Human Crumbs Homologue 1 (CRB1)

last update: 29.08.2004 Human Crumbs Homologue 1 (CRB1) Genbank: AL513325, AL136322, NM_012076, AY043325 Codon usage adjusted according to (1) |-----> Primers as published for reference see list at bottom Nucleotide numbering of full length isoform II is given in dark blue. Nucleotide numbering of shorter isoform I is given in light blue. Nucleotide numbering is adjusted to Adenin of the first Methionine codon as nucleotide no. 1. Aminoacid numbering is given in green (Isoform I, Isoform II) | RP12 | LCA6 | RP + Coats | RP + Coats + LCA6 | early onset RP | Polymorphisms Numbers in brackets indicate the references at the end of the document Functional units

CCCC = Cytoplasmic Domain TTTT = Transmembrane Domain E##E = EGF-Domain L##L = laminin A G-like domain SSSS = Signalpeptide

-210 -200 -190 -180 -170 -160 -150 cccca tcctc ccgtg taagt gatgc taaga agcac aaact gcatt ttgaa tctaa gtccc tgtat tttct gtgaa ggggt aggag ggcac attca ctacg attct tcgtg tttga cgtaa aactt agatt caggg acata aaaga cactt

-140 -130 -120 -110 -100 -90 -80 -70 ggagc tgtaa gtagg gtggg acaga gatgg cacct ggggg ttctg aggca cccgc tcctc tctga gacag acagg cctcg acatt catcc caccc tgtct ctacc gtgga ccccc aagac tccgt gggcg aggag agact ctgtc tgtcc

-60 -50 -40 -30 -20 -10 1 gatca ggagc cggac tggga ccaga ccacc agcaa cacac cagag gatgt tctct aaata agacc ATG GCA CTT ctagt cctcg gcctg accct ggtct ggtgg tcgtt gtgtg gtctc ctaca agaga tttat tctgg TAC CGT GAA Met Ala Leu M A L 1

15 30 45 60 70 AAG AAC ATT AAC TAC CTT CTC ATC TTC TAC CTC AGT TTC TCA CTG CTT ATC TAC ATA AAA A gtaag TTC TTG TAA TTG ATG GAA GAG TAG AAG ATG GAG TCA AAG AGT GAC GAA TAG ATG TAT TTT T cattc Lys Asn Ile Asn Tyr Leu Leu Ile Phe Tyr Leu Ser Phe Ser Leu Leu Ile Tyr Ile Lys Asn K N I N Y L L I F Y L S F S L L I Y I K N SSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSS 5 10 15 20 24 ccttt cccac tttgg gcatt tttcc tggtt tattt ctggc ttatt atatt tctta caaat aatgg ataat gttgc ggaaa gggtg aaacc cgtaa aaagg accaa ataaa gaccg aataa tataa agaat gttta ttacc tatta caacg atgtt ctata aaata caatg ctaaa aaagg aagtt tttat ttgtt ttttt tttaa gtgtc ctgtg ttaaa gaaat tacaa gatat tttat gttac gattt tttcc ttcaa aaata aacaa aaaaa aaatt cacag gacac aattt cttta cagtg atacc agtca atgtg aacag tcagt tttaa gattc tatga tttcc aatag gtatt caggt acaga aattt gtcac tatgg tcagt tacac ttgtc agtca aaatt ctaag atact aaagg ttatc cataa gtcca tgtct ttaaa tgttt ttaac ctttg tagta gtgag ctgga gaatg aaatg gtcac ataga ctaga agata ttttg ttgtg tttac acaaa aattg gaaac atcat cactc gacct cttac tttac cagtg tatct gatct tctat aaaac aacac aaatg gcttt tacaa aatag atttg gccct tacta attga tatcc tttaa aagga agtta ttcat aacct gtatt tcatt cgaaa atgtt ttatc taaac cggga atgat taact atagg aaatt ttcct tcaat aagta ttgga cataa agtaa ttatt cccac atact atata tttat cttca ctttt aaata actct gtgtt gcaac atttg ctctc ataat taagg aataa gggtg tatga tatat aaata gaagt gaaaa tttat tgaga cacaa cgttg taaac gagag tatta attcc

IVS 1 (+59039 bp) taaac tctac atcca gtaaa atttg ctatc ctgta tataa gtctt ctgtt aaatc aggaa acaaa attct ctatg atttg agatg taggt cattt taaac gatag gacat atatt cagaa gacaa tttag tcctt tgttt taaga gatac gcaat taaac tctac atcca gtaaa atttg ctatc ctgta tataa gtctt ctgtt aaatc aggaa acaaa attct last update: 29.08.2004 cgtta atttg agatg taggt cattt taaac gatag gacat atatt cagaa gacaa tttag tcctt tgttt taaga gtact ttctc tggga actaa atttc aatta taatt taaaa tatcc tataa cttct ttctg tgtcc attta agtct catga aagag accct tgatt taaag ttaat attaa atttt atagg atatt gaaga aagac acagg taaat tcaga tgctc tgaag gtatt atcac tatga aaatt attgc attgt tcact gaaag tacat acaat gtgct aggta tagta acgag acttc cataa tagtg atact tttaa taacg taaca agtga ctttc atgta tgtta cacga tccat atcat atgta gatga cgtag ttttt tcatt aggat gaacc caact atgta tttta ttaat gagtt tggtt gaggc agcac tacat ctact gcatc aaaaa agtaa tccta cttgg gttga tacat aaaat aatta ctcaa accaa ctccg tcgtg

t (6) | aaagg tcaca aagaa agatt tttaa ctttg tcctc attta taaat ttaat cttgt tactt tttat ttcct tgtag tttcc agtgt ttctt tctaa aaatt gaaac aggag taaat attta aatta gaaca atgaa aaata aagga acatc

del (3) 71 75 90 105 | 120 135 AT TCC TTT TGC AAT AAA AAC AAC ACC AGG TGC CTC TCA AAT TCT TGC CAA AAC AAT TCT ACA TGC TA AGG AAA ACG TTA TTT TTG TTG TGG TCC ACG GAG AGT TTA AGA ACG GTT TTG TTA AGA TGT ACG Asn Ser Phe Cys Asn Lys Asn Asn Thr Arg Cys Leu Ser Asn Ser Cys Gln Asn Asn Ser Thr Cys N S F C N K N N T R C L S N S C Q N N S T C SSSSSS E01EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 24 25 30 35 40 45

