 i(1 =80 r527(,1 /$1* 81' (5)25'(57 (,1( =(,7/,&+ 81' ?57/,&+ :2+/$%*(67,007( k17(5$.7,21 9,(/(5 =(//8/>5(5 m20321(1O 7(1P f,( n>1*( ',(6(6 y(*(6 %,(7(7 '(5 |(//( (,1(56(,76 c16$7=381.7( )@5 9,(/( t(O *8/$7,2166&+5,77(] $1'(5(56(,76 (;,67,(5(1 (%(1629,(/( o?*/,&+.(,7(1 )@5 3$7+2/2*,O 6&+( u7?581*(1P f,( =81(+0(1'( m(1171,6 02/(.8/$5(5 g,1=(/+(,7(1 '(5 i(1(;O 35(66,21 81' 02/(.8/$5(5 w56$&+(1 921 g5.5$1.81*(1 ,67 '(5 c86*$1*6381.7 )@5 ',( g17:,&./81* 1(8(5 5$7,21$/(5 81' .$86$/(5 f,$*126(O 81' v+(5$3,(Ou75$7(*,(1P

[V

U o2/(.8/$50(',=,1,6&+( r+&+67 817(56&+,('/,&+( x(56$7=67@&.( '(6 %(75(5(1'(1 i(1/2&86 =8 (,1(5 ,1',9,'8(//(1 k1)250$7,21 =86$00(1*(6(7=7P g567 ',(6( 1(8 5(.20%,1,(57(1 fpcOu(48(1=(1 :(5'(1 '$11 75$16.5,%,(57 81' (17635(O &+(1' '(1 2%(1 %(6&+5,(%(1(1 r5,1=,3,(1 ,1 (,1 r527(,1 @%(56(7=7P o$1 817(56&+(,'(7 dO|(//(1N ',( $/6 $86',5(5(1=,(57( r/$60$=(//(1 k0081*/2%8O /,1( ,16 d/87 6(=(51,(5(1 J+8025$/( c%:(+5K 921 vOn5( c%:(+5 9(50,77(/1P k0O 081*/2%8/,1( Jk*K 6(7=(1 6,&+ (%(162 :,( vO|(//Ot(=(3725(1 JvetK $86 =:(, 9(5O 6&+,('(1(1 m(77(171=7N :(/&+(5 '(5 g5.(1181* 921 h5(0'02/(.@/(1 ',(17 81' ',( u3(=,77>7 '(5 -(:(,/,*(1 k*O 2'(5 vetOm(77( $860$&+7P f,( i(1( '(5 9(56&+,('(1(1 k*O 81' vetOm(77(1 6,1' $8) V e+5202620(1 9(57(,/7 81' (5675(&.(1 6,&+ -(:(,/6 @%(5 (,1( f,67$1= 921 TRR %,6 URRR m% Jc%%P UPVRKP f,( d(621'(5+(,7 ',(6(5 i(1/2&, %(67(+7 '$5,1N '$M ',( 9$5,$%/(1 m(77(1$17(,/( '85&+ =$+/5(,&+( i(16(*0(17( 5(35>6(17,(57 :(5'(1N ',( =81>&+67 '85&+ (,1( fpcOt(O .20%,1$7,21 =8 )81.7,2167@&+7,*(1 g,1+(,7(1 9(5.1@3)7 :(5'(1 0@66(1P f,(6(6 r5,1=,3 '(6 620$7,6&+(1 t($55$1*(0(176 921 fpcOu(48(1=(1 (50?*/,&+7 '(0 k008161*( =8 (,1(5 5(,)(1 0tpc :(,7(59(5$5%(,7(7 81' 6&+/,(M/,&+ ,1 (,1 r52O 7(,1 75$16/$7,(57P f,( WAOg;216 '(5 xOg/(0(17( .2',(5(1 ',( 62*(1$117(1 /($'(5JnKO u(48(1=(1P f$%(, +$1'(/7 (6 6,&+ 80 '(1 +6(17,(57P

UPW i(15(.20%,1$7,21 V

CACAGTG 12 Nukleotide

ACAAAAACC

Nonamer

Spacer (23)

5´ 3´

Heptamer

[Y J

3´ V

RSS

RSS

J

5´

RAG1+RAG2 V

J

signal joint

Ligase KU70/KU80 DNA-PKcs V

CCT G GGAC

Endonuklease, Polymerase Exonuklease, TdT V

CC GGACGT P

T GTC ACAG

J Deletion

+++ CCA TC GG T AG N

J

XRC4 Ligase4 V

CCTGCA CCA T C GGACGT GGT A G P N

J

coding joint

c%%P UPVT u&+(0$ '(5 xJfKl t(.20%,1$7,21P xO 81' lOg/(0(17( :(5'(1 921 u,*1$/6(48(1O =(1 JtuuK 9$1.,(57 Jf5(,(&.(KN ',( 817(56&+,('/,&+( *52M( 63$&(5 JSTBTU %3K (17+$/7(1P r81.7( .(11=(,&+1(1 ',( )@5 '(1 t(.20%,1$7,216352=(M 81$%',1*%$5(1 p8./(27,'( '(5 tuuP f,( *(120,6&+( f,67$1= %(,'(5 .2',(5(1'(5 u(*0(17( .$11 0(+5(5( SRR .% $860$&+(1P tciS 81' tciT 6&+1(,'(1 *(1$8 =:,6&+(1 tuu 81' .2',(5(1'(0 g/(0(17 (,1N :2%(, ',( .2',(O 5(1'(1 g1'(1 (,1( j$$51$'(/6758.785 %,/'(1P mwOj(7(52',0(5( %,1'(1 $1 ',( )5(,(1 fpcO g1'(1P d(,'( tuu :(5'(1 =80 5,1*)?50,*(1 NN6,*1$/ -2,17DD 9(5.1@3)7 81' '(/(7,(57P p$&+ j,1=875(7(1 '(5 .$7$/=,6( =:,6&+(1 '(0 /(7=7(1 p8./(27,' '(6 i(16(*0(17(6 81' '(0 (567(1 p8./(27,' '(6 tuu j(37$0(56 (,1P f$%(, :(5'(1 ',( 6(16( 81' $17,6(16( u75>1*( '(6 -(:(,/,*(1 xON fO 2'(5 lOu(*0(17(6 .29$/(17 0,7(,1$1'(5 9(5%81'(1N :$6 =85 c86%,/'81* (,1(5 j$$51$'(/6758.785 J+$,53,1K )@+57P f,( %(,'(1 tuu g1'(1 :(5'(1 ,0 :(,7(5(1 x(5/$8) 0,77(/6 (,1(5 fpc n,*$6( 2+1( =86>7=/,&+( o2',7.$7,21 =8 (,1(5 5,1*)?50,*(1 u758.785 9(5%81'(1 J6,*1$/ -2,17KN ',( .(,1( h81.7,21 %(6,7=7 81' $/6 (;75$&+5202620$/( fpc %$/' (/,0,1,(57 :,5'P u(+5 9,(/ .203/(;(5 9(5/>8)7 ',( x(5.1@3)81* '(5 .2',(5(1'(1 g/(0(17( J&2'O ,1* -2,17KP |81>&+67 )$//(1 tciS 81' tciT 921 '(5 j$$51$'(/6758.785 $%P g6 .2007 =85 d,1'81* '(6 mwOm203/(;(6N (,1(0 $86 '(1 r527(,1(1 mwYR 81' mwZR %(67(+(1'(1 j(7(52',0(5N '$6 $1 '(1 )5(,(1 g1'(1 '(6 f233(/675$1*%58&+(6 %,1'(7N $1 '(5 fpc (17/$1**/(,7(7 81' (,1 :(,7(5(6 r527(,1 0,7 '(5 .$7$/+5(1' '(5 t(.20%,1$7,21 u20$7,6&+( o87$7,21(1 ,1 5(.20%,1,(57(1 i(1(1

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SSR

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SSV

U o2/(.8/$50(',=,1,6&+( r+6,21(1 .25O 5,*,(57N :(/&+( $8) (,1(1 u75$1* '(5 fpcOf233(/+(/,; %(*5(1=7 6,1'N '$%(, .$11

A T G

Purin-Verlust 12.000/Z/T

C T

Doppelstrangbruch 9/Z/T T G T A Pyrimidin-Verlust 600/Z/T

G

C

G

C

A

U Cytosindesaminierung 200/Z/T

C G A C C

Pyrimidindimer T T C

C

G A

A

G

C G Crosslink 8/Z/T

G

Einzelstrangbruch 55.000/Z/T

G

C C

G A

T

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SUR

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UPY fpcOt(3$5$785

5´ 3´

SUU

3´ 5´

XPA

XPA

XPE

XPE

XPB XPD

1 XPF

XPA XPB HSSB

21–23

XPE XPD XPG

5

3´

DNA Ligase

DNA Polymerase ‰/Â PCNA RFC

c%%P UPXV p8./(27,' g;=,6,2165(3$5$785 J9(5>1'(57 1$&+ j2(,-0$.(56 81' d22760$KP u&+(O 0$7,6&+ '$5*(67(//7 ,67 ',( 6&+5,77:(,6( g5.(1181* 81' g17)(5181* wxO,1'8=,(57(5 n>6,21(1 $86 '(5 fpc ,1 0(16&+/,&+(1 |(//(1P o87$7,21(1 ,1 9,(/(1 '(5 r527(,1(N ',( +,(5%(, 0,7:,5.(1N 6,1' )@5 ',( 6(/7(1( *(1(7,6&+ %(',1*7( g5.5$1.81* z(52'(50$ 3,*0(172680 9(5$17:257/,&+P f(6+$/% 75$*(1 6,( ',( p$0(1 zrc A zrgP g,1=(/+(,7(1 6,1' '(0 v(;7 =8 (171(+0(1P

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SMPMPMQ a!+4%2)/0(!'%. x,5(1 6,1' %,2/2*,6&+ '$5$8) (,1*(67(//7N ,+5 *(1(7,6&+(6 o$7(5,$/ '85&+ k1)(.7,21 ,1 )5(0'( |(//(1 (,1=8%5,1*(1 J6,(+( m$3P YPTKP h@5 ',( fpcOm/21,(581* 6,1' d$.O 7(5,23+$*(1 '$+(5 2)7 (5,=,(17(5( x(.725(1 $/6 r/$60,'( Jc%%P VPSKP |80 %(66(5(1 x(567>1'1,6 ',(6(5 m/21,(581*6675$7(*,( 62// +,(5 .85= $8) '(1 k1)(.7,216=1*(1'(6 o2/(.@/ Jm21.$7(0(5K 5(3/,O =,(57N :2%(, ',( (,1=(/1(1 m23,(1 '85&+ 63(=,76&+( fpcOu(48(1=(1N '(1 62*(1$11O 7(1 &26Ou7(//(1N 921(,1$1'(5 $%*(*5(1=7 6,1'P f$5$8)+,1 :,5' '$6 m21.$7(0(5 $1 '(1 &26Ou7(//(1 *(63$/7(1 81' -(:(,/6 (,1 i(120 ,1 ',( )(57,*(1 j@//(1 9(53$&.7P n(7=7/,&+ 3/$7=7 ',( ,17=,(57( |(//( 81' 6(7=7 (,1( x,(/=$+/ 1(8(5 5(,)(5 d$.7(5,23+$*(1 )5(,N ',( -(7=7 6(/%67 :,('(5 12&+ 1,&+7 ,17=,(57( p$&+%$5=(//(1 ,17=,(5(1P k0 w17(5O 6&+,(' =8 '(1 r/$60,'(1 @%(575>*7 (,1 ,1.25325,(57(5 r+$*( .(,1( c17,%,27,.$5(6,O 67(1=P f,(6(6 u(/(.7,21635,1=,3 67(+7 '$0,7 $8&+ 1,&+7 =85 c15(,&+(581* 75$16)25O 0,(57(5 |(//(1 =85 x(5)@*81*P h@5 ',( w17(56&+(,'81* 921 5(.20%,1$17(1 *(*(1O @%(5 1$7,9(1 r+$*(1 0$&+7 0$1 6,&+ =8187=(N '$M '$6 r+$*(1*(120 (567(16 6(,1( (66(17,(//(1 i(1( $8) 185 .1$33 UR .% (17+>/7N 81' '$M =:(,7(16 185 62/&+( fpcO o2/(.@/( 9(53$&.7 :(5'(1 .?11(1N '(5(1 n>1*( 1,&+7 :(6(17/,&+ 921 '(5 1$7@5/,&+(1 i5?M( '(6 i(1206 '(6 +>87* 9(5:(1'(7(1 d$.7(5,23+$*(1 n$0%'$ 921 &$P VZ .% $%:(,&+7P |85 fpcOm/21,(581* ,1 r+$*(1 .?11(1 ',( 1,&+7O(66(17,(//(1 &$P SZ .% (17)(517 81' '85&+ (;2*(1( fpc (56(7=7 :(5'(1P f,( 5(.20%,1$17( fpc :,5' '$11 ,1 9,752 9(53$&.7 81' *((,*1(7( gP &2/, u7>00( 0,7 '(1 92//67>1',*(1 r+$O *(13$57,.(/1 ,17=,(57P f,( n>1*(163(=,77>7 '(6 x(53$&.81*60(&+$1,6086 %(:,5.7N '$M 1,&+7O5(.20%,1$17( r+$*(1Ofpc :(*(1 '(5 )(+/(1'(1 SZ .% 1,&+7 9(53$&.7 :(5'(1 .$11 81' 620,7 1,&+7 =85 k1)(.7,21 '(5 |(//(1 *((,*1(7 ,67P f(5 x257(,/ '(5 fpcOm/21,(581* ,1 r+$*(1 /,(*7 620,7 '$5,1N '$M ',( 0$;,0$/( n>1*( '(5 (;2*(1(1 fpc (7:$ '233(/7 62 *52M ,67 :,( %(, '(1 r/$60,'(1N 81' '$M gP &2/, |(//(1 '85&+ ',( k1)(.7,21 0,7 r+$*(1 :(,7$86 (5(.7,9(5 75$16)250,(57 :(5'(1 $/6 '85&+ (,1( 3$66,9( c8)1$+0( 921 r/$60,'(1P

SMPMPMR b/3-)$% g,1( +>87* %(187=7( '5,77( c/7(51$7,9( ,67 ',( x(5:(1'81* '(5 1$7@5/,&+(5:(,6( 1,&+7 925.200(1'(1 e260,'( $/6 x(.725(1 Jc%%P VPSKP g6 +$1'(/7 6,&+ +,(5%(, 80 r/$6O 0,'( 0,7 %$.7(5,(//(1 t(3/,.$7,21685635@1*(1 81' c17,%,27,.$Ot(6,67(1=*(1(1N ,1 ',( &26Ou(48(1=(1 $/6 u,*1$/(/(0(17( )@5 '(1 9,5$/(1 x(53$&.81*60(&+$1,6086 (,1O *(6(7=7 :85'(1P f,( (66(17,(//(1 d(67$1'7(,/( 62/&+(5 x(.725(1 6,1' 1,&+7 9,(/ 0(+5 $/6 W .% /$1*P f85&+ k1.25325$7,21 921 6 VR .% J81' ,0 62*(1$117(1 rS e260,' 921 %,6 =8 SRR .%K (;2*(1(5 fpc ,1 (,1 e260,' (1767(+7 (,1( t(.20%,1$17(N ',( ,1 9,752 ,1 r+$*(1+@//(1 9(53$&.7 81' =85 k1)(.7,21 921 gP &2/, %(187=7 :(5'(1 .$11P f$ e260,'( .(,1( i(1( )@5 9,5$/( j@//3527(,1( 2'(5 )@5 ',( t(*8/$7,21 '(6 9,5$/(1 k1)(.7,216=1*( '(5 ,1 (,1(5 |(//( ./21,(5%$5(1 fpc $8) (7:$ VR .%P c/O /(5',1*6 6,1' ',( *52M(1 e260,'( ,1 '(5 |(//( *(1(7,6&+ 1,&+7 62 67$%,/ :,( r+$*(1 2'(5 r/$60,'(N :$6 *(/(*(17/,&+ =8 t(.20%,1$7,21(1 '(5 ./21,(57(1 fpc )@+5(1 .$11P

VPS d$6,6:(5.=(8*(

SYU

SMPMPMS d802%33)/.36%+4/2%. y(11 0$1 1,&+7 185 ',( i(1$1$/+(5 (5/>87(57N %(1?7,*7 (,1 i(1 )@5 6(,1( g;35(66,21 $8M(5 '(1 r527(,1O.2',(5(1'(1 d(5(,&+(1 u7(8(5(/(0(17(P h@5 ',( g;35(66,21 (,1(6 (8.$5/7P f,( 0(,67(1 (176&+(,'(1'(1 fpcOg/(0(17( )@5 (,1( (5,=,(17( i(O 1(;35(66,21 ,1 gP &2/, /,(*(1 $/62 ,0 W^Od(5(,&+ '(6 i(16P f$+(5 :,5' ',( (;2*(1( fpc '(0 r5202725 (,1(6 gP &2/, i(16 0,7 (,1(0 2'(5 2+1( (,1(1 W^Ov(,/ '(5 .2O ',(5(1'(1 u(48(1=(1 1$&+*(6&+$/7(7P j>87* :,5' +,(5 '$6 tOi$/$&726,'$6(*(1 JtO i$/K 9(5:(1'(7P p$&+ '(5 %$.7(5,(//(1 v5$16)250$7,21 (1767(+(1 '$11 h86,2163O 527(,1( 0,7 (,1(0 tOi$/ c0,12O 81' (,1(0 5(.20%,1$17(1 e$5%2;1.(1N 5(675,1*,(5(1N 0,7 '(5 (6 (,1 d$.7(5,80 ,17O =,(5(1 .$11P f(5 p$0( '(5 t(675,.7,216(1'218./($6(1 /(,7(7 6,&+ $86 ',(6(5 1$7@5O /,&+(1 h81.7,21 $%P f,( )@5 35$.7,6&+( |:(&.( +(5$865$*(1'( g,*(16&+$)7 '(5 t(675,.7,216(1'218.O /($6(1 ,67 ',( u3(=,77>7 ,+5(5 g5.(1181*66(48(1=(1 921 0(,67 9,(5 %,6 $&+7 d$6(1O 3$$5(1 n>1*( Jv$%P VPSN c%%P VPUKP f,(6 %('(87(7N '$M (,1 %(67,007(6 t(675,.7,21O Spaltung der beiden DNA Stränge an gegenüberliegenden Stellen 5´