150 165 180 195 AAA GAT TTT TCA AAA GAC AAT GAT TGT TCT TGT TCA GAC ACA GCC AAT AAT TTG GAC AAA GAC TGT TTT CTA AAA AGT TTT CTG TTA CTA ACA AGA ACA AGT CTG TGT CGG TTA TTA AAC CTG TTT CTG ACA Lys Asp Phe Ser Lys Asp Asn Asp Cys Ser Cys Ser Asp Thr Ala Asn Asn Leu Asp Lys Asp Cys K D F S K D N D C S C S D T A N N L D K D C EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 50 55 60 65

insGT (3) 210 225 240 255 | GAC AAC ATG AAA GAC CCT TGC TTC TCC AAT CCC TGT CAA GGA AGT GCC ACT TGT GTG AAC ACC CCA CTG TTG TAC TTT CTG GGA ACG AAG AGG TTA GGG ACA GTT CCT TCA CGG TGA ACA CAC TTG TGG GGT Asp Asn Met Lys Asp Pro Cys Phe Ser Asn Pro Cys Gln Gly Ser Ala Thr Cys Val Asn Thr Pro D N M K D P C F S N P C Q G S A T C V N T P EEE E02EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 70 75 80 85

270 285 300 315 330 GGA GAA AGG AGC TTT CTG TGC AAA TGT CCT CCT GGG TAC AGT GGG ACA ATC TGT GAA ACT ACC ATT CCT CTT TCC TCG AAA GAC ACG TTT ACA GGA GGA CCC ATG TCA CCC TGT TAG ACA CTT TGA TGG TAA Gly Glu Arg Ser Phe Leu Cys Lys Cys Pro Pro Gly Tyr Ser Gly Thr Ile Cys Glu Thr Thr Ile G E R S F L C K C P P G Y S G T I C E T T I EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE E03EEEE 90 95 100 105 110

345 360 375 390 GGT TCC TGT GGC AAG AAC TCC TGC CAA CAT GGA GGT ATT TGC CAT CAG GAC CCT ATT TAT CCT GTC CCA AGG ACA CCG TTC TTG AGG ACG GTT GTA CCT CCA TAA ACG GTA GTC CTG GGA TAA ATA GGA CAG Gly Ser Cys Gly Lys Asn Ser Cys Gln His Gly Gly Ile Cys His Gln Asp Pro Ile Tyr Pro Val G S C G K N S C Q H G G I C H Q D P I Y P V EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 115 120 125 130

G=Val (3) | del (3) 405 420 |--|-| 435 450 465 TGC ATC TGC CCT GCT GGA TAT GCT GGA AGA TTC TGT GAG ATA GAT CAC GAT GAG TGT GCT TCC AGC ACG TAG ACG GGA CGA CCT ATA CGA CCT TCT AAG ACA CTC TAT CTA GTG CTA CTC ACA CGA AGG TCG Cys Ile Cys Pro Ala Gly Tyr Ala Gly Arg Phe Cys Glu Ile Asp His Asp Glu Cys Ala Ser Ser C I C P A G Y A G R F C E I D H D E C A S S EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE E04EEEEEEEEEEEEEEEEEEEEEEEEEEEE 135 140 145 150 155 last update: 29.08.2004

insG (6) | T=Val (1) |480 | 495 510 525 CCT TGC CAA AAT GGG GCC GTG TGC CAG GAT GGA ATT GAT GGT TAC TCC TGC TTC TGT GTC CCA GGA GGA ACG GTT TTA CCC CGG CAC ACG GTC CTA CCT TAA CTA CCA ATG AGG ACG AAG ACA CAG GGT CCT Pro Cys Gln Asn Gly Ala Val Cys Gln Asp Gly Ile Asp Gly Tyr Ser Cys Phe Cys Val Pro Gly P C Q N G A V C Q D G I D G Y S C F C V P G EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 160 165 170 175

540 555 570 585 TAT CAA GGC AGA CAC TGC GAC TTG GAA GTG GAT GAA TGT GCT TCA GAT CCC TGC AAG AAC GAG GCT ATA GTT CCG TCT GTG ACG CTG AAC CTT CAC CTA CTT ACA CGA AGT CTA GGG ACG TTC TTG CTC CGA Tyr Gln Gly Arg His Cys Asp Leu Glu Val Asp Glu Cys Ala Ser Asp Pro Cys Lys Asn Glu Ala Y Q G R H C D L E V D E C A S D P C K N E A EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE E05EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 180 185 190 195

C=Thr (6) | del (2) del (3)|-----| |------| del (7) |------| 600 630 645 651 ACA TGC CTC AAT GAA ATA GGA AGA TAT ACT TGT ATC TGT CCC CAC AAT TAT TCT ggtaa gtgtg atcat TGT ACG GAG TTA CTT TAT CCT TCT ATA TGA ACA TAG ACA GGG GTG TTA ATA AGA ccatt cacac tagta Thr Cys Leu Asn Glu Ile Gly Arg Tyr Thr Cys Ile Cys Pro His Asn Tyr Ser T C L N E I G R Y T C I C P H N Y S EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 200 205 210 215 217 atctg aatca cagat ggtgt agtta gctct ttcta agtgg cagaa gcaga ggtga cattt tattt ttcac acaat tagac ttagt gtcta ccaca tcaat cgaga aagat tcacc gtctt cgtct ccact gtaaa ataaa aagtg tgtta cattt atgaa aatgg ccaag ttctt gacag gaatc aatca ctaga tagaa actcc ctaaa ctgct gaaaa tccac gtaaa tactt ttacc ggttc aagaa ctgtc cttag ttagt gatct atctt tgagg gattt gacga ctttt aggtg tgaat gcact gaatt ctaag tggtt gcctg ctgtc actgt tgctg tttta aatgg agctc tacat gattt aaaac actta cgtga cttaa gattc accaa cggac gacag tgaca acgac aaaat ttacc tcgag atgta ctaaa ttttg tggat tcagt ctaga atgaa tgagg tccaa gagaa actca agggc agttc aggtt tcctc atcag tgcat gttcc accta agtca gatct tactt actcc aggtt ctctt tgagt tcccg tcaag tccaa aggag tagtc acgta caagg tttca ttcca gttca agcct gcttt ctaat cccca aagcc tggca ctgca acctt ctggg aaggc agttt ggaag aaagt aaggt caagt tcgga cgaaa gatta ggggt ttcgg accgt gacgt tggaa gaccc ttccg tcaaa ccttc

IVS 2 (+ 17,572 bp)

cttac ccact gttct ctctg ctcct ttact aaatt aagtg tttaa aaata atgga aaaac atcga ccagc cactt gaatg ggtga caaga gagac gagga aatga tttaa ttcac aaatt tttat tacct ttttg tagct ggtcg gtgaa ttagg cttcc aacaa aagtg cagtt aacaa taaac tttgt tctaa aaatg actta tttgt tttca cggac taaac aatcc gaagg ttgtt ttcac gtcaa ttgtt atttg aaaca agatt tttac tgaat aaaca aaagt gcctg atttg accac aagct gttgt atgca ataat tcttt gtaac agctg ctctg ccttg tgcaa cttcc cacaa gcaca ccaaa tggtg ttcga caaca tacgt tatta agaaa cattg tcgac gagac ggaac acgtt gaagg gtgtt cgtgt ggttt agtta atatc aatta caatt aaggg ggaaa gttat tttgg gtaac agaac atttg acaag tgctc tggta aacaa tcaat tatag ttaat gttaa ttccc ccttt caata aaacc cattg tcttg taaac tgttc acgag accat ttgtt last update: 29.08.2004 t (3) | agcat tgtca aattg ctaaa ttatg aacac tttgc taaaa ctttt tctgt ttttt ctgtg ctgac ttttt taaaa tcgta acagt ttaac gattt aatac ttgtg aaacg atttt gaaaa agaca aaaaa gacac gactg aaaaa atttt

654 660 675 690 705 GGT GTA AAC TGT GAA TTG GAA ATT GAC GAA TGT TGG TCC CAG CCT TGT TTA AAT GGT GCA ACT TGT CCA CAT TTG ACA CTT AAC CTT TAA CTG CTT ACA ACC AGG GTC GGA ACA AAT TTA CCA CGT TGA ACA Gly Val Asn Cys Glu Leu Glu Ile Asp Glu Cys Trp Ser Gln Pro Cys Leu Asn Gly Ala Thr Cys G V N C E L E I D E C W S Q P C L N G A T C EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 218 220 225 230 235

G= Trp (2) 720 735 | 765 780 CAG GAT GCT CTG GGG GCC TAT TTC TGC GAC TGT GCC CCT GGA TTC CTG GGG GAT CAC TGT GAA CTC GTC CTA CGA GAC CCC CGG ATA AAG ACG CTG ACA CGG GGA CCT AAG GAC CCC CTA GTG ACA CTT GAG Gln Asp Ala Leu Gly Ala Tyr Phe Cys Asp Cys Ala Pro Gly Phe Leu Gly Asp His Cys Glu Leu Q D A L G A Y F C D C A P G F L G D H C E L EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE E06EEEEEEEEEEEEEEEE 240 245 250 255 260

795 810 825 840 848 AAC ACT GAT GAG TGT GCC AGT CAA CCT TGT CTC CAT GGA GGG CTG TGT GTG GAT GGA GAA AAC AG TTG TGA CTA CTC ACA CGG TCA GTT GGA ACA GAG GTA CCT CCC GAC ACA CAC CTA CCT CTT TTG TC Asn Thr Asp Glu Cys Ala Ser Gln Pro Cys Leu His Gly Gly Leu Cys Val Asp Gly Glu Asn Arg N T D E C A S Q P C L H G G L C V D G E N R EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 265 270 275 280 283 gtaca ttttc tctgg cgttg ggtga ttggc ttaga actcc ctgac catga actat tttac cactc tgttg aattt catgt aaaag agacc gcaac ccact aaccg aatct tgagg gactg gtact tgata aaatg gtgag acaac ttaaa agagc tctca cgttc tcggc ttaaa atttg gggtg taact ttata cttta actga tgaaa acatt cagat ttcac tctcg agagt gcaag agccg aattt taaac cccac attga aatat gaaat tgact acttt tgtaa gtcta aagtg taaaa agggt attct tggag accat ctgtc tcaag aggga agatt ttaca agtca ttctt gtaat agttt agaac atttt tccca taaga acctc tggta gacag agttc tccct tctaa aatgt tcagt aagaa catta tcaaa tcttg tgctt atcct atgga aaatg gccaa ttttt caatt ccatg aaata aagct gttgt agata ggaaa ggtgc aaaaa acgaa tagga tacct tttac cggtt aaaaa gttaa ggtac tttat ttcga caaca tctat ccttt ccacg ttttt cagag ctaga gatta ttata tatgt gtaca taagt ttgta tctat atgtc aagga tataa atcag atgac agcaa gtctc gatct ctaat aatat ataca catgt attca aacat agata tacag ttcct atatt tagtc tactg tcgtt

IVS 3 (+2,114 bp)

atttt attaa gtgct attta gtagc aacat attta gtact tcaga tatgt ggaat actgt gtcta ttctt tatat taaaa taatt cacga taaat catcg ttgta taaat catga agtct ataca cctta tgaca cagat aagaa atata gcata cttaa ttgtc acaat aacct tgtaa tatag gtact atatt caatt tatga atgaa gaaac tgaac taaat cgtat gaatt aacag tgtta ttgga acatt atatc catga tataa gttaa atact tactt ctttg acttg attta agtca tggtt tgcat gaccc tgtac tttaa atttt ttaaa gttaa taaga catta atatg gaaat aaatc atgca tcagt accaa acgta ctggg acatg aaatt taaaa aattt caatt attct gtaat tatac cttta tttag tacgt ttcag tcctg tatag ataat tcccc agagt ttttg aggta gtaag atgat gccat gggtc ttggg ttgat agaca aagtc aggac atatc tatta agggg tctca aaaac tccat cattc tacta cggta cccag aaccc aacta tctgt gttga agaaa cagta taaag atatc tgatc tcaat atgac taaga gttga catga aaatt tcatt tactt tccag caact tcttt gtcat atttc tatag actag agtta tactg attct caact gtact tttaa agtaa atgaa aggtc last update: 29.08.2004 T=Met (3) 849 855 | 870 885 900 A TAT AGC TGT AAC TGC ACG GGT AGT GGA TTC ACA GGG ACA CAC TGT GAG ACC TTG ATG CCT CTT T ATA TCG ACA TTG ACG TGC CCA TCA CCT AAG TGT CCC TGT GTG ACA CTC TGG AAC TAC GGA GAA Arg Tyr Ser Cys Asn Cys Thr Gly Ser Gly Phe Thr Gly Thr His Cys Glu Thr Leu Met Pro Leu R Y S C N C T G S G F T G T H C E T L M P L EEEEEEEEEEEEEEEEEEEEE E07EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE E08EEEEEEEEEEEE 283 285 290 295 300