G

G

G

C

C

C

3´

5´

G

G

G

3´

5´

C

C

C

3´

3´

C

C

C

G

G

G

5´

3´

C

C

C

5´

3´

G

G

G

5´

G

C

Smal Spaltung der beiden DNA Stränge an versetzten Stellen 5´

C

T

G

C

A

G

3´

5´

C

T

A

3´

G

A

C

G

T

C

5´

3´

G

5´ 3´

A

C

G

A

3´ 5´

G

3´

G

T

C

5´

T

C

C

3´

5´ 3´

G

5´

Pstl

5´

G

G

A

T

C

C

3´

5´

G

3´ 5´

3´

C

C

T

A

G

G

5´

3´

C

C

T

A

G

BamHl

c%%P VPU g1767(+81* 9(56&+,('(1(5 fpcOh5$*0(17(1'(1 1$&+ x(5'$8 0,7 817(56&+,('/,&+(1 v1*,*(5 =P dP 5$',2$.7,9 0$5.,(5O 7(5 5(.20%,1$17(5 2'(5 687* %(187=7(1 5$',2$.7,9(1 o$5.,(581* />M7 6,&+ (,1( j5=81* (,1(6 $8)*(/(*7(1 t?17*(17/06 ,1 '(5 62*(1$117(1 c8725$',2*5$3+,( 1$&+:(,6(1P d(621'(56 5(/(9$17( c1:(1'81*(1 '(5 fpc j87*67(1 $1*(:(1'(7( 02/(.8/$5O %,2/2*,6&+( w17(568&+81* ,1 '(5 35$.7,6&+O./,1,6&+(1 o(',=,1P u,( ',(17 =85 g5.(1O 181* 921 v5>*(51 9(5(5%7(5 g5.5$1.81*(1 62:,( =85 35>61'(581*(1 '(5 *(120,6&+(1 fpc =8/>M7P k0 i(*(16$7= '$=8 :,5' ',( 5(/$7,9 @%(56,&+7/,&+( *(120,6&+( fpc '(6 d$.7(5,23+$*(1 n$0%'$ 921 185 VZ .% '85&+ 9,(/( t(675,.7,216(1=1*,*( fpc =81>&+67 '85&+ (,1( c/.$/,%(+$1'/81* ,1 ,+5( g,1O =(/675>1*( =(5/(*7 81' '$11 '85&+ .$3,//$5( y,5.81* $/6 (;$.7( t(3/,.$ $8) (,1( 0(&+$1,6&+ 81' &+(0,6&+ 5(6,67(17( o(0%5$1 $86 p,752&(//8/26( 2'(5 p5%7(6 c*$526(*(/ 0,7 9(5'$8(5 *(120,6&+(5 fpcP f(5 h/825O (6=(1=)$5%6725 g7+,',80%520,' %,1'(7 6,&+ ,1 ',( fpcOf233(/+(/,;N 62 '$M fpc ,1 (,1(0 0,7 wxOn,&+7 75$16,//80,1,(57(1 i(/ 6,&+7%$5 :,5'P f,( 9,(/(1 +81'(577$86(1' %,6 (,1,*( o,/O /,21(1 817(56&+,('/,&+(1 h5$*0(17( '(5 9(5'$87(1 *(120,6&+(1 fpc 9(56&+:,00(1 '$%(, ,1 (,1(5 +202*(1 (56&+(,1(1'(1 u385P g,1 j,1' kkkOx(5'$8 921 n$0%'$Or+$*(1Ofpc (5*,%7 185 :(1,*( t(675,.7,216)5$*0(17( '(71,(57(5 i5?M(N ',( 620,7 $/6 n>1*(10$5.(5 (,1*(6(7=7 :(5'(1 .?11(1 JoN r)(,/(KP

kapillare Flußrichtung

VPT w17(568&+81* 921 fpc kg saugfähiges Filterpapier Nylonmembran Agarosegel saugfähiges Filterpapier Schale mit Puffer

c%%P VPY

SY[

Auflage

u&+(0$7,6&+( f$567(//81* (,1(5 u287+(51 d/27Oc33$5$785P

f(5 .5,7,6&+( u&+5,77 '(5 u287+(51 d/27Oc1$/7(5 %(,0 62*(1$117(1 675,1*(17(1 y$6&+(1 %(, +2+(5 v(03(5$785 81' 1,('5,*(5 u$/=O .21=(175$7,21 *(/?67 :(5'(1P f,( 0$5.,(57( i(1621'( %/(,%7 '$%(, '85&+ ',( y$6O 6(56725%5@&.(1%,1'81*(1 =:,6&+(1 '(1 .203/(0(17>5(1 p8./(27,'(1 63(=,76&+ $1 ,+5(5 |,(/6(48(1= +$)7(1N 62 '$M '85&+ c8725$',2*5$3+,( ',( r26,7,21 %=:P ',( n>1*( '(6 (17635(&+(1'(1 t(675,.7,216)5$*0(17(6 (50,77(/7 :(5'(1 .$11 Jc%%P VPZKP r5,O Agarosegel Agarosegel-GelElektrophorese

Restriktionsverdau

unverdaute chromosomale DNA

--

Auftragungsstelle

verdaute chromosomale DNA +

1

2

3 Southern BlotTransfer

Röntgenfilm

Nylonmembran Hybridisierung mit markierter Gensonde stringentes Waschen und Autoradiographie

1

2

3

1

2

3

c%%P VPZ u&+(0$7,6&+( f$567(//81* (,1(5 fpcOjM7 6,&+ $86 '(5 u287+(51 d/27Oc1$/5(B+202/2*( u(48(1=(1 0,7 '(5 u21'( d (17+$/7(1P f$6 g5*(%1,6 '(5 u287+(51 d/27Oc1$/1*7 620,7 921 '(5 9(5'$87(1 fpcN 921 '(0 9(5:(1'(7(1 g1=5,1)250$7,21 ,1 35$.7,6&+ 9(5:(57%$5( f,$*126(1 2'(5 02/(.8/$5O$1$720,O 6&+( g5.(1171,66( 80=86(7=(1 ,67P f,5(.7( g5.(1181* 921 r81.7087$7,21(1 y(11 x(5>1'(581*(1 '(5 p8./(27,'6(48(1= '$6 g5.(1181*66,*1$/ (,1(6 t(675,.O 7,216(1=1'(57( t(675,.7,216O P

V

M

F

SS

AA 1,4kb 1,2kb

Sonde normales ‚ Globingen

GAG

1,2kb

0,2kb

GTG

1,4kb

MstII Schnittstellen

Sichelzellgen

MstII Schnittstellen

c%%P VP[ u&+(0$7,6&+( 81' $8725$',2*5$3+,6&+( f$567(//81* '(5 f,$*126( '(5 u,&+(/=(//08O 7$7,21P p$&+ c*$526(Oi(/(/(.7523+25(6( 81' u287+(51 d/27Ov5$16)(5 o67 kk 9(5'$87(5 fpc ,'(17,7=,(57 (,1( i(1621'( $86 '(0 WAOd(5(,&+ '(6 tOi/2%,1*(16 %(, '(5 1250$/(1 fpc (,1 SNT .% 81' %(, '(5 3$7+2/2*,6&+(1 fpc (,1 SNV .% /$1*(6 h5$*0(17P f,( u,&+(/=(//087$7,21 Jici B iviK =(567?57 ',( o67 kk t(675,.7,21667(//( ,0 e2'21 X '(6 tOi/2%,1*(16P f,( c8725$',2*5$3+,( =(,*7 (,1( r5>1$7$/',$*126(N ',( %(,0 h(786 (,1(1 +202=023+,/,(1 81' %(, '(5 o86.(/'5(1P c8M(5'(0 0@66(1 9(56&+,('(1( c//(/( '(6 o$5.(5/2&86 -(:(,/6 $1 '$6 *(681'( %=:P $1 '$6 3$7+2/2*,6&+( i(1 *(.233(/7 6(,1P h,1'(7 6,&+ ,1 '(5 %(7525(1(1 h$0,/,( 185 (,1 c//(/ '(6 o$5.(56N 62 /$66(1 6,&+ '$5$86 .(,1( ,1',5(.7(1 t@&.6&+/@66( $8) '(1 |8O 67$1' '(6 i(16 =,(+(1P f,( h$0,/,( ,67 %(=@*/,&+ ',(6(6 o$5.(56 1,&+7 ,1)250$7,9P h@5 (,1( 6,1192//( g5:(,7(581* '(5 ,1',5(.7(1 02/(.8/$5*(1(7,6&+(1 f,$*1267,. 9(5O (5%7(5 g5.5$1.81*(1 6,1' $/62 62/&+( o$5.(5/2&, $0 %(67(1 *((,*1(7N ',( %(, 0?*O /,&+67 9,(/(1 %(575>*(51 ,1 +(7(52=1*,*( fpc .203/(0(17>5 =80 f233(/675$1* ,1 '(5 W^ B U^ t,&+781* =8 (5*>1=(1P c0 g1'( '(6 '5,77(1 u&+5,77(6N 81' '$0,7 '(6 (567(1 |*1.81* '(5 ret /,(*7 ,1 '(5 0$;,0$/(1 n>1*( '(6 $03/,7=,(5%$5(1 h5$*0(17(6N ',( 5287,1(0>M,* ,1 '(5 i5?M(125'181* 921 :(1,*(1 .% /,(*7P c8M(5O '(0 (5)25'(57 ',( (;321(17,(//( p$785 '(5 t($.7,21 %(, (,1(5 s8$17,7=,(581* '(5 $03/,7=,(57(1 u(48(1=(1 ,0 c86*$1*60$7(5,$/ %(621'(5( x(5)$+5(1P f,( (1250( u(16,7,9,7>7 81' '$6 (;321(17,(//( r5,1=,3 '(5 (1=+(5 (5/>87(57N ',( 921 retO$03/,7=,(57(5 *(120,6&+(5 fpc $86*(+(1P

SMQMQMP `,,%,L30%:)&)3#(% n,)'/.5+,%/4)$Lg9"2)$)3)%25.' f,( fpc :,5' '85&+ y$66(56725%5@&.(1%,1'81*(1 =:,6&+(1 '(1 *(*(1@%(5/,(*(1O '(1 p8./(27,'(1 i 81' e %=:P c 81' v ,1 ,+5(5 &+$5$.7(5,67,6&+(1 '233(/675>1*,*(1 m217*85$7,21 *(+$/7(1 J6,(+( m$3P TPVPTKP f,(6 *,/7 62:2+/ )@5 ',( u,78$7,21 ,1 9,92 $/6 $8&+ ,1 9,752 )@5 $1 ',( |,(/Ofpc +1',* .203/(0(17>5(6 j7 '(5 fpcOo2/(.@/( *(*(1@%(5 3267O 0257$/(1 c%%$8352=(66(1 81' w0:(/7(,19@66(1 81' ,1 '(5 (5+?+7(1 u(16,7,9,7>7 '(5 p$&+:(,67(&+1,. ,16%(621'(5( 1$&+ g,1)@+581* '(5 r2/3$5$7(1 '85&+*()@+57 81' e+,0>5,6O 0(1 1$&+ v5$163/$17$7,21(1 '(7(.7,(57P k1 '(5 )25(16,6&+(1 u385(1$1$/581* 675$)5(&+7/,&+(5 h5$*(1N %(,63,(/6:(,6( ,1 6385(1.81'O /,&+(1 i87$&+7(1N %(, u(;8$/'(/,.7(1N k'(17,7=,(581*(1 921 n(%(1'(1 2'(5 v27(1N i(:(%(1 81' m?53(59@66,*.(,7(1P f$5@%(5 +,1$86 /$66(1 6,&+ '$0,7 $8&+ =,9,/5(&+7O /,&+( h5$*(1 ,1 c%67$0081*6*87$&+7(1 ./>5(1P q%:2+/ retO*(67@7=7( x(5)$+5(1 0,7 ,+5(5 +2+(1 u(16,7,9,7>7 81' *(5,1*(1 f(*5$'$7,216$1)>//,*.(,7 6&+21 c1)$1* '(5 1(81=,*(5 l$+5( ',( j+/7(1 o2/(.8/$5*(:,&+76%(5(,&+P j,(5$86 :,5' ',( NN%$1'O6+$5,1*O5$7(DD $/6 o$M '(5 x(5:$1'76&+$)7 =:(,(5 k1',9,'8(1 %(5(&+O 1(7P c57()$.7( 81' (9(178(//( o87$7,216(5(,*1,66( :(5'(1 %(:(57(7P f$ ',( f(71,O 7,21 921 c//(/(1 81' ,+5( j>87*.(,76%(67,0081* +,(5 1,&+7 0?*/,&+ ,67N 6,1' (,1( t(,+( $/7(51$7,9(5 t(&+(1$16>7=( (17:,&.(/7 :25'(1N ',( $8) i581'/$*( 6,1192//(5 o2'(//Oc11$+0(1 (%(1)$//6 =8 =89(5/>66,*(1 u&+>7=81*(1 :,( =P dP '(5 x$7(5O 6&+$)76:$+56&+(,1/,&+.(,7 )@+5(1P f,( o8/7,/2&86OfpcOc1$/1O

1

A 2 3

1

B 2 3

C 1 2 3

c%%P VPTT w17(568&+81* '(6 e+,0>5,6086 1$&+ m12&+(10$5.Bu7$00=(//Ov5$163/$17$7,21 0,77(/6 onuOc1$/5,6086N '(5 ./,1,6&+ (,1( %(*,11(1'( v5$163/$17$7$%672M81* 2'(5 (,1 %(*,11(1'(6 t(=,',9 '(5 i581'(5.5$1.81* $1=(,*(1 .$11P e\ x2//67>1',*( g03O )>1*(5+>0$7232(6( 1$&+ v5$163/$17$7Oc%672M81*P

TRR

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DNA-Ligierung

vollständige Spaltung mit dem 2. Restriktionsenzym

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SMV f%.+!24)%25.' 5.$ f%.)$%.4)&):)%25.' f,( 02/(.8/$5( c1$/581* '(5 02/(.8/$5(1 r$7+2/2*,( +(5(',7>5(5 81' (5:25%(1(5 g5O .5$1.81*(1 .2117( ,1 9,(/(1 h>//(1 (,1 x(567>1'1,6 '(5 *581'/(*(1'(1 r$7+2*(1(6( (55(,&+7 :(5'(1P k1 (,1,*(1 h>//(1 :$5 ',(6 $8&+ (,1 (567(5 c16$7=381.7 )@5 ',( g17:,&./81* 1(8(5 2'(5 9(5%(66(57(5 .219(17,21(//(5 v+(5$3,()250(1P j,(5 62//(1 9(56&+,('(1( u75$7(*,(1 =85 m$57,(581*N k'(17,7=,(581* 81' e+$5$.7(5,6,(581* 921 0(16&+/,&+(1 i(1(1 (5/>87(57 :(5'(1 Jc%%P VPUXKP f$6 0(16&+/,&+( i(120 (17+>/7 (7:$ SVRPRRR i(1(P f(0*(*(1@%(5 6,1' 185 (7:$ YPRRR +(5(',7>5( m5$1.+(,7(1 '(6 o(16&+(1 .$7$/2*,6,(57 Jo&m86,&.I6 o(1O '(/,$1 k1+(5,7$1&( ,1 o$1KP f,(6( f,6.5(3$1= ,67 =80 (,1(1 '$'85&+ (5./>5%$5N '$M %(, 9,(/(1 g5.5$1.81*(1 (,1( *(1(7,6&+( m20321(17( +(87( 12&+ 1,&+7 (7$%/,(57 ,67P |80 $1'(5(1 ,67 =8 (5:$57(1N '$M 9,(/( i(1( ,0 i(120 +,16,&+7/,&+ ,+5(5 h81.7,21 5('81'$17 6,1' 81' $1'(5( i(1352'8.7( (,1(1 0?*/,&+(1 f()(.7 .203(16,(5(1 .?11(1P c8&+ *,%7 (6 i(1'()(.7(N ',( 6,&+ %(5(,76 ,1 '(5 g0%5/71,6 :,5' $8&+

TTV

V o2/(.8/$50(',=,1,6&+( o(7+2'(1 Positionsklonierung

funktionelle Klonierung

reverse Genetik

Phänotyp

bekannter biochemischer Defekt (Enzym)

Gen mit unbekannter Funktion

genetische Kartierung

Isolation des Gens

in vitro Mutagenese

Isolation des Gens

Identifizierung von Mutationen

Phänotyp

Identifizierung von Mutationen

Funktionsanalyse

c%%P VPUX u75$7(*,(1 =85 c1$/7(5 $8&+ ',( .203/(;(5(1 08/7,)$.725,(//(1 m5$1.+(,7(1 9(5O 67(+(1 =8 .?11(1P