915 930 945 960 975 TGT TGG TCA AAA CCT TGT CAC AAT AAT GCT ACA TGT GAG GAC AGT GTT GAC AAT TAC ACT TGT CAC ACA ACC AGT TTT GGA ACA GTG TTA TTA CGA TGT ACA CTC CTG TCA CAA CTG TTA ATG TGA ACA GTG Cys Trp Ser Lys Pro Cys His Asn Asn Ala Thr Cys Glu Asp Ser Val Asp Asn Tyr Thr Cys His C W S K P C H N N A T C E D S V D N Y T C H EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 305 310 315 320 325

989 TGC TGG CCT GG tgagt gacaa aatac cttcc accaa ttatt tttca tttgt ttaga ataca catat cgctt ACG ACC GGA CC actca ctgtt ttatg gaagg tggtt aataa aaagt aaaca aatct tatgt gtata gcgaa Cys Trp Pro Gly C W P G EEEEEEEEEEEEEE 330 atagc aaatg aaatg aaaaa ttatt gttgt taaat gtttt aaatc aattt cttct agcta atatt gttta gtttt tatcg tttac tttac ttttt aataa caaca attta caaaa tttag ttaaa gaaga tcgat tataa caaat caaaa attct tcagt gctca cacat attta ctgct atact aaatg ttgtc tgaag taggt tacca agctg cccaa tgatc taaga agtca cgagt gtgta taaat gacga tatga tttac aacag acttc atcca atggt tcgac gggtt actag ataac cctct agagg aatag aaggg aaaaa tcaat ggaaa gatga aattc agcat gatct tcatg gagaa aaatt tattg ggaga tctcc ttatc ttccc ttttt agtta ccttt ctact ttaag tcgta ctaga agtac ctctt tttaa cactg gaaga tgctc ttttc ttcca agatg ttctc ttata tggca ggaat atata gaaat ccatg aaata atgtt gtgac cttct acgag aaaag aaggt tctac aagag aatat accgt cctta tatat cttta ggtac tttat tacaa aaact attag aaact tgtat tctct taggc atttg taaag agtta tattt gttaa tataa taaaa agtta attat tttga taatc tttga acata agaga atccg taaac atttc tcaat ataaa caatt atatt atttt tcaat taata

IVS 4 (+9,076 bp)

ggata tttgc tgact tttca gctat tgaaa tattt ttaaa tacaa attca caaat gagta tttga aaaat tggag cctat aaacg actga aaagt cgata acttt ataaa aattt atgtt taagt gttta ctcat aaact tttta acctc gcttt catta aaatg ttcag gttaa atcca ggtta tcctg acatc taatt ttatt tcaag tctta ttaat caaat cgaaa gtaat tttac aagtc caatt taggt ccaat aggac tgtag attaa aataa agttc agaat aatta gttta ttttc tttaa aattt tttgg tcaaa attat ttaag tgatt ttact gatac tagta cttgt ttcca ctaag cctcc aaaag aaatt ttaaa aaacc agttt taata aattc actaa aatga ctatg atcat gaaca aaggt gattc ggagg tctta ccaga ttccc cttac cagct ccttg agggc aggca catca acttg ctaaa tcaat gccag tatag cagtc agaat ggtct aaggg gaatg gtcga ggaac tcccg tccgt gtagt tgaac gattt agtta cggtc atatc gtcag

g (6) g (2) | |del| (3) aacct ccttt taggc aaatg ctcta taatt caaca ccttt gactt agcag cttct ctgaa ttttc atcat gcagg ttgga ggaaa atccg tttac gagat attaa gttgt ggaaa ctgaa tcgtc gaaga gactt aaaag tagta cgtcc

990 1005 1020 1035 1050 A TAC ACA GGT GCC CAG TGT GAG ATC GAC CTC AAT GAA TGC AAT AGT AAC CCC TGC CAG TCC AAT T ATG TGT CCA CGG GTC ACA CTC TAG CTG GAG TTA CTT ACG TTA TCA TTG GGG ACG GTC AGG TTA last update: 29.08.2004 Gly Tyr Thr Gly Ala Gln Cys Glu Ile Asp Leu Asn Glu Cys Asn Ser Asn Pro Cys Gln Ser Asn G Y T G A Q C E I D L N E C N S N P C Q S N EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE E09EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 330 335 340 345 350

1065 1080 1095 1110 GGG GAA TGT GTG GAG CTG TCC TCA GAG AAA CAA TAT GGA CGC ATC ACT GGA CTG CCT TCT TCT TTC CCC CTT ACA CAC CTC GAC AGG AGT CTC TTT GTT ATA CCT GCG TAG TGA CCT GAC GGA AGA AGA AAG Gly Glu Cys Val Glu Leu Ser Ser Glu Lys Gln Tyr Gly Arg Ile Thr Gly Leu Pro Ser Ser Phe G E C V E L S S E K Q Y G R I T G L P S S F EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 355 360 365 370

A=Tyr (3) 1125 1140 | 1155 1171 AGC TAC CAT GAA GCC TCA GGT TAT GTC TGT ATC TGT CAG CCT GGA TTC ACA G gtgag gccaa ggaga TCG ATG GTA CTT CGG AGT CCA ATA CAG ACA TAG ACA GTC GGA CCT AAG TGT C cactc cggtt cctct Ser Tyr His Glu Ala Ser Gly Tyr Val Cys Ile Cys Gln Pro Gly Phe Thr Glu EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE S Y H E A S G Y V C I C Q P G F T E 375 380 385 390 391

t (2) | tggga tatga cttga ctttc tggta tttta tggca gacca tggct ttaac caaat ggtgt attag cagga agagc accct atact gaact gaaag accat aaaat accgt ctggt accga aattg gttta ccaca taatc gtcct tctcg tgtac tgtgt aaact ctgct gctgt ggtgc aaagg gtccc ccttg tgggc atgaa aagta tcttg tttca cattt acatg acaca tttga gacga cgaca ccacg tttcc caggg ggaac acccg tactt ttcat agaac aaagt gtaaa cagaa ttcct caaat cacga gagaa atatt aaaga gggat aaagg aggaa tgaaa gggat gacat tttta tatgc gtctt aagga gttta gtgct ctctt tataa tttct cccta tttcc tcctt acttt cccta ctgta aaaat atacg tatac tggga actgg agtgc atctc aagtt cttta cgtta cacac agaaa atgtt gaaat tttta tgcta tcaaa atatg accct tgacc tcacg tagag ttcaa gaaat gcaat gtgtg tcttt tacaa cttta aaaat acgat agttt tttga taatg atgtt aaatt ttatg ttatt caaat ttgct agaaa agtta ttgta cttat attta cactg ggaaa aaact attac tacaa tttaa aatac aataa gttta aacga tcttt tcaat aacat gaata taaat gtgac ccttt

IVS 5 (+63,220 bp) gaaaa aagtc tcgaa ataaa taaat tgtat cttac atcag tgcca agagc gatct ttttt cttgt ttttg tttgt ctttt ttcag agctt tattt attta acata gaatg tagtc acggt tctcg ctaga aaaaa gaaca aaaac aaaca atgat attca gtgct gcatg tatat ctgac agtga tagtt ggaat caatc acagt atttg gcaaa ttatt cctag tacta taagt cacga cgtac atata gactg tcact atcaa cctta gttag tgtca taaac cgttt aataa ggatc aggaa gaata caaag cctgc catga ctgca tcttt tttct tcatg acaca ggtgg aatat agaat tgatt ttact tcctt cttat gtttc ggacg gtact gacgt agaaa aaaga agtac tgtgt ccacc ttata tctta actaa aatga tttcc ttatt aagtg tttac atttt actcc attac agtcc taaac ctgag ctatt catgc acttc tgcaa gatta aaagg aataa ttcac aaatg taaaa tgagg taatg tcagg atttg gactc gataa gtacg tgaag acgtt ctaat tacaa gtaaa ttacg tgaaa cttct atttt tgatg tgaat atata taatt ttagc ccttt tttat tattt aacag atgtt cattt aatgc acttt gaaga taaaa actac actta tatat attaa aatcg ggaaa aaata ataaa ttgtc

G=ter (1,2) 1173 1185 1200 | 1215 1230 GA ATC CAC TGC GAA GAA GAC GTC AAT GAA TGT TCT TCA AAC CCT TGC CAA AAT GGT GGT ACT TGT CT TAG GTG ACG CTT CTT CTG CAG TTA CTT ACA AGA AGT TTG GGA ACG GTT TTA CCA CCA TGA ACA Gly Ile His Cys Glu Glu Asp Val Asn Glu Cys Ser Ser Asn Pro Cys Gln Asn Gly Gly Thr Cys G I H C E E D V N E C S S N P C Q N G G T C EEEEEEEEEEEEEEEEEEEEEE E10EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 391 395 400 405 410 last update: 29.08.2004 G=Cys(2) 1245 1260 1275 1290 | GAG AAC TTG CCT GGG AAT TAT ACT TGC CAT TGC CCA TTT GAT AAC CTT TCT AGA ACT TTT TAT GGA CTC TTG AAC GGA CCC TTA ATA TGA ACG GTA ACG GGT AAA CTA TTG GAA AGA TCT TGA AAA ATA CCT Glu Asn Leu Pro Gly Asn Tyr Thr Cys His Cys Pro Phe Asp Asn Leu Ser Arg Thr Phe Tyr Gly E N L P G N Y T C H C P F D N L S R T F Y G EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 415 420 425 430

1305 1320 1335 1350 1365 GGA AGG GAC TGT TCT GAT ATT CTC CTG GGC TGT ACC CAT CAG CAA TGT CTA AAT AAT GGA ACA TGC CCT TCC CTG ACA AGA CTA TAA GAG GAC CCG ACA TGG GTA GTC GTT ACA GAT TTA TTA CCT TGT ACG Gly Arg Asp Cys Ser Asp Ile Leu Leu Gly Cys Thr His Gln Gln Cys Leu Asn Asn Gly Thr Cys G R D C S D I L L G C T H Q Q C L N N G T C EEEEEEEEEEEEEEEEEEEEEEEE E11EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 435 440 445 450 455

G=Leu (3) T=Thr (3) 1380 1395 | 1425 | ATC CCT CAC TTC CAA GAT GGC CAG CAT GGA TTC AGC TGC CTA TGT CCA TCT GGC TAC ACC GGG TCC TAG GGA GTG AAG GTT CTA CCG GTC GTA CCT AAG TCG ACG GAT ACA GGT AGA CCG ATG TGG CCC AGG Ile Pro His Phe Gln Asp Gly Gln His Gly Phe Ser Cys Leu Cys Pro Ser Gly Tyr Thr Gly Ser I P H F Q D G Q H G F S C L C P S G Y T G S EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 460 465 470 475

C=Arg (3) |A=Gly (3) | 1455 1470 1485 1500 CTG TGT GAA ATC GCA ACC ACA CTT TCA TTT GAG GGC GAT GGC TTC CTG TGG GTC AAA AGT GGC TCA GAC ACA CTT TAG CGT TGG TGT GAA AGT AAA CTC CCG CTA CCG AAG GAC ACC CAG TTT TCA CCG AGT Leu Cys Glu Ile Ala Thr Thr Leu Ser Phe Glu Gly Asp Gly Phe Leu Trp Val Lys Ser Gly Ser L C E I A T T L S F E G D G F L W V K S G S EEEEEEEEEEEEEEE L01LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 480 485 490 495 500

1515 1530 1545 1560 GTG ACA ACC AAG GGC TCA GTT TGT AAC ATA GCC CTC AGG TTT CAG ACT GTT CAG CCA ATG GCT CTT CAC TGT TGG TTC CCG AGT CAA ACA TTG TAT CGG GAG TCC AAA GTC TGA CAA GTC GGT TAC CGA GAA Val Thr Thr Lys Gly Ser Val Cys Asn Ile Ala Leu Arg Phe Gln Thr Val Gln Pro Met Ala Leu V T T K G S V C N I A L R F Q T V Q P M A L LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 505 510 515 520

1575 1590 1605 1620 CTA CTT TTC CGA AGC AAC AGG GAT GTG TTT GTG AAG CTG GAG CTG CTA AGT GGC TAC ATT CAC TTA GAT GAA AAG GCT TCG TTG TCC CTA CAC AAA CAC TTC GAC CTC GAC GAT TCA CCG ATG TAA GTG AAT Leu Leu Phe Arg Ser Asn Arg Asp Val Phe Val Lys Leu Glu Leu Leu Ser Gly Tyr Ile His Leu L L F R S N R D V F V K L E L L S G Y I H L LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 525 530 535 540

C=Asn (3) 1635 |1650 1665 1680 1695 TCA ATT CAG GTC AAT AAT CAG TCA AAG GTG CTT CTG TTC ATT TCC CAC AAC ACC AGC GAT GGA GAG AGT TAA GTC CAG TTA TTA GTC AGT TTC CAC GAA GAC AAG TAA AGG GTG TTG TGG TCG CTA CCT CTC Ser Ile Gln Val Asn Asn Gln Ser Lys Val Leu Leu Phe Ile Ser His Asn Thr Ser Asp Gly Glu S I Q V N N Q S K V L L F I S H N T S D G E LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 545 550 555 560 565