SMVMP j!24)%25.' -/./'%.%2 d2+2!.+5.'%. c/6 (567(5 u&+5,77 =85 k'(17,7=,(581* 921 i(1(1 08M 0(,67 '(5 i(1257 ,0 i(120 .$57,(57 :(5'(1P x(5*/(,&+6:(,6( (,1)$&+ ,67 ',( m$57,(581* ,1 h>//(1 0,7 :(*:(,O 6(1'(1 &//,*(1 d()81'(1N :,( (7:$ v5$16/2.$7,21(1N ',( (,1(1 ',O 5(.7(1 g,167,(* ,1 ',( r26,7,216./21,(581* '(6 5(/(9$17(1 i(16 (5/$8%(1 J6,(+( m$3P VPYPWKP k1 $1'(5(1 h>//(1 08M ',( &+5202620$/( u8%/2.$/,6$7,21 '(6 *(68&+7(1 i(16 =81>&+67 '85&+ (,1( m233/81*6817(568&+81* 0,7 32/1*7N 2% '(5 32/M,* 9(57(,/7 6(,1 .?11(1P f$+(5 6,1' 9,(/( o,7*/,('(5 (,1(6 u7$00%$806 )@5 ',( 0(,67(1 thnr6 +202=7=/,&+(1 r$5$0(7(5 (5*,%7 (,1( m233/81*6$1$/+5(1' '(5 o(,26( =85 t(.20%,1$7,21 81' '$'85&+ =85 v5(1181* 921 925+(5 *(.233(/7(1 c//(/(1P f(5 c%67$1' =:,6&+(1 '(1 n2&, .$11 620,7 ,1',5(.7 @%(5 ',( 62*(1$117( t(.20O %,1$7,216)5$.7,21 '(71,(57 :(5'(1P g,1( t(.20%,1$7,216)5$.7,21 921 RNRS *,%7 $/62 $1N '$M (6 ,1 S@ '(5 o(,26(1 =85 t(.20%,1$7,21 .2007 JS &(17,Oo25*$1N &oKP f,( 0$;,0$/( t(.20%,1$7,216)5$.7,21N (7:$ 921 =:(, $8) 817(56&+,('/,&+(1 e+52O 02620(1 /2.$/,6,(57(1 n2&,N %(75>*7 RNWP f,( d(67,0081* '(5 t(.20%,1$7,216)5$.O 7,21 />M7 6,&+ :(*(1 '(5 6(+5 817(56&+,('/,&+(1 t(.20%,1$7,2161(,*81* 9(56&+,(O '(1(5 u(48(1=$%6&+1,77( 185 %(',1*7 ,1 (,1(1 7$76>&+/,&+(1 3+M7P f,(6 80)$M7 $//(5',1*6 12&+ ,00(5 (,1( fpcO t(*,21 921 &$P WPRRR .%P f,( *(1$8( g,1*5(1=81* '(6 m233/81*6,17(59$//6 ,67 (,1( :(6(17/,&+( x25$866(7=81* =85 k62/,(581* '(6 *(68&+7(1 i(16P l( 1$&+ i5?M( ',(6(6 k17(59$//6 .$11 ',(6 81' '(5 $16&+/,(M(1'( p$&+:(,6 921 o87$7,21(1 %(, %(7525(1(1 r$7,(17(1 0(+5(5( l$+5( ,1 c16358&+ 1(+0(1P d(, '(5 o8.29,6=,'26( /$*(1 =:,6&+(1 '(5 *(1(7,6&+(1 m$57,(581* ,0 l$+5( S[ZW 81' '(5 k62/,(581* '(6 i(16 S[Z[ 9,(5 l$+5(N %(, '(5 o86.(/'87*(1 g5.5$1.81*(1 1>+(5=8.200(1N ,67 ',( k'(17,7.$7,21 921 i(1(1N ',( ,1 '(0 .203/(;(1 p(7=:(5. (,1(5 32/581* '(5 h81.7,21 (,1=(/1(5 i(1( 81' '(5 3$7+2*(1(7,6&+(1 |86$00(1+>1*( 921 g,1=(/*(1'()(.7(1 $8&+ %(, '(1 .20O 3/(;(1 g5.5$1.81*(1 :(,7(5+(/)(1 :,5'P

SMVMR h$%.4)&):)%25.' 6/. f%.%. $52#( &5.+4)/.%,,% j,/.)%25.' f,( )81.7,21(//( m/21,(581* 921 i(1(1 6(7=7 ',( m(1171,6 @%(5 '(1 35,0>5(1 %,2O &+(0,6&+(1 f()(.7 925$86P o,7 j,/)( 02/(.8/$5*(1(7,6&+(5 o(7+2'(1 .$11 '$11 '$6 .255(6321',(5(1'( i(1 ,62/,(57 :(5'(1P f,(6( u75$7(*,( :85'( (7:$ =85 k'(1O 7,7=,(581* '(5 i(1( )@5 ',( j>023+,/,(1 2'(5 '(5 r+(187(57 :(5'(1P f,( j>023+,/,( c ,67 (,1( zO&+5202620$/ 5(=(66,9 9(5(5%7( g5.5$1.81*N ',( '85&+ o87$7,21(1 ,0 i(1 )@5 '(1 d/87*(5,1181*6)$.725 xkkk JhxkkkK 9(5856$&+7 :,5'P g,1 (176&+(,'(1'(5 u&+5,77 )@5 ',( k62/,(581* '(6 hxkkkOi(16 :$5 ',( k62/,(581* 81' t(,1,*81* '(6 r527(,16 $86 '(0 r/$60$ 921 *(681'(1 r(5621(1P o,7 %,2&+(O 0,6&+(1 o(7+2'(1 .2117( ',( c0,126>85(6(48(1= (,1(6 v(,/6 ',(6(6 *52M(1 r527(,16 %(67,007 :(5'(1P c8) '(5 d$6,6 '(6 *(1(7,6&+(1 e2'(6 J6,(+( m$3P UPVPTK .2117(1 '$5$8)+,1 i(1621'(1 67(5 '(5 *(120,6&+(1 fpc *(/$1*P k0 c16&+/8M .2117( %(, r$7,(17(1 0,7 (,1(5 j>023+,/,( c 687*( 3$57,(//( i(1,19(56,21 )(67*(67(//7 :(5O '(1N ',( '85&+ +202/2*( fpcOc%6&+1,77( ,11(5+$/% '(5 r52027255(*,21 81' ,0 k17521 TT 9(5856$&+7 :,5'P f,(6( i(1,19(56,21 :85'( %(, 0(+5 $/6 VR@ '(5 %(621O '(56 6&+:(5 %(7525(1(1 r$7,(17(1 1$&+*(:,(6(1P p(%(1 '(5 m(1171,6 @%(5 ',( o87$7,21(1 0,7 '(1 '$5$86 5(68/7,(5(1'(1 ',$*1267,6&+(1 o?*/,&+.(,7(1N =80 d(,O 63,(/ =85 k'(17,7=,(581* 921 m21'8.725,11(1N :$5 ',( m/21,(581* '(6 hxkkkOi(16 (,1( (176&+(,'(1'( x25$866(7=81* )@5 ',( *(17(&+1,6&+( j(567(//81* ',(6(6 r527(,16 J6,(+( m$3P ZPSKP f,( .$7$67523+$/(1 h2/*(1 '(5 c33/,.$7,21 jkxO 81' j(3$7,7,6O

VPY i(1.$57,(581* 81' i(1,'(17,7=,(581*

TT[

,17=,(57(5 .219(17,21(// +(5*(67(//7(5 r5>3$5$7( 9(5'(87/,&+(1 ',( *$1= 35$.7,6&+(1 k03/,.$7,21(1 ',(6(5 u75$7(*,(P f,( r+(1%&+(1 '(5 p(7=+$87P d(, '(5 (5%/,&+(1 p(7=+$87'(*(1(5$7,21 Jt(7,1,7,6 3,*0(1726$] trK .2007 (6 %(, '(1 %(7525(1(1 r$7,(17(1 =80 925=(,7,*(1 c%67(5%(1 '(5 r+2725(=(3725=(//(1 ,1 '(5 p(7=+$87 81' 6&+/,(M/,&+ =85 9?//,*(1 g5O %/,1'81* '(6 r$7,(17(1 ,1 '(5 UP %,6 VP n(%(16'(.$'(P f,( *(1(7,6&+( m233/81*6$1$O /1*,* '$921 :$5 '$6 t+2'236,1*(1 ,1 '(56(/%(1 t(*,21 JU4TSO4TVK .$5O 7,(57 :25'(1P t+2'236,1 *(+?57 =8 '(5 m/$66( 921 v5$160(0%5$1Ot(=(3725(1 81' 67(+7 ,1 '(5 p(7=+$87 $0 c1)$1* (,1(5 u,*1$/75$16'8.7,216.$6.$'(N ',( n,&+7O ,1 &+(0,6&+( t(,=( 80:$1'(/7P i581'6>7=/,&+ :$5 (,1 t+2'236,1'()(.7 %(, '(5 tr $/62 *87 92567(//%$5N 81' '$6 t+2'236,1*(1 5(35>6(17,(57( '$+(5 (,1 7&+67 .(,1( t2//(P f,( r26,7,216./21,(581* :85'( (5670$/6 (5)2/*5(,&+ S[ZX %(, '(5 e+521,6&+(1 i5$18/20$726( $1*(:$1'7N ',( (567 62 $/6 i(1'()(.7 '(6 e//(1 .2117(1 '$O '85&+ (176&+(,'(1'( m(1171,66( @%(5 ',( d,2&+(0,( 81' ',( r$7+2*(1(6( *(:211(1 :(5'(1P

22.3

Kopplungsintervall

22.2 22.1

Suche nach strukturellen Chromosomenveränderungen (z.B. Deletionen)

Identifizierung von Genen

Mutationsanalyse

21.1 11.4 11.3 11.23 11.22 cen

Kontrolle

21.3

Kontrolle

Xp

Assemblierung überlappender genomischer DNA-Fragmente in contigs

Patienten

Patienten 1 2 3 4 5 6

12

Mutationen

13 21.1

SSCP-Analyse

21.3

Xq

22.1 22.3 23

Southern-Blot-Analyse

24 25 26 27

-2.000 kbp

50 – 500 kbp

1– 200 kbp

einzelne Basenpaare

28

genetische Karte

physikalische Karte

Gen (Transkriptions)-Karte

DNA-Sequenzanalyse

c%%P VPU[ u&+(0$7,6&+( f$567(//81* '(5 9(56&+,('(1(1 v(,/6&+5,77( '(5 r26,7,216./21,(581* $0 d(,63,(/ (,1(6 zO&+5202620$/(1 i(16P c86*$1*6381.7 ,67 ',( f(71,7,21 '(6 m233/81*6O ,17(59$/6 0,7 j,/)( *(1(7,6&+(5 o$5.(5P c16&+/,(66(1' (5)2/*7 ',( c66(0%/,(581* (,1=(/1(5 fpcOh5$*0(17( ,1 (,1(0 e217,*P g,1(6 ',(6(5 h5$*0(17( '(7(.7,(57 f(/(7,21(1 Jx(5/867 921 *(1(7,6&+(0 o$7(5,$/K %(, (,1(0 v(,/ '(5 r$7,(17(1P f,( $16&+/,(66(1'( o87$7,216$1$/1'(57(1 n$8)9(5O +$/7(1 >866(51P

VPY i(1.$57,(581* 81' i(1,'(17,7=,(581*

TUS

g,1 (567(5 u&+5,77 %(, '(5 r26,7,216./21,(581* ,67 ',( m$57,(581* '(6 i(1/2&86 ,0 i(120 Jc%%P VPU[] 6,(+( m$3P VPYPSKP f,(6 .$11 (17:('(5 '85&+ (,1( m233/81*6O $1$/1'(581*(1N ',( 0,7 '(5 g5.5$1.81* =86$00(1 9(5(5%7 :(5'(1 2'(5 ,0 h$//( 921 (5:25%(1(1 m5$1.+(,7(1 0,7 '(0 r+>127&+67 ',( ,0 m233/81*6,17(59$// *(/(*(1(1 i(1( ,'(17,7=,(57 81' %(=@*/,&+ ,+5(5 3$7+2O *(1(7,6&+(1 t(/(9$1= 817(568&+7 :(5'(1P h@5 ',(6( k'(17,7=,(581* 921 .2',(5(1'(1 fpcOu(48(1=(1 81' ',( c8)./>581* '(5 i(16758.785 ,67 (,1( m20%,1$7,21 9(5O 6&+,('(1(5 x(5)$+5(1 (5)25'(5/,&+P f$=8 *(+?5(1 ',( k62/,(581* 921 &fpc6N '$6 NN(;21 75$33,1*DDN ',( u8&+( 1$&+ 3+1(1 (5.(11(1 /$66(1P u20,7 ,67 ',( c8)./>581* '(5 h81.7,21 '(5 i(1352'8.7( '(5 1>&+67( :,&+7,*( u&+5,77 =80 x(567>1'1,6 '(5 r$7+2*(1(6( '(5 817(568&+7(1 g5.5$1.81*P

SMVMU l%4(/$%. ). $%2 d.47)#+,5.'30(!3% k1 |86$00(1+$1* 0,7 '(0 j80$1*(120352-(.7 J6,(+( m$3P VPZK +$7 ',( m$57,(581* 81' k'(17,7=,(581* 921 i(1(1 (,1(1 %(75>&+7/,&+(1 k1)250$7,216=8:$&+6 1,&+7 185 %(=@*/,&+ '(5 *(1(5,(57(1 u(48(1='$7(1 (5%5$&+7N 621'(51 $8&+ ',( g17:,&./81* 921 1(8(1 o(7+2'(1 *()?5'(57N ',( '$6 3$7+2*(1(7,6&+( x(567>1'1,6 9,(/(5 g5.5$1O .81*(1 81' ',( ',$*1267,6&+( r5$;,6 5(92/87,21,(5(1 :(5'(1P |80 (,1(1 :,5' ',( g17:,&./81* 921 fpcOe+,36 ',( o87$7,216(5.(1181* :(6(17/,&+ 9(5(,1)$&+(1 Jc%%P VPVRKP o,7 ',(6(5 o(7+2'( .?11(1 0(+5(5( =(+17$86(1' u(48(1=9$5,$17(1 ,1 (,1(0 (,1=,*(1 c16$7= 817(568&+7 :(5'(1N 62 '$M =(,7$8):(1',*( u&5((1,1*9(5)$+5(1 $%*(/?67 :(5'(1 .?11(1P c8&+ (5+257 0$1 6,&+ 921 ',(6(5 v(&+12/2*,( (,1( +?+(5( ',$*1267,6&+( u,&+(5+(,7P c8&+ ',( *(1(7,6&+( m233/81*6$1$/1*/,&+ :85'( (,1 jir 925 $//(0 ,1 '(1 wuc %()@5:257(7 81' '257 ,0 l$+5( S[[R %(*211(1P k1=:,6&+(1 +$7 (6 6,&+ =8 (,1(0 */2%$/(1 i(0(,16&+$)76352-(.7 (17:,&.(/7N $1 '(0 6,&+ f(876&+/$1' (567 5(/$7,9 63>7 JS[[XK %(7(,/,*7 +$7P f$6 jir :,5' 921 '(5 j80$1 i(120( q5*$1,=$7,21 JjwiqK 25*$1,6$725,6&+ 817(567@7=7 81' :(,7*(+(1' $86 ?5(17/,&+(1 o,77(/1 71$1=,(57P g6 (56&+(,17 :$+56&+(,1/,&+N '$M ',( 92//67>1',*( u(48(1=,(581* '(6 0(16&+/,&+(1 i(1206 %,6 =80 g1'( '(6 l$+5(6 TRRU (5)2/*5(,&+ $%*(6&+/266(1 6(,1 :,5'P f,( u(48(1= :,5' ?5(17/,&+ 9(5)@*%$5

VPZ f$6 j80$1*(120352-(.7

TUW

6(,1P u(48(1=,(57 :,5' (,1 i(0,6&+ 921 fpc 9(56&+,('(1(5N $121*( ',( u(48(1= '(6 0(16&+/,&+(1 i(1206 =80 WRP l$+5(67$* '(5 g176&+/@66(/81* '(5 '233(/+(/,.$/(1 u758.785 '(5 fpc 925P f(5 352-(.7,(57( =(,7O /,&+( c%/$8) 9(5'(87/,&+7 $8&+N ,1 :(/&+ +2+(0 o$M( h2576&+5,77( $8) '(1 i(%,(7(1 '(5 $8720$7,6,(57(1 u(48(1=,(581*67(&+12/2*,(1 81' '(5 d,2,1)250$7,. (5)25'(5O /,&+ 6(,1 :(5'(1 J81' %,6/$1* $8&+ 6&+21 67$77*()81'(1 +$%(1KP f,( $1*(675(%7( h(+/(54827( 921 :(1,*(5 $/6 S h(+/(5BSRPRRR p8./(27,'( /,(*7 '$%(, '(87/,&+ 817(5 '(5 j>87*.(,7 921 ,17(5,1',9,'8(//(1 u(48(1=9$5,$%,/,7>7(1 921 &$P SBSPRRR p8./(2O 7,'(P f,( n2*,67,. '(6 jir %$6,(57 $8) (,1(0 f5(,6&+5,779(5)$+5(1P |8(567 *$/7 (6N '$6 0(16&+/,&+( i(120 0?*/,&+67 *(1$8 =8 .$57,(5(1P f$=8 ',(1(1 (,1(56(,76 w17(5O 68&+81*(1 @%(5 *(1(7,6&+( t(.20%,1$7,216+>87*.(,7(1 $/6 o(M*5?M( )@5 ',( p>+( =:(,(5 i(15(*,21(1 J*(1(7,6&+( m$57,(581*KN $/6 $8&+ '$6 c8)63@5(1 .21.5(7(5 u(O 48(1=32/7=( =85 x(5)@O *81*P c%6&+1,77( '(6 i(1206N ',( ,1 0tpc 80*(6(7=7 :(5'(1N 6,1' NN$.7,9DDP f85&+ k62/,(581* 921 0tpc 81' 3$57,(//( u(48(1=,(581* '(5 &fpcOm/21( :(5'(1 *(O *(1:>57,* f$7(1%$1.(1 $1*(/(*7N ',( '$6 o867(5 (;35,0,(57(5 i(1( ,1 9(56&+,('(1(1 |(//(1 81' i(:(%(1 81' g17:,&./81*667$',(1 :,'(563,(*(/1P f,(6( f$7(1%$1.(1 1(117 0$1 guv J)@5 NN(;35(66(' 6(48(1&( 7$*6DDK d$1.(1P f85&+ x(5*/(,&+( '(5 ,1 guvOd$1.(1 *(6$00(/7(1 k1)250$7,21(1 0,7 '(1 *(120,6&+(1 '(6 jir .?11(1 620,7 =80,1'(67 ',( ,1 guvOd$1.(1 5(35>6(17,(57(1 i(1( ,'(17,7=,(57 :(5'(1P u&+:,(5,*(5 ,67 ',(6( x25*(+(16:(,6( )@5 i(1(N ',( 185 6&+:$&+ 81'B2'(5 ,1 :(1,*(1

TUX

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

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TVR

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

w17(568&+81*(1 Jm203/(0(17$7,216$16$7=K .?11(1 ,17$.7( i(1( ,1 (,1(0 087$1O 7(1 o$8667$00 (;35,0,(57 :(5'(1P g,1 x257(,/ ',(6(5 o(7+2'( *(*(1@%(5 '(5 817(5 .12&.O,1 o87$17(1 J6,(+( 817(1K %(6&+5,(%(1(1 o(7+2'( ,67N '$M .(,1( |(//.8/785 %(1?7,*7 :,5' 81' '$+(5 $8) (,1 u(/(.7,2160$5.(5*(1 9(5=,&+7(7 :(5'(1 .$11P f$6 fpcOh5$*0(17N :(/&+(6 '$6 v5$16*(1 75>*7N :,5' 817(5 x(5:(1'81* (,1(6 +2&+$89?6(1'(1 o,.526.236 ',5(.7 0,7 j,/)( )(,1 $86*(=2*(1(5 i/$6.$3,//$5(1 ,1 '(1 x25.(51 %()58&+7(7(5 g,=(//(1 ,1-,=,(57 Jc%%P VPVT %KP YW@ '(5 g0%511/,&+(1 v,(5(1P p$&+ (,1(5 v5$*=(,7 921 (7:$ TR v$*(1 :(5'(1 ',( p$&+.200(1 *(%25(1P g7:$ TRAUR@ '(5 p$&+.200(1 75$*(1 '$6 v5$16*(1 ,1 ,+5(0 i(120P l('(6 v5$16*(1O326,7,9( v,(5 ',(6(5 i(1(5$7,21 5(35>6(17,(57 0,1'(67(16 (,1 81O $%+>1*,*(6 k17(*5$7,216(5(,*1,6N 'P +P '$6 v5$16*(1 ,17(*5,(57 =8)>//,* 81' 81*(5,&+O 7(7 $8) (,1(0 e+5202620P f$+(5 6,1' ',( v,(5( *(1(7,6&+ 1,&+7 ,'(17,6&+P l('(6 ,67 9,(/0(+5 '(5 d(*5@1'(5 J)281'(5K (,1(6 1(8(1 o$8667$00(6P o$1&+0$/ .2007 (6 925N '$M (,1 v(,/ '(5 v5$16*(1.23,(1 ,1 (,1(1 =:(,7(1 i(1/2&86 ,16(5,(57 81' '$+(5 %(,0 1>&+67(1 m5(8=81*66&+5,77 81$%+>1*,* 9(5(5%7 :,5' Ju(*5(*$7,21KP u2 (1767(+(1 '$11 $86*(+(1' 921 (,1(0 75$16*(1(1 h281'(5 =:(, 75$16*(1( u8%/,1,(1P

Transgenkonstrukt

Promotor

pA

mRNA

A (n)

(a) Herstellung transgener Mäuse Injektion von DNA in den Vorkern befruchteter Oozyten Zygote

Übertragung injizierter Oozyten in scheinschwangere Empfängertiere

^ ]

Züchtung transgener „founder”

^ transgener „founder”

Injektionskapillare mit DNA Zona pellucida

Pronuklei

50 % der Nachkommen tragen das Transgen

(b)

c%%P VPVT v5$16*(1( o>86(P J$K u&+(0$7,6&+( f$567(//81* (,1(6 786( 0,77(/6 x25.(51,1-(.7,21 %()58&+7(7(5 g,=(//(1P f,( fpc :,5' ,1 (,1(1 '(5 %(,'(1 r5218./(, ,1-,=,(57P f,( ,1-,=,(57(1 |86(N ',( '$6 v5$16*(1 75$*(1N :(5'(1 (7:$ TAV 0$/ 62 *52M :,( k+5( i(6&+:,67(5 2+1( v5$16*(1P g,1(1 :(,7(5(1 u&+8% (5+,(/7 ',(6( h256&+81*65,&+781* $/6 o,77( '(5 $&+7=,*(5 l$+5( ',( t(/(9$1= '(5 g5*(%1,66( 921 ,1 9,752 c1$/=,6,21 817(568&+7 :(5'(1P f,( *(1(7,6&+( x(5>1'(581* (,1(6 1$7@5/,&+ J63217$1K (1767$1'(1(1 087$17(1 o$8667$00(6 '(5 +3* o$86 Jj86(1 ,67 ',( 32671$7$/( g17:,&./81* '(5 i21$'(1 %/2&.,(57N :$6 ',( w1)58&+7%$5.(,7 '(5 o87$17(1 +(592558)7P f,( g,1.5(8=81* '(6 i1tj y,/'7O 12711/,&+(1 81' :(,%/,&+(1 v,(5(1P

SMXMR j./#+L/54 5.$ +./#+L). l;53% f,( g5=(8*81* 921 o87$17(1 0,7 (,1(5 =,(/*(5,&+7(7(1 *(1(7,6&+(1 x(5>1'(581* ,1 (,1(0 %(67,007(1 i(1/2&86 %$6,(57 $8) '(5(1 g,1)@+581* '85&+ +202/2*( t(.20O %,1$7,21 ,1 (0%586(1 ,67 ',( o?*/,&+.(,7 '(5 +2O 02/2*(1 t(.20%,1$7,21 '(5 *(120,6&+(1 u(48(1=(1 0,7 (;2*(1(5 fpc 817(5 *(O (,*1(7(1 d(',1*81*(1P o,77(/6 g/(.75275$16)(.7,21 *(/$1* S[ZY ',( (567( *(=,(/7( g,1)@+581* (,1(5 o87$7,21 '85&+ +202/2*( t(.20%,1$7,21 ,1 guO|(//(1 ,1 9,752P

TVT

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

f,( (567( *(=,(/7 ,1 '(5 m(,0%$+1 087,(57( o$86 817(5 '(5 x(5:(1'81* +202/2* 5(.20%,1,(57(5 guO|(//(1 :85'( S[Z[ %(6&+5,(%(1P f(5 (567( u&+5,77 %(, ',(6(5 v(&+1,. ,67 ',( g/(.75275$16)(.7,21 Jg/(.752325$7,21K (;2*(1(5 fpc ,1 guO|(//(1P f,( (;2*(1( fpc (17+>/7 ',( %($%6,&+7,*7( o87$7,21 81' -(:(,/6 %(1$&+%$57( +202/2*( J*(120,6&+(K u(48(1=(1 =80 5(/(9$17(1 i(1O /2&86 J7$5*(7,1* x(.725K Jc%%P VPVUKP f85&+ '(1 r52=(66 '(5 +202/2*(1 t(.20%,O 1$7,21 :,5' ',( 087,(57( (;2*(1( u(48(1= $1 '(5 %($%6,&+7,*7(1 u7(//( ,0 i(1/2&86 *(*(1 ',( *(120,6&+( u(48(1= $86*(7$86&+7P f,( h>+,*.(,7 =85 +202/2*(1 t(.20O %,1$7,21 ,67 +,(5%(, (,1( 1$7@5/,&+( g,*(16&+$)7 $8&+ 921 guO|(//(1N ',( '85&+ g1O =/7 '85&+ (,1 u(/(.7,2160$5.(5*(1 (56(7=7 J5(3/$&(0(17 76(17,(5(1 +202/2*( u(48(1=(1 ,0 x(.725N y,/'7//,*(5 J1,&+7O+202/2*(5K t(.20%,1$7,21 /,(*7 %(, '(1 0(,67(1 g;3(5,O 0(17(1 ,0 d(5(,&+ 921 S\U %,6 S\WRR 5(6,67(17(5 m/21(P j$7 0$1 (,1(1 +202/2* 5(.20%,1,(57(1 guO|(//./21 ,'(17,7=,(57N :(5'(1 ',(6( |(//(1 ,1 m8/785 9(50(+57 81' ,1 g0%5+/7 0$1 '$6 u7$',80 '(5 d/$672=5(1 p$&+.200(1N '(5(1 i(:(%( 9,(/( |(//(1 0,7 '(0 75$16*(1(1 guO|(//Oi(12700(1N ',( 6,&+ ,1 ,+5(5 h(//)$5%( 817(56&+(,'(1P f,( p$&+.200(1N ',( (,1(1 *52M(1 c17(,/ 921 |(//(1 '(6 guO|(//Oi(1271'(57(1 guO|(//(1 ,1 d/$672=86(N '(5(1 i(:(%( 6,&+ $86 |(//(1 '(5 d/$672=1'(57(1 guO|(//(1 =86$00(16(7=7N :(5'(1 *(%25(1P

c8635>*81* '(6 e+,0>5,6086 0(+5 2'(5 :(1,*(5 67$5. *(9(&.7(6 2'(5 *(675(,)7(6 h(//P p81 6&+/,(M7 0$1 921 '(5 d(7(,/,*81* '(5 guO|(//(1 $0 c8)%$8 921 j$87 81' h(// $8) '(5(1 d(7(,/,*81* $0 m(,0%$+1*(:(%(P m5(8=7 0$1 &+,0>5( 0>11/,&+( v,(5( 0,7 y,/'7127127+,* Jn(7$/087$17(KP c8&+ .?11(1 (5=(8*7( o87$7,21(1 3+>1271*(1N ,1 :(/&+(0 o$8667$00 6,( (5=(8*7 :85'(1P k1 ',(6(1 h>//(1 )@+5(1 ',(6(/%(1 o87$7,21(1 =8 817(56&+,('/,&+(1 r+>O 127//( '(87(1 $8) ',( g;,67(1= 921 67$00$%+>1*,* 817(56&+,('/,&+ $86*(35>*7(1 h$.725(1 +,1N ',( (,1( c86:,5.81* $8) ',( 3+>127*81* '(6 817(568&+7(1 i(16 +$%(1 .?11(1 JNN675$,1O63(&,7& 02',7(56DDKP

SMXMRMP a%)30)%,Y s)%2-/$%,,% &=2 b934)3#(% e)"2/3% f,( e87*67(1 /(7$/(1 +(5(',7>5(1 m5$1.+(,7(1 ,1 f(876&+/$1'P f$6 %(7525(1( i(1 :85'( S[Z[ ./21,(57P d(, '(0 i(1352'8.7 +$1'(/7 (6 6,&+ 80 (,1(1 e+/25,'Ok21(1.$1$/N '(1 NN&+1/,&+(5 ,67P d(621'(56 ',( ,17(67,1$/(1 x(56723)81*(1 6,1' *(*(1@%(5 '(1 p8//087$17(1 '(87O /,&+ 9(50,1'(57 81' ',( %(5/(%(165$7( (5+?+7P f$'85&+ 67(//(1 6,( (;=(//(17( o2O '(//( '$5N %(, '(1(1 ',( eh r$7+2*(1(6( '(5 n81*(1 817(568&+7 :(5'(1 .$11P

TVX

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

SMXMRMQ s)%2-/$%,,% &=(2%. :52 h$%.4)&):)%25.' -%.3#(,)#(%2 f%.$%&%+4% f,( ,1=:,6&+(1 :(,79(5%5(,7(7( p87=81* '(5 .12&.O287 v(&+1,. ,1 '(5 i581'/$*(1O )256&+81* +$7 =8 (,1(0 )@5 ',( o(',=,1 :,&+7,*(1 |86$7=$63(.7 *()@+57\ |8:(,/(1 (1767(+(1 0(+5 2'(5 :(1,*(5 =8)>//,* v,(5087$17(1N '(5(1 r+>1271277 '(5 o87$17( 80O *$1*(1 :(5'(1P u3>7(5( h81.7,21(1 (,1(6 |,(/*(16 ,1 $1'(5(1 i(:(%(1 .?11(1 620,7 $1$///(1 6(+5 1@7=/,&+N ,1 '(1(1 ',( g17:,&./81* =:(,(5 u758.785(1 (1* 0,7(,1$1'(5 *(.233(/7 ,67N :,( =P dP ',( g17:,&./81* 921 o86.(/1 81' ,+5( k11(59,(581* '85&+ o27251(8521(P q+1( o86.(/1 9(5.@00(51 ',( p(59(1N 81' 2+1( k11(59,(581* '(*(1(5,(5(1 ',( o86.(/1P k67 181 (,1 i(1352'8.7 )@5 ',( g17:,&./81* %(,'(5 u758.785(1 (66(17,(//N .$11 ',( i(1)81.7,21 ,1 (,1(5 u758.785 $86*(6&+$/7(7 :(5'(1 J=P dP o27251(8521(K 81' ,+5( c86:,5.81*(1 $8) ',( $1'(5( u758.785 Jo86.(/K 817(568&+7 :(5'(1P

TVZ

V o2/(.8/$50(',=,1,6&+( o(7+2'(1 Cre Maus

cre

X

gefloxte Maus

cre Ziel-Gen

cre

cre

Ziel-Gen

Ziel-Gen

Ziel-Gen

Induktion während der Ontognese gemäss den regulatorischen Elementen von Cre oder extern durch einen Indikator

cre

cre

Ziel-Gen

Ziel-Gen deletiert

c%%P VPVY |8&+76&+(0$ )@5 ',( .21',7,21$/( o87$*(1(6( ,1 o>86(1 '85&+ +202/2*( 81' NN6,7(O63(&,7&DD t(.20%,1$7,21P p85 (,1 c//(/ '(6 |,(/*(16 ,67 '$5*(67(//7P |:(, 81$%+>1*,*( o$8667>00( 6,1' +,(5)@5 1?7,*P g,1 u7$00 (;35,0,(57 ',( e5(Ot(.20%,1$6( ,1'8=,(5%$5 2'(5 ,1 *(:(%(63(=,76&+(5 h250P |(//(1 ',( e5( 1,&+7 (;35,0,(5(1 6,1' 0,7 6&+:$5=(0 t$1' '$5*(67(//7N ',(-(1,*(1N ',( (;35,0,(5(1 0,7 %/$8(0 t$1'P f(5 $1'(5( o$8667$00 75>*7 '(1 NN*(92;7(1DD n2&86 '(6 |,(/*(16N :(/&+(6 ,1 $//(1 |(//(1 (;35,0,(57 :,5'P p$&+ m5(8=81* (17O +>/7 -('( |(//( '$6 e5(Oi(1 81' '$6 NN*(92;7(DD i(1P |8 (,1(0 %(67,007(1 |(,7381.7 '(5 g17:,&./81* :,5' e5( *(:(%(63(=,76&+ (;35,0,(57 J%/$8 805$1'(7( |(//(K 2'(5 1$&+ |8*$%( (,1(6 k1'8.7256 921 $8M(1 $.7,9,(57 J1,&+7 *(=(,*7KP k1 '(1 5(/(9$17(1 i(:(%(1 71'(7 t(O .20%,1$7,21 67$77N ',( =85 g,1)@+581* '(5 %($%6,&+7,*7(1 o87$7,21 )@+57 J%/$8 805$1'(7( |(//( 0,7 +(//%/$8(0 j,17(5*581'KP

SMXMSMP f%7%"%30%:)&)3#(% l54!'%.%3% f,( 62*(1$117( NN92;O$1'O'(/(7(DD u75$7(*,( Jc%%P VPVXK :85'( =8(567 )@5 ',( ,1 9,92 c1$/1.7(6 *(:(%(63(=,76&+(6 g;35(66,2160867(5N 62 '$M ',(O 6(5 c16$7= )@5 (,1( */2%$/( ,1 9,92 c1:(1'81* 1,&+7 %5$8&+%$5 ,67P c1'(5(56(,76 62// e5( (5,=,(17 ,1 $//(1 |(//(1 (,1(6 i(:(%(6 2'(5 ,1 (,1(0 %(67,007(1 |(//71*,* ,0 i(120 326,7,21,(57(1 5(*8/$725,6&+(1 g/(0(17(1P f(5=(,7 %(71'(1 6,&+ 62/&+( m21=(37( ,1 '(5 r+$6( '(5 7(&+1,6&+(1 g17:,&./81* 81' q37,0,(581*N (567( g;3(5,0(17( :85'(1 ,1 o>86(1 817(51200(1P c1:(1'81O *(1 ,0 %,20(',=,1,6&+(1 d(5(,&+ =85 g567(//81* 921 o$8602'(//(1 )@5 0(16&+/,&+( m5$1.+(,7(1 %$6,(5(1' $8) (,1(5 ,1'8=,(5%$5(1 g,1)@+581* '(5 o87$7,21 :(5'(1 9,(//(,&+7 %$/' 0?*/,&+ 6(,1P