T=Tyr (7) 1710 1725 1740 | 1755 TGG CAT TTC GTG GAG GTA ATA TTT GCA GAG GCT GTG ACC CTT ACC TTA ATC GAC GAC TCC TGT AAG ACC GTA AAG CAC CTC CAT TAT AAA CGT CTC CGA CAC TGG GAA TGG AAT TAG CTG CTG AGG ACA TTC Trp His Phe Val Glu Val Ile Phe Ala Glu Ala Val Thr Leu Thr Leu Ile Asp Asp Ser Cys Lys W H F V E V I F A E A V T L T L I D D S C K last update: 29.08.2004 LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 570 575 580 585

1770 1785 1800 1815 1830 GAG AAA TGC ATC GCG AAA GCT CCT ACT CCA CTT GAA AGT GAT CAA TCA ATA TGT GCT TTT CAG AAC CTC TTT ACG TAG CGC TTT CGA GGA TGA GGT GAA CTT TCA CTA GTT AGT TAT ACA CGA AAA GTC TTG Glu Lys Cys Ile Ala Lys Ala Pro Thr Pro Leu Glu Ser Asp Gln Ser Ile Cys Ala Phe Gln Asn E K C I A K A P T P L E S D Q S I C A F Q N LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 590 595 600 605 610

1845 1860 1875 1890 TCC TTT TTG GGT GGT TTA CCA GTG GGA ATG ACC AGC AAT GGT GTT GCT CTG CTT AAC TTC TAT AAT AGG AAA AAC CCA CCA AAT GGT CAC CCT TAC TGG TCG TTA CCA CAA CGA GAC GAA TTG AAG ATA TTA Ser Phe Leu Gly Gly Leu Pro Val Gly Met Thr Ser Asn Gly Val Ala Leu Leu Asn Phe Tyr Asn S F L G G L P V G M T S N G V A L L N F Y N LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 615 620 625 630

1905 1920 1935 1950 ATG CCA TCC ACA CCT TCG TTT GTA GGC TGT CTC CAA GAC ATT AAA ATT GAT TGG AAT CAC ATT ACC TAC GGT AGG TGT GGA AGC AAA CAT CCG ACA GAG GTT CTG TAA TTT TAA CTA ACC TTA GTG TAA TGG Met Pro Ser Thr Pro Ser Phe Val Gly Cys Leu Gln Asp Ile Lys Ile Asp Trp Asn His Ile Thr M P S T P S F V G C L Q D I K I D W N H I T LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 635 640 645 650

1965 1980 1995 2010 2025 CTG GAG AAC ATC TCG TCT GGC TCA TCA TTA AAT GTC AAG GCA GGC TGT GTG AGA AAG GAT TGG TGT GAC CTC TTG TAG AGC AGA CCG AGT AGT AAT TTA CAG TTC CGT CCG ACA CAC TCT TTC CTA ACC ACA Leu Glu Asn Ile Ser Ser Gly Ser Ser Leu Asn Val Lys Ala Gly Cys Val Arg Lys Asp Trp Cys L E N I S S G S S L N V K A G C V R K D W C LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL E12EEEEEEEEEEEEEEEE 655 660 665 670 675

G=Glu (6)A=Tyr (3) | 2040 | 2055 2070 2085 GAA AGC CAA CCT TGT CAA AGC AGA GGA CGC TGC ATC AAC TTG TGG CTG AGT TAC CAG TGT GAC TGC CTT TCG GTT GGA ACA GTT TCG TCT CCT GCG ACG TAG TTG AAC ACC GAC TCA ATG GTC ACA CTG ACG Glu Ser Gln Pro Cys Gln Ser Arg Gly Arg Cys Ile Asn Leu Trp Leu Ser Tyr Gln Cys Asp Cys E S Q P C Q S R G R C I N L W L S Y Q C D C EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 680 685 690 695

C=Glu (7) 2100 2115 2128| CAC AGG CCC TAT GAA GGC CCC AAC TGT CTG AGA G gagca gaaac agcaa aaaca gccag actgc ttctg GTG TCC GGG ATA CTT CCG GGG TTG ACA GAC TCT C ctcgt ctttg tcgtt tttgt cggtc tgacg aagac His Arg Pro Tyr Glu Gly Pro Asn Cys Leu Arg Glu H R P Y E G P N C L R E EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE L 700 705 710 cctgc tatga aacat aatga cccca caaga cttct gctgc tggtt gccca ctgat gagaa agaaa agaag agggc ggacg atact ttgta ttact ggggt gttct gaaga cgacg accaa cgggt gacta ctctt tcttt tcttc tcccg agtga tgtgc gttaa ttaat tttga gtgga ttcat aggac atcag tttca ctcat acaga gaagt aaaaa aaata tcact acacg caatt aatta aaact cacct aagta tcctg tagtc aaagt gagta tgtct cttca ttttt tttat agcag atagc tcttt tccaa agagg ttttc atctt tgtgt ttgca aaatg ctact gcaat tttac cattg gtcac tcgtc tatcg agaaa aggtt tctcc aaaag tagaa acaca aacgt tttac gatga cgtta aaatg gtaac cagtg atatc agaaa tttat tgtaa atctt atttg aaaga gaaat aatct tttga aaaaa aaaaa cctta gacat aaaat tatag tcttt aaata acatt tagaa taaac tttct cttta ttaga aaact ttttt ttttt ggaat ctgta tttta ttgtc agtgc cacat actag catga tatct tgtgc atagt aaatt ctcgg taaat attca tttcc ttgct ctcct aacag tcacg gtgta tgatc gtact ataga acacg tatca tttaa gagcc attta taagt aaagg aacga gagga last update: 29.08.2004