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autosomal rezessiv

autosomal dominant

X-chromosomal rezessiv

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q172*(1(6( f,( ,1',9,'8(//(1 i/2%,1*(1( :(5'(1 ,1 '(1 (5+5 SV v$*( 1$&+ '(5 m21=(37,21 :(5'(1 ',( j>02*/2%,1( i2:(5 k 81' kk 81' j% r257/$1' 62:,( :(1,* 63>7(5 '$6 j%h ,0 f277(56$&. 68)(51 ,0 m12O &+(10$5. 81' )@+5(1 %(, +202=02/0$O 72/2*,6&+ 6,1' j(7(52=02*/2%,1*(+$/7 '(6 g,1=(/(5=,3,7,(5(1P f,(6 )@+57 =85 ,1(5(.7,9(1 g50$O 72/2*,6&+(1 o$1,)(67$7,21 =:,6&+(1 '(5 v+$/$66$(0,$ 0,125 81' 0$-25P c8&+ *,%7 (6 *87 '2.80(17,(57( d(5,&+7( 921 j(7(52=/7 ',( *(1(7,6&+( k1)250$7,21 )@5 ',( SVX c0,126>85(1 /$1*( tOi/2%,1.(77( $8) (7:$ SNW .% fpcP f$6 tOi/2%,1*(1 %(71'(7 6,&+ =86$00(1 0,7 '(0 )(7$/(1 uO 81' '(0 (0%57 '(5 i/2%,1*(1( ,1 (5+5(1' '(5 q172*(1(6( $1*(25'1(7P f,( net 5(35>6(17,(57 (,1 @%(5*(25'1(7(6 5(*8/$7,9(6 g/(0(17N '$6 ,1 (51*/,&+ 0$&+7 81' :>+5(1' '(5 g0%587*P k0 *(1(7,6&+(1 e2'( 6,*1$/,6,(5(1 ',( v5,O 3/(776 wccN wic 81' wci '(1 c%%58&+ '(5 r527(,1%,2687*(5 o(&+$1,6086 ,67 ',( x(5>1'(581* (,1(5 fpcOu(48(1=N ',( 925+(5 1,&+7 $/6 u3/(,M6,*1$/ (5.$117 :85'(N %(, '(5 ',( o87$7,21 -('2&+ (,1( u3/(,M6,O *1$/6(48(1= (1767(+(1 />M7 81' '$0,7 (,1 62*(1$117(6 .57 '(5 1250$/(1 g;35(66,21 921 (7:$

TXT

W j(5(',7>5( g5.5$1.81*(1

SRATR@ )@+57P c1'(5(N 6(/7(1( t)Oo87$7,21(1 %(75(5(1 ',( e$3Ou7(//( 2'(5 '$6 r2/< JcKOu,*1$/ J6,(+( m$3P UPTPS 81' UPTPTKP f,(6( o87$7,21(1 )@+5(1 =85 9(50,1O '(57(1 v5$16/$7,216(5,=,(1= 81' tpcOu7$%,/,7>7P f,( j(7(52*(1,7>7 '(5 tOi/2%,1*(1087$7,21(1 )@+57 620,7 =85 817(56&+,('/,&+(1 g;35(66,9,7>7 81' 67(//7 (,1(1 :,&+7,*(1 h$.725 )@5 ',( ./,1,6&+( x$5,$%,/,7>7 '(5 tO v+$/$66>0,( '$5P f,(6(6 r+>120(1 ,67 +(87( %(, 9,(/(1 0212*(1(1 g5%.5$1.+(,7(1 :,( (7:$ '(5 o8.29,6=,'26( J6P 2PK %(.$117P k17(5$.7,21 0,7 02',7=,(5(1'(1 *(1(7,6&+(1 g,198M)$.725(1 f(5 =(175$/( 3$7+23+7 '(6 i(16 J6P 2PK /,(*7 $8) '(5 j$1'P f,( sOv+$/$66>0,( 81' ',( 32671$7$/O3(56,67,(5(1'( j%hOu0,(N =8 (,1(0 %(5/(%(169257(,/ ,1 t(*,21(1 0,7 (1'(0,6&+(5 o$/$5,$P f$'85&+ ,67 ',( +>87*( m2,1=,'(1= +2+(5 i(1)5(48(1=(1 )@5 %(,'( h250(1 '(5 v+$/$66>0,( (5./>5/,&+P g,1( %(621'(5( ./,1,6&+( d('(8781* .2007 '(5 sOv+$/$66>0,( '$11 =8N :(11 %(, (,1(0 r$7,(17(1 0,7 +202=0,( (,1 *(0,6&+7 +(7(52=7 '(5 tOv+$/$66>0,( .$11 620,7 921 (,1(0 i(1/2&86 (176&+(,'(1' %((,198M7 :(5'(1N '(5 $8) (,1(0 $1'(5(1 e+52O 02620 /2.$/,6,(57 ,67P h@5 ',( d(5$781* '(5 h$0,/,(1 ,67 ',(6 '(6:(*(1 921 $//(5O *5?M7(5 d('(8781*N '$ ',(6( %(,'(1 i(1/2&, %(, :(,7(5(1 m,1'(51 1$7@5/,&+ 81$%O +>1*,* 921(,1$1'(5 :(,7(5*(*(%(1 81' (,1 (5+(%/,&+ 817(56&+,('/,&+(6 ./,1,6&+(6 g56&+(,181*6%,/' %(',1*(1 .?11(1P f$6 m,1' 0,7 '(0 tHBt)Oi(1270,( ,67 5(*(/0>M,* 75$16)86,216%('@5)7,* 81' /(,'(7 $1 (,1(5 v+$/$66$(0,$ 0$-25N :2+,1*(*(1 i(6&+:,67(5 0,7 (,1(5 }Ov+$/$66>0,( 185 921 (,1(5 0,/'(1 v+$/$66$(0,$ ,17(50(',$ %(7525(1 6(,1 .?11(1P f,( *(1(7,6&+( k17(5$.7,21 =:,6&+(1 '(5 sO 81' '(5 tOv+$/$66>0,( ,67 ,162)(51 (,1 o2'(// )@5 ',( 817(56&+,('/,&+( g;35(66,9,7>7 (,1(5 NN0212*(1(1DD g5.5$1.81* ,1 '(56(/%(1 h$0,/,(P j(5(',7>5( r(56,67(1= )(7$/(1 j>02*/2%,16P c8&+ %(, 92//67>1',* (5/26&+(1(5 tOi/2O %,1*(1(;35(66,21 .$11 '(5 5(68/7,(5(1'( sOi/2%,1.(77(1@%(56&+8M '85&+ (,1( 9(5O 0(+57( 32671$7$/( uO 02*/2%,1P c/6 02/(.8/$5(5 f()(.7 71'(7 6,&+ ,1 ',(6(1 h>//(1 +>87* (,1( f(/(7,21 '(5 $'8/7(1 vO 81' tOi/2%,1*(1(P f$'85&+ :,5.7 ',( @%(5 ',( n2&86.21752//5(*,21 9(50,77(/7(

WPS m5$1.+(,7(1 0,7 o(1'(/6&+(0 x(5(5%81*602'86

TXU

75$16.5,37,21$/( c.7,9,7>7 '(6 tOi/2%,1*(1.203/(;(6 $8&+ 32671$7$/ $8) ',( )(7$/(1 i(1( Jc%%P WPXKP c/7(51$7,9 .$11 ',( 3(5,1$7$/( c%6&+$/781* '(5 uOi/2%,1*(1$.7,9,7>7 '85&+ r81.7087$7,21(1 ,0 r5202725 ',(6(5 i(1( %(+,1'(57 :(5'(1P f85&+ ',(6( o87$7,21(1 %/(,%7 ',( k17(5$.7,21 =:,6&+(1 '(5 n2&86.21752//5(*,21 81' '(1 uOi/2O %,1*(135202725(1 %(67(+(1N 62 '$M $8&+ 32671$7$/ j%h 67 '(5 tOv+$/$66>0,(P p(%(1 '(0 02'(//+$)7(1 e+$5$.7(5 )@5 ./,1,6&+ :,5.6$0( *(1(7,6&+( k17(5$.7,21(1 ,67 (,1( ',5(.7( 7+(5$3(87,6&+( q37,21 $%6(+%$5 %=:P 5($O /,6,(57P d((,1986681* (,1(6 NN02',)7 '(5 uOi/2%,1*(1( .$11 3+$50$.2/2*,6&+ 32671$7$/ 5(O,1'8=,(57 :(5'(1P d(, 6&+:(5 %(O 7525(1(1 r$7,(17(1 0,7 (,1(5 u,&+(/=(//(5.5$1.81* ,67 ',( j%hOk1'8.7,21 '85&+ j7 '(5 uOi/2%,1*(135202725(1 '85&+ fpcOo(7+1'1,6 +$7 +,(5 620,7 =85 g17:,&./81* (,1(5 1(8(1 NN.219(17,21(//(1DD u7$1'$5'7+(5$3,( *(O )@+57P u7=/,&+(1 sOi/2%,1*(1( 6,1' $.7,9 81' )@+5(1 =8 (,1(5 =86>7=/,&+(1 sOi/2%,1O .(77(1685(68%67,787,21(1 '(5 tOi/2%,1.(77(N ',( =8 (,1(5 (5+(%/,&+(1 k167$%,/,7>7 %(5(,76 '(6 o2120(56 2'(5 $8&+ '(6 j(7(527(75$0(56 )@+5(1P h81.7,21(//(6 j>02*/2%,1 (1767(+7 1,&+7P f$6 3527(2O /0,( $/62 1,&+7 185 ',( ,0 5(/$7,9(1 %(56&+8M %(71'/,&+(1 sOi/2%,1.(77(1 621'(51 $8&+ ',( 1,&+7 )81.7,21$/(1 tOi/2%,1.(77(1 $%%$8(1P f,( '$'85&+ %(',1*7( %(5/$6781* '(6 u//,*(1 81' )81.7,21(// ,1(5(.7,9(1 g50,(P k16*(6$07 *(6(+(1 .$11 ',( 9$5,$%/( g;35(66,9,7>7 '(5 tOv+$/$66>0,( $/62 '85&+ ',( j(7(52*(1,7>7 '(5 MOi/2%,1087$7,21(1 81' ',( 817(56&+,('/,&+( t(67$.7,9,7>7 '(6 %(7525(1(1 i(16 '85&+ k17(5$.7,21(1 0,7 1,&+7 $//(/(1 i(1/2&, (5./>57 :(5'(1 Jv$%P WPVKP

TXV

W j(5(',7>5( g5.5$1.81*(1 ·1 5´

3´ X-box

·2

Rekombinationsprodukt 1: ·+- Thalassämie

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5´

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3´ Rekombinationsprodukt 2: Tripliziertes ·-Globingen

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Expansionswahrscheinlichkeit

pathologische Funktion

Poly (A)

minimal

–

Poly (A)

hoch

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Poly (A)

hoch

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(CAG)10-35

CAP

5´– UTR

kodierende Sequenz (CAG)\40

CAP

kodierende Sequenz (CAG)\100

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.O5$6 ST .O5$6 .ON +ON 1O5$6 .O5$6 .O5$6

[R @ WR @ WR @ VW @ TW @

d(1,*1( m(5$72$.$17+20

+O5$6

UR @

XPV c.7,9,(581* 921 q1.2*(1(1

USS

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XPV c.7,9,(581* 921 q1.2*(1(1

US[

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UTR

X q1.2/2*,6&+( m5$1.+(,7(1 normal CoRK

RA

RAR RXR

CoRK

Transkription reprimiert

ATRA

ATRA

PLZF

PLZF

RAR RXR

PLZF-RAR· Fusion

PML

PML

RAR RXR

PML-RAR· Fusion

Transkription aktiviert

c%%P XPZ f,( t(7,16>85(5(=(3725(1 tct 81' tzt %,/'(1 0,7 :(,7(5(1 18./(>5(1 r527(,1(1 (,1(1 v5$16.5,37,2165(35(6625Om203/(;P f(5 3+87*67(1 62/,'(1 v8025(1 '(6 m,1'(6$/7(56P u,( /(,7(1 6,&+ 920 3(5,3+(5(1 p(59(1*(:(%( $%P o$1 817(56&+(,'(7 V u7$',(1N $86*(O +(1' 921 (,1(0 /2.$/ %(*5(1=7(1N ,1 7272 5(6(=,(5%$5(1 v8025 0,7 *87(5 r52*126( %,6 +,1 =8 (,1(0 0(,67 7+(5$3,(5(6,67(17(1 ',66(0,1,(57(1 m5$1.+(,76%,/' 0,7 h(51O

XPV c.7,9,(581* 921 q1.2*(1(1

UTU

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XPW h(+/5(*8/$7,21 '(5 c323726(

UTW

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393

Mutationen N

C Transaktivierung

DNA-Bindung

Regulator-Domäne

c%%P XPSU f(5 v5$16.5,37,216)$.725 rWU %(67(+7 $86 U[U c0,126>85(1 81' .$11 ,1 '5(, )81.O 7,21(//( f20>1(1 Jv5$16$.7,9,(581*N fpcOd,1'81*N t(*8/$7,21K $8)*(7(,/7 :(5'(1P o87$O 7,21(1 ,1 ',(6(0 i(1 71'(1 6,&+ )$67 $866&+/,(M/,&+ ,1 '(5 fpcOd,1'81*6'20>1( 81' %(O 75(5(1 %(621'(56 +>87* X e2'216P

UUR

X q1.2/2*,6&+( m5$1.+(,7(1

h250(1 921 3WUOo87$7,21(1 f,( h81.7,21(1 921 rWU .?11(1 $8) *$1= 817(56&+,('/,&+( y(,6( 817(5%81'(1 :(5O '(1P j,(5=8 *(+?57 ,1 9(56&+,('(1(1 v8025(1 ',( f(/(7,21 '(6 3WUOn2&86P c8&+ ',( 3$7+2/2*,6&+( k17(5$.7,21 0,7 $1'(5(1 r527(,1(1 .$11 =8 (,1(0 rWUOx(5/867 )@+5(1P g,1 d(,63,(/ ,67 '(5 *(67(,*(57( c%%$8 921 rWU 1$&+ m233/81* $1 ofoT J6,(+( m$3P UPXPVKN (7:$ $8) '(5 d$6,6 (,1(5 0'0TOc03/,7.$7,21 ,1 (,1(0 f5,77(/ '(5 y(,&+7(,/6$5.20(P g,1 ./,1,6&+ 5(/(9$17(5 r$7+20(&+$1,6086 (5*,%7 6,&+ $86 '(5 d,1'81* 921 rWU $1 9,5$/( q1.23527(,1( :,( %(,63,(/6:(,6( gX 921 +80$1O 3$7+2*(1(1 r$3,//209,5(1 '(6 v//( +$1'(/7 (6 6,&+ 80 0,66(16( o87$7,21(1N ',( ',( c.7,9,7>7 921 rWU 1,&+7 9?//,* 817(5%,1'(1 81' =85 c..808/$7,21 '(6 08O 7,(57(1 r527(,16 )@+5(1P k1 '(1 0(,67(1 h>//(1 :,5' '$6 =:(,7( 3WUOc//(/ ,1)2/*( (,1(5 f(/(7,21 $86*(6&+$/7(7N 62 '$M '(5 )@5 v802568335(6625*(1( 7&+7,*7] 0$1 635,&+7 921 (,1(5 '20,1$17 1(*$7,9(1 y,5.81* 62/&+(5 185 $8) (,1 c//(/ %(6&+5>1.7(1 3WUOo87$7,21(1P k1 6(/7(1(1 h>//(1 :85'(1 62*$5 3WUO o87$7,21(1 %(6&+5,(%(1N ',( 1,&+7 =8 (,1(0 h81.7,2169(5/867 )@+57(1 621'(51 '(0 r527(,1 (,1( 1(8(N 75$16)250,(5(1'( s8$/,7>7 9(5/,(+(1P f,(6( u,78$7,21 ,67 9(5*/(,&+O %$5 0,7 '(5 c.7,9,(581* (,1(6 q1.2*(16 81' 9(5'(87/,&+7N '$M (,1( ./$5( i5(1=O =,(+81* =:,6&+(1 %(,'(1 m/$66(1 921 v8025*(1(1 1,&+7 ,00(5 0?*/,&+ ,67P 3WUOo87$7,21(1 .?11(1 ,1 817(56&+,('/,&+(1 u7$',(1 (,1(5 v8025(17:,&./81* $8)75(7(1P u,( /$66(1 6,&+ $%(5 $8&+ ,1 u1'(581*(1 |(//(1 (,1(1 y$&+678069257(,/ 9(56&+$5(1N =85 v80250$1,)(67$7,21 -('2&+ 12&+ :(,7(5( *(1(7,6&+( n>6,21(1 +,1=8.200(1 0@66(1P r$7+2*(1(6( '(5 3WUOo87$7,21(1 %(5 [R@ $//(5 3WUOo87$7,21(1 75(7(1 ,1 '(5 fpcOd,1'81*6'20>1( $8) J6,(+( c%%P XPSUKP c8&+ :(11 ',( o87$7,21(1 921 9(56&+,('(1(1 v8025(1 @%(5 ',( *$1=( f20>1( 9(57(,/7 6,1'N 62 (5*(%(1 6,&+ '2&+ (,1,*( +27O63276N ,16%(621'(5( ,1 e2'21 SYWN TVWN TVZN TV[N TYU 81' TZTP x21 *52M(0 k17(5(66( ,67 ',( *(1$8( c57 '(5 3WUO o87$7,21N :(,/ 6,( t@&.6&+/@66( @%(5 '(1 g1767(+81*6352=(M =8/>M7 81' ',( d$6,6 )@5 (,1( 02/(.8/$5( g3,'(0,2/2*,( 921 m5(%6(5.5$1.81*(1 %,/'(7P f,( 0(,67(1 3WUO o87$7,21(1 5(35>6(17,(5(1 i B c v5$16,7,21(1 Jc867$86&+ (,1(6 r85,16 2'(5 r1'(581* 67(//7 $8&+ ',( +>87*67( h250 '(5 3WUOo87$7,21 %(, n81*(1.$5=,120(1N ,16%(621'(5( '(1 ./(,1=(//,*(1 r/$77(1(3,7+(/O .$5=,120(1 '$5N '(5(1 c8)75(7(1 =8'(0 0,7 '(0 c860$M '(6 |,*$5(77(1.216806 '(6 -(:(,/,*(1 r$7,(17(1 .255(/,(57P c1$/5( 3WUOo87$7,21(1 g,1( %(621'(5( ./,1,6&+( u,78$7,21 (5*,%7 6,&+ $86 '(5 m(,0%$+1087$7,21 921 3WU %(,0 n,Oh5$80(1, u*(5 $1 (,1(0 v8025 (5.5$1.7N [R@ %,6 =80 c/7(5 921 XW l$+5(1P d(, '(5 d(75(881* 921 h$0,/,(1 0,7 n,Oh5$80(1, u1.7(1 o?*/,&+.(,7 )@5 *(=,(/7( x25O 625*(352*5$00( )81'$0(17$/( r52%/(0(N ',( ,16%(621'(5( ,0 m217(;7 (,1(5 35>O ',.7,9(1 f,$*1267,. J12&+K 1,&+7O(5.5$1.7(5 h$0,/,(1$1*(+?5,*(5 (,1 ,17(5',6=,3/,O 1>5(6 d(75(881*6.21=(37 925$866(7=(1 Jm$3P XPZKP

UMVMPMS s(%2!0)%342!4%')%. }+1/,&+ :,( %(, v8025(1 0,7 087,(57(1 5$6Oi(1(1 .?11(1 $8&+ 3WUOo87$7,21(1 $/6 02/(.8/$5*(1(7,6&+( o$5.(5 =85 1,&+7O,19$6,9(1 f,$*1267,. 921 0$/,*1(1 |(//(1 ,0 u38780N w5,1 2'(5 ,1 u78+/352%(1 +(5$1*(=2*(1 :(5'(1P c1*(6,&+76 '(5 j>8O 7*.(,7 921 3WUOo87$7,21(1 81' '(5 0,7 ',(6(0 *(1(7,6&+(1 f()(.7 $662=,,(57(1 t(O 6,67(1= *(*(1 e+(02O 81' u75$+/(17+(5$3,( :,5' '(5=(,7 ,17(16,9 1$&+ 1(8(1 d(O +$1'/81*6.21=(37(1 *(68&+7P g,1 %(621'(56 ,17(5(66$17(5 *(17+(5$3(87,6&+(5 c1O 6$7= 187=7 c'(129,586087$17(1N ',( 6,&+ 185 ,1 rWU '(7=,(17(1 v8025=(//(1 9(5O 0(+5(1 81' ',(6( /+,*7 :(5'(1P x,(/O 9(5635(&+(1' 6,1' $8&+ u75$7(*,(1 '(5 02/(.8/$5(1 r+$50$.2/2*,( 81' d,2,1)25O 0$7,.N $86 '(5 *52M(1 h@//( %(.$117(5 x(5%,1'81*(1 62/&+( e+(027+(5$3(87,.$ =8 ,'(17,7=,(5(1N ',( 81$%+>1*,* 921 rWUO9(50,77(/7(1 h81.7,21(1 &//( 6325$',6&+ $8) 81' 6,1' '$11 ,1 '(5 t(*(/ $8) (,1 c8*( %(6&+5>1.7N :>+5(1' %(, '(1 @%5,*(1 VR @ (,1( (5%/,&+( h250 925/,(*7N %(, '(5 ',( v8025( 0(,67 %,/$7(5$/ 81' 08/7,)2.$/ (1767(+(1P c//(5',1*6 :(,6(1 185 SR @ '(5 m,1'(5 (,1( 326,7,9( h$O 0,/,(1$1$01(6( $8)] %(, '(1 $1'(5(1 r$7,(17(1 0,7 +(5(',7>5(0 t(7,12%/$6720 6,1' ',( o87$7,21(1 63217$1 ,1 '(1 m(,0=(//(1 0(,67 '(6 x$7(56 (1767$1'(1P u7$7,67,6&+( c1$/1*,*( 620$7,6&+( g5(,*1,66( =80 x(5/867 %(,'(5 5%Oc//(/( ,1 (,1(0 t(7,12%/$67(1 81' '$0,7 =85 v8025(17:,&.O /81*P f$ (6 67$7,67,6&+ *(6(+(1 +?&+67 81:$+56&+(,1/,&+ ,67N '$M ',(6( 6(/7(1(1 g5O (,*1,66( ,1 0(+5(5(1 |(//(1 =:(,0$/ +,17(5(,1$1'(5 $8)75(7(1N (17:,&.(/1 6,&+ 632O 5$',6&+( t(7,12%/$6720( 0(,67 81,)2.$/ 81' 63>7(5 $/6 +(5(',7>5( t(7,12%/$6720(P f,(6(6 m21=(37 921 m18'621 :85'( '85&+ 02/(.8/$5*(1(7,6&+( c1$/7,*7P d(, (,1(5 m(,0%$+1087$7,21 '(6 5%Oi(16 %(67(+7 (,1( y$+56&+(,1/,&+.(,7 921 @%(5 [W @N '$M $8&+ '$6 =:(,7( c//(/ ,1 (,1(0 t(7,12%/$67(1 6(,1( h81.7,21 9(5/,(57 81' (6 620,7 =85 v80250$1,)(67$7,21 .2007P q%:2+/ $/62 185 (,1 '()(.7(6 c//(/ '(6 5(=(66,9(1 v802568335(6625*(16 9(5(5%7 :,5'N .2007 (6 1$+(=8 ,00(5 =8 ./,O 1,6&+(1 o$1,)(67$7,21(1P f,(6 (5./>57 '(1 $872620$/ '20,1$17(1 g5%*$1* +(5(',O 7>5(5 t(7,12%/$6720(P f,( m(1171,6 '(6 5%Ou7$786 (,1(6 m,1'(6 ,67 %(,0 )$0,/,>5(1 t(7,12%/$6720 921 *52M(5 ./,1,6&+(5 d('(8781* Jm$3P XPZKP h,1'(7 6,&+ %(, (,1(5 810,77(/%$5 32671$7$/ '85&+*()@+57(1 c1$/O ',6321,(57] -('( :(,7(5(N 620$7,6&+( o87$7,21 '(6 =:(,7(1 5%Oc//(/6 (,1(5 t(7,1$=(//( />M7 (,1(1 v8025)2&86 (1767(+(1P d(, '(5 6325$',6&+(1 h250 .2007 (6 185 '$11 =85 c86%,/'81* (,1(6 t(7,12%/$67206N :(11 =:(, 81$%+>1*,*( 620$7,6&+( o87$7,21(1 %(,'( 5%Oc//(/( '(56(/%(1 t(7,1$=(//( 75(5(1P

5(56(,76 .?11(1 c1/$*(75>*(5 62 (1*0$6&+,* .21752//,(57 :(5'(1N '$M (,1 v8025 5(&+7=(,7,* (5.$117 :,5' 81' (,1( v+(5$3,( J(7:$ ,1 h250 (,1(5 n$6(5.2$*8/$7,21K 817(5 g5+$/7 '(6 u(+9(50?*(16 '85&+*()@+57 :(5'(1 .$11P d(, 5%Om(,0%$+108O 7$7,21(1 %(6&+5>1.7 6,&+ '$6 t,6,.2 )@5 ',( g1767(+81* 921 t(7,12%/$6720(1 J,0 f85&+6&+1,77 (17:,&.(/1 6,&+ '5(, v8025(K $8) ',( (567(1 9,(5 n(%(16-$+5(N )@5 ',( 6,&+ '$6 $1*()@+57( x25625*(352*5$00 %(:>+57 +$7P c//(5',1*6 71'(7 6,&+ '(5 (5O (5%7( 5%Of()(.7 ,1 $//(1 m?53(5=(//(1P u2 %(67(+7 )@5 c1/$*(75>*(5 (,1 =86>7=/,&+(6 t,6,.2 921 (7:$ UW @ %,6 =80 '5,77(1 n(%(16-$+5=(+17 $1 (,1(0 :(,7(5(1 o$/,*120N ,16%(621'(5( (,1(0 q67(26$5.20 2'(5 y(,&+7(,/6$5.20N =8 (5.5$1.(1P

XPZ h$0,/,>5( v8025(5.5$1.81*(1

UUW

UMW e!-),);2% s5-/2%2+2!.+5.'%. g3,'(0,2/2*,6&+( f$7(1 :(,6(1 '$5$8) +,1N '$M (7:$ SR @ $//(5 m5(%6(5.5$1.81*(1 $8) (,1( (5%/,&+( v8025',6326,7,21 =85@&.=8)@+5(1 6,1'P l( 1$&+ v8025$57 6&+:$1.7 '(5 c17(,/ ',(6(5 +(5(',7>5(1 m20321(17(] 62 /,(*7 %(,0 t(7,12%/$6720 ,1 VR @ '(5 h>//( (,1( (5%/,&+( h250 925N :>+5(1' m(,0%$+1087$7,21(1 %(, n(8.>0,(1 .$80 (,1( t2//( 63,(/(1P u(,7 9,(/(1 l$+5(1 6,1' (,1,*( 6(/7(1( $872620$/O5(=(66,9 9(5(5%7( m5$1.+(,7(1 :,( c7$;,$ 7(/($1*,(&7$6,$N h$1&21, c1>0,(N d/220 u',.7,9(1 J35>65(5 d5867OBq9$5,$/.5(%6 h$0,/,>5(5 d5867.5(%6 n, h5$80(1, u5(6 o(/$120 p(8527%520$726( v5( m5(%6(5.5$1.81*(1 (;,67,(5(1 1$&+ 35>',.7,9(5 i(1$1$/5(5 u&+,/''5@6(1.$5=,120( J6P 8PKP k1 $1'(5(1 h>//(1 :,( '(0 +(5(',7>5(1 o$00$.$5=,120 :(5'(1 (17635(&+(1'( d(75(881*6$1*(%27( '(5=(,7 (567 (17:,&.(/7P o8/7,3/( v8025',6326,7,21(1 :,( (7:$ %(,0 n,Oh5$80(1, u5(0 u&+,/''5@6(1.$5=,120 %(67(+7 $%(5 (,1( (5%/,&+( f,6326,O 7,21N ',( 6,&+ $86 m(,0%$+1087$7,21(1 '(6 5(7Oi(16 $8) e+5202620 SR4SS (5*(%(1P 5(7 .2',(57 (,1(1 v1*,*(1N .2167,787,9(1 c.7,9,(581* '(5 v5(0 0('8//>5(0 u&+,/''5@6(1.$5=,120 JhoveK ',( o87$7,21(1 ,1 (;75$O 81' ,175$=(//8/>5(1 tgvOf20>1(1] %(621'(56 +>8O 7* ,67 e2'21 XTR %(7525(1P c1'(5( o87$7,21(1 6,1' 0,7 '(0 =86>7=/,&+(1 t,6,.2 )@5 g1'2.5,123$7+,(1 9(5%81'(1P d(, r$7,(17(1 0,7 08/7,3/(5 (1'2.5,1(5 p(23/$6,( JogpK 920 v2&+O 5202=1',*(6 m5$1.+(,76%,/'N ',( ogp 920 v7 621'(51 $8&+ =8 (,1(5 9(5>1'(57(1 u8%675$7O $5,1,7>7 '(6 t(=(37256P u&+,/''5@6(1.$5=,120( %(, ogp Td 6,1' %(621'(56 $**5(66,9P c8&+ +,(5 (17:,&.(/7 6,&+ ,1 WR@ '(5 h>//( (,1 r+>2&+5202&5( v8025(5.5$1.81*(1

UUY

RET

GDNF

CD

CRD GDNF-R·

620 FMTC 634 MEN-2A

Zellmembran TK1 TK 2

918 MEN-2B

c%%P XPSX 5(7 .2',(57 (,1(1 0(0%5$167>1',*(1 v1(1 )@+5(1 =8 (,1(5 .2167,787,9(1 c.7,9,(581* 81' ',6321,(5(1 )@5 ',( g17:,&./81* (,1(6 0('8//>5(1 u&+,/'O '5@6(1.$5=,1206P f(5 t(=(3725 (17+>/7 (,1( (;75$=(//8/>5( e$'+(5,1O>+1/,&+( JefK 81' e1( JeftK 62:,( =:(, ,175$=(//8/>5( v1(1 JvmKP

g7:$ YR@ '(5 c1/$*(75>*(5 (17:,&.(/1 %(,0 ogp v5( 5(7Oo87$7,21(1N ',( =8 (,1(0 c86O )$// ',(6(6 t(=(37256 )@+5(1N 6,1' (%(1)$//6 %(.$117N $//(5',1*6 %(',1*(1 6,( (,1 *>1=O /,&+ $1'(5(6 m5$1.+(,76%,/'N 1>0/,&+ (,1( $872620$/O'20,1$17 9(5(5%7( h250 '(6 o(*$&2/21 &21*(1,780 Jo25%86 j,56&+63581*KP j,(5%(, .2007 (6 =8 (,1(5 c3/$6,( '(6 c8(5%$&+6&+(1 81' o(,M1(56&+(1 r/(;86 Jr$5$65(1 f,6.866,21 81' m223(5$7,21 $15(*7P

UMWMQ d2",)#(%3 l!--!+!2:)./f$6 o$00$.$5=,120 ,67 ',( +>87*67( m5(%6(5.5$1.81* 81' v2'(6856$&+( '85&+ (,1( 0$/,*1( g5.5$1.81* %(, h5$8(1P k1 f(876&+/$1' (5.5$1.(1 (7:$ VU RRR h5$8(1 ->+5/,&+] $1'(56 $86*('5@&.7 %(67(+7 )@5 -('( h5$8 (,1 1$+(=8 SR@,*(6 t,6,.2 ,0 n$8)( ,+5(6 n(%(16 $1 d5867.5(%6 =8 (5.5$1.(1P p85 (,1 ./(,1(5 v(,/ ',(6(5 h>//( ,67 $8) (,1(1 f()(.7 ,1 (,1(0 $872620$/O'20,1$17 (5%/,&+(1 i(1 =85@&.=8)@+5(1P g3,'(0,2/2*,6&+( f$7(1 635(&+(1 )@5 (,1( i5?M(125'181* 921 (7:$ W@ $//(5 d5867.5(%6(5.5$1.81*(1] ',(6 (17635,&+7 ,1 f(876&+/$1' ->+5/,&+ (7:$ TRRR (5%/,&+ %(',1*7(1 p(8(5.5$1.81*(1 $1 (,1(0 d5867.5(%6N ',( '85&+ (,1 5(/$7,9 )5@+(6 g5O .5$1.81*6$/7(5 J925 '(5 o(123$86(K 81' (,1 +>87*(5(6 c8)75(7(1 %,/$7(5$/(5 m$5O =,120( &+$5$.7(5,6,(57 6,1'P h@5 '$6 (5%/,&+( o$00$.$5=,120 6,1' =:(, ',6321,(O 5(1'( i(1( %(.$117N %5&$S $8) e+5202620 SY4TS 81' %5&$T $8) e+5202620 SU4STP f,( h81.7,21 ',(6(5 %(,'(1 v802568335(6625*(1( ,67 (567 $16$7=:(,6( 9(567$1'(1P u,( .2',(5(1 v5$16.5,37,216)$.725(1N ',( %(, '(5 |(//=+1/,&+ +2+(1 t,6,.2 )@5 d5867.5(%6 9(5%81'(1] '$6 t,6,.2 )@5 g,(5672&..5(%6 :,5' 0,7 SRATR@ 1,('5,*(5 $1*(6(7=7P c8&+ 0>11/,&+( v5>*(5 (,1(5 %5&$T o87$7,21 =(,O *(1 (,1 '(87/,&+ (5+?+7(6 t,6,.2N d5867.5(%6 =8 (17:,&.(/1\ (7:$ W@ %,6 =80 YRP n(O %(16-$+5P o87$7,21(1 ,1 %5&$S 81' %5&$T 6,1' $8M(5'(0 0,7 (5+?+7(1 t,6,.(1 )@5 o$/,*120( $1'(5(5 q5*$1( :,( m2/21N r$1.5($6 81' r5267$7$ 9(5%81'(1P f$6 7$7O 6>&+/,&+( t,6,.2 )@5 m5(%6(5.5$1.81*(1 %(, v5>*(51 921 %5&$SO 81' %5&$TO o87$7,21(1 08M -('2&+ (567 12&+ (50,77(/7 :(5'(1P d(,'( i(1( 6,1' 6(+5 *52M 81' ',( o87$7,21(1 9(57(,/(1 6,&+ @%(5 ',( i(6$07/>1*(N 62 '$M c1*$%(1 =85 ./,1,6&+O 352*1267,6&+(1 t(/(9$1= (,1(5 63(=,76&+(1 m(,0%$+1087$7,21 Ji(12712O 787* $8)N 62 '$M $1 (,1(5 *5?M(5(1 |$+/ 921 d(7525(1(1 *(1$8(5( 352*1267,6&+( c866$*(1 (567(//7 :(5'(1