IVS 6 (+ 4,694 bp) cacca ggttg gagta tagta gtgtc tgata tacca ccatt aaggc ccata tttta gggca gcaaa gggga gattc gtggt ccaac ctcat atcat cacag actat atggt ggtaa ttccg ggtat aaaat cccgt cgttt cccct ctaag tttag tttat cagtg cagag atctt tttgg tctgt tttgt gatca atatg cctga agtgt aaact acaaa ccaaa aaatc aaata gtcac gtctc tagaa aaacc agaca aaaca ctagt tatac ggact tcaca tttga tgttt ggttt atata gttat tttag ggtta aagta aactc agaag tccag aaaga ggcca aatca ttatt ctatt taata aacct tatat caata aaatc ccaat ttcat ttgag tcttc aggtc tttct ccggt ttagt aataa gataa attat ttgga gtcct gaact ttaaa agcta tgtat gagtg tgtat gcttg tgtgc atgtg tgtgt gtgaa atgta taatt ttcgt cagga cttga aattt tcgat acata ctcac acata cgaac acacg tacac acaca cactt tacat attaa aagca

t (3) | cttcc atccc ttctg tcttt tgagc cttaa gatgt ttctt ttttt ttctc ctcct cctct atttt gacat tgaag gaagg taggg aagac agaaa actcg gaatt ctaca aagaa aaaaa aagag gagga ggaga taaaa ctgta acttc

ins AluY(1) 2145 2160 2175 | 2190 AG TAT GTG GCA GGC AGA TTT GGC CAG GAT GAC TCC ACT GGT TAT GTC ATC TTT ACT CTT GAT GAG TC ATA CAC CGT CCG TCT AAA CCG GTC CTA CTG AGG TGA CCA ATA CAG TAG AAA TGA GAA CTA CTC Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp Ser Thr Gly Tyr Val Ile Phe Thr Leu Asp Glu E Y V A G R F G Q D D S T G Y V I F T L D E L02LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 710 715 720 725 730

C=Thr (7) T=Met (1,7) del (6) 2205 2220 | | |--| 2250 AGC TAT GGA GAC ACC ATC AGC CTC TCC ATG TTT GTC CGA ACG CTT CAA CCA TCA GGC TTA CTT CTA TCG ATA CCT CTG TGG TAG TCG GAG AGG TAC AAA CAG GCT TGC GAA GTT GGT AGT CCG AAT GAA GAT Ser Tyr Gly Asp Thr Ile Ser Leu Ser Met Phe Val Arg Thr Leu Gln Pro Ser Gly Leu Leu Leu S Y G D T I S L S M F V R T L Q P S G L L L LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 735 740 745 750

A=His (6) T=Cys (1,3,5,7) AG=Glu (3) 2265 2280 | 2295 ||2310 2325 GCT TTG GAA AAC AGC ACT TAT CAA TAT ATC CGT GTC TGG CTA GAG CGC GGC AGA CTA GCA ATG CTG CGA AAC CTT TTG TCG TGA ATA GTT ATA TAG GCA CAG ACC GAT CTC GCG CCG TCT GAT CGT TAC GAC Ala Leu Glu Asn Ser Thr Tyr Gln Tyr Ile CGT Val Trp Leu Glu Arg Gly Arg Leu Ala Met Leu A L E N S T Y Q Y I R V W L E R G R L A M L LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 755 760 765 770 775

2340 2355 2370 2385 ACT CCA AAC TCT CCC AAA TTA GTA GTA AAA TTT GTT CTT AAT GAT GGA AAT GTC CAC TTG ATA TCT TGA GGT TTG AGA GGG TTT AAT CAT CAT TTT AAA CAA GAA TTA CTA CCT TTA CAG GTG AAC TAT AGA Thr Pro Asn Ser Pro Lys Leu Val Val Lys Phe Val Leu Asn Asp Gly Asn Val His Leu Ile Ser T P N S P K L V V K F V L N D G N V H L I S LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 780 785 790 795

T=ter (2) ins >100 bp (poly A)(3) 2400 | 2415 2430 | 2445 TTG AAA ATC AAG CCA TAT AAA ATT GAA CTG TAT CAG TCT TCA CAA AAC CTA GGA TTT ATT TCT GCT AAC TTT TAG TTC GGT ATA TTT TAA CTT GAC ATA GTC AGA AGT GTT TTG GAT CCT AAA TAA AGA CGA Leu Lys Ile Lys Pro Tyr Lys Ile Glu Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe Ile Ser Ala L K I K P Y K I E L Y Q S S Q N L G F I S A LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 800 805 810 815 last update: 29.08.2004 T=ter (7) C=His (2) 2460 2475 | 2490 2505 | 2520 TCT ACG TGG AAA ATC GAA AAG GGA GAT GTC ATC TAC ATT GGT GGC CTA CCT GAC AAG CAA GAG ACT AGA TGC ACC TTT TAG CTT TTC CCT CTA CAG TAG ATG TAA CCA CCG GAT GGA CTG TTC GTT CTC TGA Ser Thr Trp Lys Ile Glu Lys Gly Asp Val Ile Tyr Ile Gly Gly Leu Pro Asp Lys Gln Glu Thr S T W K I E K G D V I Y I G G L P D K Q E T LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 820 825 830 835 840

del (3) C=Thr (7) 2535 |---| | 2565 2580 GAA CTT AAT GGT GGA TTC TTC AAA GGC TGT ATC CAA GAT GTA AGA CTA AAC AAC CAA AAT CTG GAA CTT GAA TTA CCA CCT AAG AAG TTT CCG ACA TAG GTT CTA CAT TCT GAT TTG TTG GTT TTA GAC CTT Glu Leu Asn Gly Gly Phe Phe Lys Gly Cys Ile Gln Asp Val Arg Leu Asn Asn Gln Asn Leu Glu E L N G G F F K G C I Q D V R L N N Q N L E LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 845 850 855 860

insT (3) 2595 2610 | 2625 2640 2655 TTC TTT CCA AAT CCA ACA AAC AAT GCA TCT CTC AAT CCA GTT CTT GTC AAT GTA ACC CAA GGC TGT AAG AAA GGT TTA GGT TGT TTG TTA CGT AGA GAG TTA GGT CAA GAA CAG TTA CAT TGG GTT CCG ACA Phe Phe Pro Asn Pro Thr Asn Asn Ala Ser Leu Asn Pro Val Leu Val Asn Val Thr Gln Gly Cys F F P N P T N N A S L N P V L V N V T Q G C LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 865 870 875 880 885