XPZ h$0,/,>5( v8025(5.5$1.81*(1

UU[

.?11(1P d(,63,(/6:(,6( 71'(1 6,&+ '5(, o87$7,21(1 ,0 %5&$SO %=:P %5&$TOi(1 %(, T@ $//(5 c6&+.(1$6,0P h@5 v5>*(5,11(1 ',(6(5 o87$7,21(1 (5*,%7 6,&+ (,1 t,6,.2 921 (7:$ WW@ %,6 =80 c/7(5 921 YR l$+5(1 $1 d5867.5(%6 =8 (5.5$1.(1P k1 k6/$1' '20,1,(57 ',( %5&$TOo87$7,21 [[['(/W] 6,( ,67 0,7 (,1(0 t,6,.2 921 UW@ )@5 d5867O .5(%6 9(5%81'(1P u&+21 +(87( '(87(1 6,&+ $/62 *52M( w17(56&+,('( ,0 ./,1,6&+(1 x(5/$8) ,1 c%+>1*,*.(,7 920 ,1',9,'8(//(1 o87$7,21667$786 $%P g6 08M =8'(0 %(O 7217 :(5'(1N '$M 35>9(17,9( ',$*1267,6&+( 81' 7+(5$3(87,6&+( q37,21(1 )@5 )$0,/,>5( h250(1 921 d5867O 81' q9$5,$/.5(%6 (567 12&+ '85&+ ,17(5',6=,3/,1>5( u78',(1.21O =(37( $8) ,+5(1 u7(//(1:(57 +,1 @%(535@)7 :(5'(1 0@66(1P j,(5=8 .?117( 1(%(1 '(1 @%/,&+(1 x25625*(352*5$00(1 $8&+ (,1( g51>+581*6%(5$781*N c1/(,781* =85 u(/%67817(568&+81* '(5 d5@67(N '(5 g,16$7= %,/'*(%(1'(5 x(5)$+5(1 :,( w/75$6&+$//N o$002*5$3+,( 2'(5 m(5163,1Ov202*5$3+,(N (,1( e+(0235>9(17,21 0,7 6(/(.7,9(1 ~6752*(1Ot(=(3725 o2'8/$725(1 :,( v$02;,)(1N 2'(5 $8&+ 817(56&+,('/,&+ $86*(O '(+17( &+,585*,6&+( o$M1$+0(1 *(+?5(1P

UMWMR d2",)#(% +/,/2%+4!,% j!2:)./-% f$6 .2/25(.7$/( m$5=,120 ,67 (,1( '(5 +>87*67(1 m5(%6)250(1 ,1 f(876&+/$1'P l>+5/,&+ (5.5$1.(1 (7:$ WR RRR r(5621(1 $1 ',(6(0 v8025N 'P +P (7:$ W@ 816(5(5 d(9?/.(581* 6,1' ,0 n$8)( '(6 n(%(16 +,(5921 %(7525(1P o$1 *(+7 '$921 $86N '$M SRASW@ '(5 g5.5$1.81*(1 $8) (,1(5 *(1(7,6&+(1 f,6326,7,21 %(58+(1P f,( )$0,/,>5( $'(120$7?6( r2///( 0(,67 ,0 9,(57(1 n(%(16-$+5=(+17 =8 (,1(0 m2/21.$5=,120P f,( hcr %(58+7 $8) (,1(0 f()(.7 '(6 $3&Oi(16 $8) e+52O 02620 W4TSP cre 625*7 ,1 m223(5$7,21 0,7 '(5 r527(,1.,1$6( i/8)7 n>6,21(1 ,1 e2'21 SVWR $8)P g,1( %(, c6&+.(1$6,0 +>87*( JX@ ',(6(5 r238/$7,21K v B c v5$169(56,21 ,1 e2'21 SURYN JcKUvJcKV B JcKZ *(1(5,(57 (,1( o,.526$7(//,7(16(48(1= 921 Z c'(1,1(1N ',( $1)>//,* )@5 n(6(O )(+/(5 '(5 tpcOr2/+5(1' '(5 v5$16.5,37,21 ,67P f,( '85&+ ',(6( o212O

UVR

X q1.2/2*,6&+( m5$1.+(,7(1 Desmoide CHRPE 1061

1309 1450

typische Polyposis attenuierte FAP

N

1

500

1000

1500

2000

2500

C 2843 AA

APC

c%%P XPSY i(1271278M(567(1 WAOd(5(,&+ '(6 $3&Oi(16N :>+5(1' $**5(66,9( m5$1.O +(,76%,/'(5 0,7 o87$7,21(1 ,1 e2'21 STWRASVXV 9(5%81'(1 6,1'P c8&+ (;75$.2/21,6&+( o$O 1,)(67$7,21(1 :,( ejtrg 2'(5 f(602,'( .255(/,(5(1 0,7 o87$7,21(1 ,1 &+$5$.7(5,67,6&+(1 $3&Ot(*,21(1P

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(,1(5 815(,)(1 u7$00=(//( 0,7 35,0>5(0 f,5(5(1=,(581*6327(17,$/ )@5 9(56&+,('(1( |(//5(,+(1 $%/(,7(1N 2'(5 $%(5N '$M '$6 )(+/*(67(8(57( *(1(7,6&+( r52*5$00 (,1(5 75$16)250,(57(1 |(//( $%(55$17( i(1(;35(66,21(1 %=:P O5(.20%,1$7,21(1 =8/>M7P k1 -('(0 h$// )2/*7 +,(5$86N '$M 185 ',( i(6$07$1$/66,*( u8%O ./$66,7.$7,21 +>0$7232(7,6&+(5 p(23/$6,(1 *(:>+5/(,67(7P g,1( (,*(167>1',*( d('(8781* .2007 '(0 p$&+:(,6 (,1(6 k*O 2'(5 vetOt($5O 5$1*(0(176 $%(5 $/6 o$5.(5 (,1=(/1(5 |(//./21( =8P c%%P XPTT =(,*7 '$6 r5,1=,3 (,1(5 (17635(&+(1'(1 u287+(51 d/27Oc1$/OdO 2'(5 dOcnn %=:P ',( &+521,6&+ /0,( JennK 81' '$6 p21O j2'*.,1 nOd cnn :(5'(1 $8&+ =85 i5833( '(5 dOx25/>8)(5 J35(&85625K cnn =86$0O 0(1*()$M7P

UVZ

X q1.2/2*,6&+( m5$1.+(,7(1

$86 '(0 .2167$17(1 m(77(17(,/ Je|K ++5(1' '$6 j0,(3$7,(17(1 J&cnnK 81' (,1(0 i(681'(1 JiKP f,( fpc :85'( 0,7 '(0 g1=*7 +,(5%(, TU .%P

XP[ m/21$/( t($55$1*(0(176 '(5 k0081*/2%8/,1 81' vO|(//Ot(=(3725 i(1(

UV[

j(5.81)7 $//(5 n(8.>0,(=(//(1 :,'(563,(*(/7N $/62 (,1(5 0212./21$/(1 |(//3238/$O 7,21 (17635,&+7N 5(35>6(17,(5(1 ',( =$+/5(,&+(1 h5$*0(17( %(, r$7,(17 Y (,1 2/,*2O ./21$/(6 o867(5P w17(568&+7 0$1 -('2&+ ',( fpc ',(6(6 r$7,(17(1 0,7 (,1(5 vettO u21'(N 71'(7 6,&+ (,1( 0212./21$/( m2167(//$7,21P |86$00(1*(1200(1 +$1'(/7 (6 6,&+ ,1 ',(6(0 h$// 80 n(8.>0,(=(//(1N :(/&+( =:$5 921 (,1(5 *(0(,16$0(1 x25O />8)(5=(//( $%67$00(1 J.(117/,&+ $0 (,1+(,7/,&+(1 t($55$1*(0(17 '(6 vettOn2O &86KN -('2&+ ,0 n$8)( '(5 g5.5$1.81* u8%./21( *(%,/'(7 +$%(1N ',( ,+5(56(,76 '85&+ ,1',9,'8(//( t(.20%,1$7,21(1 '(6 k*jOn2&86 &+$5$.7(5,6,(57 6,1'P g7:$ %(, (,1(0 f5,77(/ '(5 cnn r$7,(17(1 71'(1 ,0 d(5(,&+ '(5 k* 81' vet n2&, 921 n(8.>0,(O =(//(1 6(.81'>5( t($55$1*(0(176 67$77N ',( 0,7 (,1(5 }1'(581* '(6 (17635(&+(1'(1 t(.20%,1$7,2160867(56 9(5%81'(1 6,1'P f(5 j,1:(,6 $8) /(8.>0,6&+( u8%3238/$7,21(1 %(, r$7,(17 Y @%(55$6&+7 ,162)(51N $/6 1$&+ 0253+2/2*,6&+(1 81' ,00812/2*,6&+(1 m5,7(5,(1 (,1 (,1+(,7/,&+(5 r+>12O 70,(=(//(1 2'(5 5($.7,9 9(5>1'(57( 1250$/( |(//(1 +$1'(/7P k1 62/&+(1 h>//(1 /,()(57 (,1( k*O 2'(5 vetOc1$O /760$5O .(5 %(, u287+(51 d/27Oc1$///(1 .2007 (6 =8 (,1(5 t(.20%,1$7,21 '(5 $8) '(1 e+5202620(1 TN SV %=:P TT *(/(*(1(1 k*On2&, 0,7 '(0 0=,6( n>6,21 (,1(5 u,*1$/.$6.$'( 81' ',( ./,1,6&+( o$1,)(67$7,216)250 ,11(5+$/% '(5 n57,* (,1( %(57+(5$3,( (5)>+57 81' /$1*)5,67,*( p(%(1:,5.81*(1 %,6 +,1 =85 k1'8.7,21 921 |:(,70$/,*12O 0(1 ',( ,1,7,$/(1 d(+$1'/81*6(5)2/*( %((,175>&+7,*(1 .?11(1P f(01$&+ ,67 (6 :,&+O 7,*N '$6 c1635(&+(1 (,1(6 r$7,(17(1 $8) ',( v+(5$3,( 6(+5 6(16,7,9 =8 @%(5:$&+(1 81' c'$37$7,21(1 $1 ',( ,1',9,'8(//(1 d('@5)1,66( (,1(6 r$7,(17(1 925=81(+0(1P f$6 m12&+(10$5. (,1(6 n(8.>0,(3$7,(17(1 ,67 =80 |(,7381.7 '(5 f,$*126( 77=(1 =8 .?11(1P d(, (7:$ '(5 j>/)7( $//(5 $.87(1 n(8.>0,(1 (55(,&+7 '(5 .20O %,1,(57( p$&+:(,6 0(+5(5(5 ,00812/2*,6&+(5 o$5.(5N ',( 6,&+ ,1 ',(6(5 h250 81' m20326,7,21 1,&+7 $8) p250$/=(//(1 71'(1N (,1( (5+(%/,&+( u(16,7,9,7>7667(,*(581*P g567 ',( g,1)@+581* 921 retOu75$7(*,(1 (5%5$&+7( '$11 $%(5 (,1(1 ',$*1267,6&+(1 s8$17(163581* 0,7 '(5 o?*/,&+.(,7 =85 k'(17,7.$7,21 921 (,1(5 n(8.>0,(=(//( 817(5

UWT

X q1.2/2*,6&+( m5$1.+(,7(1 1012 10 11 10 --2

10 10 CR

10 9 10 8 107 10 6

M R D

Morphologie Southern Blot

immunologische 10 --4 Marker Kombinationen 10 --6 PCR

10 5 10 4 103 10 2 10 1 10 0

c%%P XPTV f$6 m12&+(10$5. (,1(6 n(8.>0,(3$7,(17(1 (17+>/7 (7:$ SRST 0$/,*1( |(//(1P f,( p$&+:(,6*5(1=( 0253+2/2*,6&+(5 r$5$0(7(5 /,(*7 %(, SAW@ n(8.>0,(=(//(1P g,1 c%)$// 817(5 ',(6( u&+:(//( '(71,(57 (,1( .203/(77( t(0,66,21 JetKP retOx(5)$+5(1 *(67$77(1 ',( g5)$6O 681* 6(+5 9,(/ ./(,1(5(5 n(8.>0,(=(//0(1*(1 JotfN 0,1,0$/ 5(6,'8$/ ',6($6(KP

SRX p250$/=(//(1 Jm$3P VPUPTKP c%%P XPTW =(,*7 ,1 (,1(0 u&+(0$ m,1(7,.(1 921 n(8O .>0,(=(//(1 :>+5(1' (,1(5 e+(027+(5$3,( 81' '$1$&+P d(, 1$+(=8 $//(1 m,1'(51 0,7 cnn *(/,1*7 6&+21 :>+5(1' '(5 (567(1 9,(5 y2&+(1 '(5 t(0,66,216,1'8.7,21 (,1 c%6(1.(1 '(5 n(8.>0,(=(//(1=$+/ 817(5 ',( p$&+:(,6*5(1=( .219(17,21(//(5 v(&+1,.(1P f$6 SRPRRRO)$&+ (5+?+7( c89?681*69(50?*(1 '(5 retOx(5)$+5(1 *(O 67$77(7N ,1',9,'8(//( w17(56&+,('( ,1 '(5 g/,0,1,(581* 0$/,*1(5 |(//(1 (%(162 =8 (5)$66(1 :,( '(1 p$&+:(,6 5(=,',9,(5(1'(5 n(8.>0,(1 o21$7( 925 (,1(5 ./,1,6&+(1 o$1,)(67$7,21P h@5 ',( retOf,$*1267,. .200(1 %(, n(8.>0,(1 925 $//(0 =:(, m$7(*25,(1 921 |,(/6(48(1=(1 ,1 h5$*(\ ',( 02/(.8/$5(1 }48,9$/(17( &+5202620$/(5 c%(55$7,21(1 81' ',( 620$7,6&+(1 t(.20%,1$7,21(1 921 k*O 81' vetOi(1(1P y,( ,0 m$3P UPW '$5*(67(//7N :(5'(1 ',( 9$5,$%/(1 t(*,21(1 '(5 k*O 81' vetOm(77(1 $86 9(56&+,(O '(1(1 fpcOg/(0(17(1 =86$00(1*(6(7=7 81' ,1',9,'8(// 02',7=,(57N 62 '$M '(1 x(5.1@3)81*667(//(1 (,1 ./2163(=,76&+(5 e+$5$.7(5 =8.2007P f,(6( ./2163(=,7O 6&+(1 u(48(1=(1 .?11(1 %(67,007 81' $/6 ,1',9,'8(//( i(1621'(1 =85 %(535@)81* '(6 t(0,66,21667$786 +(5$1*(=2*(1 :(5'(1P d(, (7:$ [W@ $//(5 r$7,(17(1 0,7 p(2O 3/$6,(1 '(6 ///(1 3(56,67,(5(1 n(8.>0,(O

XPSR p$&+:(,6 6(+5 ./(,1(5 o(1*(1 0$/,*1(5 |(//(1

UWU

1 klinische Manifestation

10 –1 10 –2

CR

10 –3

M R D

10 –4 10 –5 10 –6 10 –7 10 –8

Heilung 0 RI KR

1

2 E

3

4 Jahre

Therapie

c%%P XPTW u&+(0$7,6&+( f$567(//81* 817(56&+,('/,&+(5 m,1(7,.(1 921 0$/,*1(1 |(//(1 %(, cnn r$7,(17(1 :>+5(1' (,1(5 e+(027+(5$3,( 81' 1$&+ c%6&+/8M '(5 d(+$1'/81*P v+(5$O 3,(3+$6(1\ t(0,66,216,1'8.7,21 JtkKN m2162/,',(581*Bt(,17(16,9,(581* JmtKN g5+$/781* JgKP r$7,(17(1 ,1 62*(1$117(5 .203/(77(5 t(0,66,21 JetK .?11(1 $8) retOp,9($8 12&+ j,1:(,6( )@5 0,1,0$/( n(8.>0,(=(//3238/$7,21(1 JotfK =(,*(1P

=(//(1 12&+ 0(+5(5( o21$7( %,6 6,( '$11 *$1= 9(56&+:,1'(1P u&+/,(M/,&+ (;,67,(57 (,1( j2&+5,6,.2*5833( 921 (7:$ SW@ '(5 m,1'(5 0,7 cnnN %(, '(1(1 ',( n(8.>0,(O =(//(1=$+/ 185 .1$33 817(5 ',( p$&+:(,6*5(1=( 921 u7$1'$5'9(5)$+5(1 $%*(6(1.7 :,5' 81' $8) +2+(0 p,9($8 3(56,67,(57 2'(5 @%(5 0(+5(5( o21$7( (,1(1 67(7,*(1 y,('(5$167,(* =(,*7] ,1 ',(6(1 h>//(1 .2007 (6 )$67 ,00(5 =80 ./,1,6&+(1 t(=,',9P f,(6( 1(8(1 g5.(1171,66( :(5'(1 '(5=(,7 )@5 '(1 g17:85) ,1',9,'8$/,6,(57(5 v+(5$O 3,(.21=(37( 187=%$5 *(0$&+7P g,1 :(,7(5(6 o$5.(5687*( t(.20%,1$7,21(1N :(/&+( %(, (7:$ VR@ '(5 r$7,(17(1 0,7 cnnN UR@ 0,7 con 81' [W@ 0,7 eon 1$&+:(,6%$5 6,1'P f$ 6,&+ ',(6(6 o$5.(561'/,&+N '$M 6,&+ +,(5 ',( f$7(1 =80 t(0,66,21667$786 $8) retOp,9($8 -( 1$&+ m5$1.+(,76%,/' '(87/,&+ 817(56&+(,'(1P d(, r$7,(17(1 0,7 r+O326,7,9(5 cnn 71'(1 6,&+ 6(/%67 1$&+ g55(,&+(1 (,1(5 .203/(77(1 +>0$72/2*,O 6&+(1 t(0,66,21 (17635(&+(1' '(5 6(+5 +2+(1 t(=,',95$7( 0(,67 12&+ n(8.>0,(O =(//(1N :>+5(1' ',( ,17(16,9,(57(1 v+(5$3,(675$7(*,(1 %(, r$7,(17(1 0,7 $)VO$//S t(O .20%,1$7,21 j(,/81*(1 (5=,(/(1 .?11(1N ',( '$11 0,7 (,1(0 1(*$7,9(1 retOd()81' (,1+(5*(+(1P c8&+ %(, '(5 con =(,&+1(7 6,&+ (,1 ',5(5(1=,(57(6 d,/' $%P u2 .2007

Verknüpfungsregion

J‰1

Sonde

CTTGGGG · TG T T T T C AGGCCTTCCGGTGGGGGATA AAC T T GGG · ATAAC NNNNNNN PPP D‰2 NN NNNNNNNN J‰1 V‰1 D‰3

Sonde

3

2

1

10-1 10-2 10-3 10-4 10-5 10-6

Sonde: GTGTTTTCAGGCCTTCC

Sonde: CTACAGGAAGGTGGGTACTG

Sonde: ACTAGGACAACTTCCTACACTGG

D

C

Monate 1 3 6

681'(1 r52%$1'(1 JeK %(67,007 :,5'P k1 ',(6(0 h$// /,(*7 ',( g03O 71'/,&+.(,7 '(5 '5(, u21'(1 %(, -(:(,/6 (,1(5 n(8.>0,(=(//( 817(5 SRR RRR 1250$/(1 n0,(=(//(1 0(+5 1$&+:(,6(1 /$66(1N 71'(7 6,&+ %(, r$7,(17 U =8 $//(1 w17(568&+81*6O =(,7381.7(1 12&+ (,1( %(75>&+7/,&+( o(1*( 5(6,'8$/(5 d/$67(1] %(, ',(6(0 r$7,(17(1 .$0 (6 =:(, o21$7( 63>7(5 =8 (,1(0 ./,1,6&+(1 t(=,',9P

CTTG · T GCC T C T TCCTTCCTAC AGGAAGG T GGGTACTGGGGGGT · ACACCGATAAC NNNNNNNNNNPP V‰1 NNNNNNNN D‰2 D‰3 PP J51

Sonde

CTTGGGGAACT · AGG AC AACTTCCTACACTGGGGG · ACACCGATAAAC PP NNNNN D‰2 V‰1 D‰3 J‰1

V‰1

3´

c%%P XPTX retOc1$/0,(=(//(1 n(8.>0,(

q1.2*(1(

e+5202620$/( c%(55$7,21

j>87*.(,7 J,16*(6$07 %(, cnnBconK

cnn

%&5O$%/

7J[]TTK

7(/O$0/S

7JST]TSK

3%;SO(T$ $)VO$//S

7JS]S[K 7JV]SSK

6,/O7$/S

'(/JS3UTK

g5:$&+6(1( VR @ m,1'(5 W@ g5:$&+6(1( U @ m,1'(5 TW @ TW @ r5>Od UR @ r5>Or5>Od u>8*/,1*( YR @ SR ATR @ vOcnn

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XPST v(/20(5$6($.7,9,7>7

UWY

v$%P XP[ c1*,2*(1(7,6&+( 81' $17,$1*,2*(1(7,6&+( h$.725(1 c1*,2*(1(6()$.725(1

c17,Oc1*,2*(1(6()$.725(1

c1*,2*(1,1 c1*,232(7,1 g3,'(50$/ *52:7+ )$&725 JgihKsBt h,%52%/$67 *52:7+ )$&725 JhihKsBt j(3$72&O 0$7232(6( '@5)(1 ,1 ,+5(0 d(67$1' $%(5 1,&+7 925=(,7,* *()>+5'(7 :(5'(1P k1 ',(6(1 |(//3238/$7,21(1 :,5.7 '$6 g1=7=/,&+( vvciiiOo27,9( $1.233(/7N 62 '$M ',( 1$&+)2/*(1'(1 fpcO x(5/867( ,0 v2&+7(5675$1* 1,&+7 ',( r5,0>5%(67$1'7(,/( '(5 e+5202620(1(1'(1 (5O )$66(1 Jm$3P UPXPSKP u20$7,6&+( |(//(1 %(6,7=(1 ,0 i(*(16$7= =8 m(,0=(//(1 1250$O /(5:(,6( .(,1( v(/20(5$6($.7,9,7>7] ,+5( v(,/81*6.$3$=,7>7 ,67 '(01$&+ %(*5(1=7P g,1( *(:,66( g;35(66,21N ',( '(1 c/7(581*6352=(M 352/21*,(57N 71'(7 6,&+ $%(5 ,1 63(=,76&+(1 |(//3238/$7,21(1 0,7 u7$00=(//&+$5$.7(5 :,( (7:$ +>0$7232(7,6&+(1 x25/>8)(5=(//(1N d$6$/=(//(1 '(5 g3,'(50,6 2'(5 |(//(1 '(5 352/,)(5$7,9(1 |21( ,1 ,17(67,1$/(1 m57 %(2%$&+7(7] ',(6 :(,67 $8) (,1(1 v(/20(5$6(O81$%+>1*,*(1 o(&+$1,6086 '(5 v(/20(59(5/>1*(581* +,1P f,(6( g5.(1171,66( .?117(1 @%(5 ',( g17:,&./81* 921 v(/20(5$6(Ok1+,%,725(1 $8&+ 7+(5$3(87,6&+( k03/,.$7,21(1 +$%(1P f,( 61*( '(6 v(/20(5%(5(,&+(6P k1 '(1 0(,67(1 v8025=(//(1 .2007 (6 @%(5 (,1( 3$7+2/2*,6&+( c.7,9,(581* '(5 v(/20(5$6( =85 v(/20(59(5/>1*(581*P

d(2%$&+781*(1 $1 o>86(1 ,17(5(66$17N '(5(1 .$7$/86( 6,1' =81>&+67 /(%(16)>+,* 81' )(57,/P c8&+ v8025( .?11(1 (1767(+(1] ',(6 =(,*7N '$M ',( v(/20(O 5$6($.7,9,7>7 .(,1( &21',7,2 6,1( 48$ 121 '(5 m5(%6(17:,&./81* '$567(//7P g567 63>7(5( p$&+.200(1 JXP i(1(5$7,21K ',(6(5 o>86( =(,*(1 '$11 f()(.7( ,1 '(5 u3(50$72O *(1(6( 62:,( j>0$7232(6( 81' (17:,&.(/1 =81(+0(1' e+5202620(1$120$/,(1N 62 '$M 6,&+ '(5 ,00(5 67>5.(5( v(/20(59(5/867 ,1 :(,7(5(1 i(1(5$7,21(1 $/6 n(7$/O )$.725 (5:(,6(1 '@5)7(P f(112&+ /$66(1 6,&+ ',(6( f$7(1 1,&+7 810,77(/%$5 $8) '(1 o(16&+(1 @%(575$*(1P u2 %(6,7=(1 o>86( (7:$ =(+10$/ />1*(5( v(/20(5( $/6 o(1O 6&+(1N ,+5( 3+7 %,6 =80 c8)75(7(1 921 h81.7,2169(5/8O 67(1 ,67 $/62 *5?M(5P c8&+ .?117( ',( 6(+5 9,(/ />1*(5( n(%(16=(,7 '(6 o(16&+(1 0,7 ./,1,6&+(1 o$1,)(67$7,21(1 9(5%81'(1 6(,1N ',( %(, o>86(1 1,&+7 %(2%$&+7(7 :(5'(1P g6 .2007 +,1=8N '$M '(5 c86)$// '(5 v(/20(5$6( ,1 '(1 .12&.O287Oo>86(1 '85&+ 12&+ 81=85(,&+(1' &+$5$.7(5,6,(57(N $/7(51$7,9( u&+87=0(&+$1,60(1 *(*(1 v(/20(59(5.@5=81*(1 .203(16,(57 :(5'(1 .?117(P c1'(5(56(,76 :>5( (6 92567(//%$5N '$M '(5 g,16$7= 921 v(/20(5$6(Ok1+,%,725(1 (,1 %5(,7(5(6 p(%(1:,5.81*663(.7580 =(,*7 $/6 ',( *(=,(/7( c866&+$/781* '(6 g1=87*( p8./(27,')2/*(1 %(*5(1=7N ',( 62*(1$117(1 NN,19(57(' 5(3($76DDP f,(6( 5$+0(1 u(48(1=(1 (,1N ',( )@5 r527(,1( .2',(5(1N ',( )@5 '(1 r52=(M '(5 v5$16326,7,21 (5)25'(5/,&+ 6,1' Jv5$16O 326$6(N t(62/9$6(KP d(, '(5 v5$16326,7,21 +$1'(/7 (6 6,&+ 80 (,1( 1,&+7O+202/2*( t(.20%,1$7,21N 62 '$M ,'(17,6&+( k16(57,216(/(0(17( $1 9?//,* 817(56&+,('/,&+(1 u7(//(1 '(6 %$.7(5,(//(1 i(1206 ,17(*5,(5(1 .?11(1P v5$16326216 6,1' 35,1=,3,(// */(,&+$57,* $8)*(%$87 :,( k16(57,216(/(0(17(] =86>7=/,&+ =8 '(1 i(1(1 )@5 v5$16O 326,7,216)81.7,21(1 75$*(1 v5$16326216 -('2&+ 12&+ $1'(5( i(1(N %(,63,(/6:(,6(

IR

Pathogenitätsgen (Antibiotikaresistenz, Virulenzfaktor)

Mobilisationsgene (Resolvase, Transposase)

IR

ATTAT TAATA versetzter Schnitt im Wirtschromosom

TAATA

ATTAT

Transposon IR

IR

IR

IR

ATTAT TAATA IR

IR

TAATA

ATTAT

ATTAT TAATA

c%%P YPU u&+(0$7,6&+(5 c8)%$8 (,1(6 v5$16326216 81' o2'(// )@5 ',( k16(57,21 (,1(6 v5$16O 326216P i(:?+1/,&+ 6,1' ',( '$6 v5$1632621 9$1.,(5(1(1 u(48(1=(1 ,1 '(0 y,576&+5202620 ,'(17,6&+P ktN ,19(57(' 5(3($7P

YPS o2/(.8/$5( d$.7(5,2/2*,(

UXU

c17,%,27,.$5(6,67(1=(1 2'(5 x,58/(1=)$.725(1P g7:$ (,10$/ 817(5 SRK A SRP |(//(1 (,1(5 i(1(5$7,21 :,5' '$6 g/(0(17 $1 (,1( $1'(5(N 1$+(=8 %(/,(%,*( u7(//( '(6 i(O 1206 @%(575$*(1P r/$60,'( 2'(5 v5$16326216 6,1' )@5 '$6 %(5/(%(1 '(5 d$.7(5,(1=(//( 1,&+7 81O %(',1*7 (5)25'(5/,&+N 9(5/(,+(1 ,+5 -('2&+ g,*(16&+$)7(1N ',( 817(5 %(67,007(1 d(O ',1*81*(1 (,1(1 u(/(.7,2169257(,/ '$567(//(1N =P dP ',( h>+,*.(,7N 81*(:?+1/,&+( &+(O 0,6&+( x(5%,1'81*(1 $/6 p$+581*648(//( =8 9(5:(1'(1N v2;,1( 2'(5 x,58/(1=)$.O 725(1 =8 67 %(58+7 ',( d('(8781* '(5 v5$16326216 $8) =:(, h$.725(1\ SP ,0 x(5*/(,&+ =8 r/$60,'(1 =(,*(1 v5$16326216 (,1 (5:(,7(57(6 y,57663(.7580 81' TP '(5 c..808/$7,21 0(+5(5(5 t(6,67(1=O 2'(5 x,58/(1=*(1( $1 (,1(0 *(1(7,6&+(1 n2&86P v$%P YPT o(',=,1,6&+ %('(876$0( g,*(16&+$)7(1N ',( '85&+ r/$60,'( 81' v5$16326216 @%(5O 75$*(1 :(5'(1 R R R

m21-8*$7,21 c17,%,27,.$5(6,67(1= r$7+2*(1,7>76O 81' x,58/(1=)$.725(1 SP c'+>6,1( 81' k19$6,1( TP v2;,1(

VMPMPMS f%.%4)3#(% u!2)!"),)4;4 $%2 a!+4%2)%. h@5 ',( *(1(7,6&+( x$5,$%,/,7>7 '(5 d$.7(5,(1 6,1' 0(+5(5( x25*>1*( 0$M*(%/,&+\ SP o87$7,21N TP t(.20%,1$7,21 81' UP c867$86&+ 921 g5%0$7(5,$/P f$6 (92/87,21>5 >8M(567 (5)2/*5(,&+( m21=(37 '(5 %$.7(5,(//(1 y(/7 %(67(+7 ,1 (,1(5 .85=(1 i(1(5$O 7,216=(,7 81' '$0,7 9(5%81'(1 '(5 o?*/,&+.(,7N 6,&+ 0,77(/6 o87$7,21N t(.20%,O 1$7,21 81' i(1$867$86&+ 6&+1(// $1 9(5>1'(57( w0:(/7%(',1*81*(1 $1=83$66(1P f,( 0(,67(1 o87$7,21(1 :(5'(1 '85&+ t(3$5$785(1=7 6,1' %(.$117\ v5$16)250$7,21N v5$16'8.7,21 81' m21-8*$7,21 Jc%%P YPVKP e+$5$.7(5,67,6&+ )@5 ',(6( o(&+$1,60(1 ,67N '$M ,00(5 185 v(,/( '(6 i(10$7(5,$/6 (,1(5 f2125=(//( 81',5(.7,21$/ ,1 (,1( t(=(3725=(//( 75$16O )(5,(57 :(5'(1\

UXV

Y k1)(.7,216.5$1.+(,7(1

Transformation +

freie DNA

DNA-Aufnahme

Bakterienzelle

rekombinierte Bakterienzelle nach Transformation

Transduktion

+

Aufnahme der Phagen-DNA

Bakteriophagen Bakterienzelle

Donorzelle (Plasmidhaltig)

c%%P YPV

Akzeptorzelle

Rekombination

rekombinierte Bakterienzelle nach Transduktion

Konjugation +

Rekombination

Kontakt über F+ Pili

konjugative Plasmid-Übertragung

Bakterienzelle nach Konjugation

f,( 9(56&+,('(1(1 o?*/,&+.(,7(1 '(6 i(175$16)(56 %(, d$.7(5,(1P

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YPS o2/(.8/$5( d$.7(5,2/2*,(

UXW

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Kultur

Extraktion von Nukleinsäuren

Amplifikation eines 16S rRNA Genfragments

Sequenzanalyse

Computergestützte Analyse; Abgleich der Sequenz mit der Datenbank

Identifizierung

c%%P YPX u&+(0$ '(5 u(48(1=,(581* retO$03/,7=,(57(5 SXu 5tpc i(1)5$*0(17( =85 k'(1O 7,7=,(581* 921 o,.5225*$1,60(1P

YPS o2/(.8/$5( d$.7(5,2/2*,(

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TAT (Trans-Aktivator der Transkription)

Transkription

Spleißen

Provirus

Spleißen

NEF

Reifung

REV (Post-transkriptionaler Regulator der Genexpression) Transport Genomische GAG RNA Kernexport GAG-POL

Freisetzung

Zusammenbau ENV

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Prion-Gen im Genom des Wirtes (DNA) kontinuierliche Transkription + Translation Infektion

neue Prionen können mit weiteren PRPc-Molekülen interagieren

PRPc Interaktion von Prionen und PRPc

Spontane oder erblich bedingte Konversion von PRPc in PRPsc

Prionen – infektiöses PRPsc ohne Nukleinsäure

bewirkt Konversion von PRPc in infektiöses PRPsc

sporadische oder familiäre TSE

erworbene TSE neue Prionen

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Plasma-Insulinkonzentration (nmol/l)

0.50 0.40 0.30 0.20 0.10 0.00

0.0

1.5

3.0 4.5 Zeit (min)

6.0

7.5

subkutane Injektion bzw. Mahlzeit

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Fibrinogen (löslich)

Fibrin (unlösliches Blutgerinnsel)

Fibrinogen-Spaltprodukte (löslich)

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kultivierte Zielzellen

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