G=Gly (6) 2670 | 2676 GCT GGA GAC AAC AGC TGC AAG gtaat gatta ctcat acaaa ctagg tatat actgt atgct aaact tttac CGA CCT CTG TTG TCG ACG TTC catta ctaat gagta tgttt gatcc atata tgaca tacga tttga aaatg Ala Gly Asp Asn Ser Cys Lys A G D N S C K LLL E13EEEEEEEEEEEEEEEEEEEE 890 892 tttat taaaa agata actta ttaaa accat tcttt gtata taaag atgat gttac tgacc cacca gtata gaata aaata atttt tctat tgaat aattt tggta agaaa catat atttc tacta caatg actgg gtggt catat cttat atatt tcatc tatat tgttc caaca agact gtgaa attta cattg agcca tagaa atgag gcctt gatct tactg tataa agtag atata acaag gttgt tctga cactt taaat gtaac tcggt atctt tactc cggaa ctaga atgac gtatc aggat ctatt taact aacca aagta acttc ggcta taggc ttctc tcacc ctcac agcaa tcaaa ttact catag tccta gataa attga ttggt ttcat tgaag ccgat atccg aagag agtgg gagtg tcgtt agttt aatga taggt ataat aatat ttcaa ttcct aaact cctaa tggca cacca gaggt ttaac tgaat taact ctttt tggat atcca tatta ttata aagtt aagga tttga ggatt accgt gtggt ctcca aattg actta attga gaaaa accta gatat tgtta acttt atttt aaatg cccaa ctact attgt tttga acttt tatta agtca gaaac aacaa gagaa ctata acaat tgaaa taaaa tttac gggtt gatga taaca aaact tgaaa ataat tcagt ctttg ttgtt ctctt

IVS 7 (+647 bp) gaaac acctt ctttt tatca tctat aaaac cagga gtaag aatcc cttcc tcaaa tgata attag tgcat gtgaa ctttg tggaa gaaaa atagt agata ttttg gtcct cattc ttagg gaagg agttt actat taatc acgta cactt aaagt gcctg gtaat ttgta aatta cagag gacac tgcta tactt gaaaa accct ccttg tgcta tggat caatt tttca cggac catta aacat ttaat gtctc ctgtg acgat atgaa ctttt tggga ggaac acgat accta gttaa ttata tcttt tctct ctctc tgcca ccact ctgcc ctttt agaaa ggagt tggta atggc agtag tcatt tttat aatat agaaa agaga gagag acggt ggtga gacgg gaaaa tcttt cctca accat taccg tcatc agtaa aaata tctat ttagt taaca atgga tctta aaagt ttaaa atgta aagat gcagg gaaat tagca tttta aaaaa acaga agata aatca attgt tacct agaat tttca aattt tacat ttcta cgtcc cttta atcgt aaaat ttttt tgtct last update: 29.08.2004 tatgt ggttt caccg tcaac atttt tctat ttagt tgcca gtgct tttta tacct ttgat ttctt ttctg ctcag ataca ccaaa gtggc agttg taaaa agata aatca acggt cacga aaaat atgga aacta aagaa aagac gagtc

G=Ser (2) | A=ter (7) 2679 | 2685 | 2700 2715 2730 TCC AAC CCC TGT CAC AAT GGA GGT GTT TGC CAT TCC CGG TGG GAT GAC TTC TCC TGT TCC TGT CCT AGG TTG GGG ACA GTG TTA CCT CCA CAA ACG GTA AGG GCC ACC CTA CTG AAG AGG ACA AGG ACA GGA Ser Asn Pro Cys His Asn Gly Gly Val Cys His Ser Arg Trp Asp Asp Phe Ser Cys Ser Cys Pro S N P C H N G G V C H S R W D D F S C S C P EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 893 895 900 905 910

2745 2760 2775 2790 2805 GCC CTC ACA AGT GGG AAA GCC TGT GAG GAG GTT CAG TGG TGT GGA TTC AGC CCG TGT CCT CAC GGA CGG GAG TGT TCA CCC TTT CGG ACA CTC CTC CAA GTC ACC ACA CCT AAG TCG GGC ACA GGA GTG CCT Ala Leu Thr Ser Gly Lys Ala Cys Glu Glu Val Gln Trp Cys Gly Phe Ser Pro Cys Pro His Gly A L T S G K A C E E V Q W C G F S P C P H G EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE E14EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 915 920 925 930 935

A=Tyr(1-3,6,7) A=Pro (3) | a (2) 2820 | 2835 |2845 | GCC CAG TGC CAG CCG GTG CTT CAA GGA TTT GAA TGT A ggtag agttc aaacc tacca tctca ccagt CGG GTC ACG GTC GGC CAC GAA GTT CCT AAA CTT ACA T ccatc tcaag tttgg atggt agagt ggtca Ala Gln Cys Gln Pro Val Leu Gln Gly Phe Glu Cys Ile A Q C Q P V L Q G F E C I EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 940 945 949 taagt tgcga cattt gagtt gttcc aagag caaac acaga aaaag agtat agaca aagcc agttt attaa attaa attca acgct gtaaa ctcaa caagg ttctc gtttg tgtct ttttc tcata tctgt ttcgg tcaaa taatt taatt tctat ggttg tttcc cctat gcgag taggc taata ctgac tggcc tcttg cctca tcctg ccctt ggtgg ctgtc agata ccaac aaagg ggata cgctc atccg attat gactg accgg agaac ggagt aggac gggaa ccacc gacag tggat aggaa atgga ggtca cagca acact aaacc tagat gctta atcat ttaaa actga tttcc tgaaa aagaa accta tcctt tacct ccagt gtcgt tgtga tttgg atcta cgaat tagta aattt tgact aaagg acttt ttctt ttaac aaggc aatat ttgaa tttcc ttccc tcatt actgg gaaca cagaa taaat atgtg catgt tacgc attgc aattg ttccg ttata aactt aaagg aaggg agtaa tgacc cttgt gtctt attta tacac gtaca atgcg taacg cattt attaa ctatg aggcc tcagg caatt catgt gatct ccatc atcta aagct tcctc acctg taaaa taggg gtaaa taatt gatac tccgg agtcc gttaa gtaca ctaga ggtag tagat ttcga aggag tggac atttt atccc

IVS 8 (+ 4,311 bp) agcaa atgca aaata aaaat tggca tgcat tagga tttca ctgga aaaga aatgt atagt tttgg ttttg ctatc tcgtt tacgt tttat tttta accgt acgta atcct aaagt gacct tttct ttaca tatca aaacc aaaac gatag agacc atccc agttt gatat tctgg ctttg ttatt tatta attac atgac catga acaaa attac ttaaa ttctg tctgg taggg tcaaa ctata agacc gaaac aataa ataat taatg tactg gtact tgttt taatg aattt aagac tgagt ctcaa cttct tcttc cataa aatgg ggata ataat aatac ctgta ttcaa aagtt tgata ttaga aataa actca gagtt gaaga agaag gtatt ttacc cctat tatta ttatg gacat aagtt ttcaa actat aatct ttatt tataa aagca actag cacag tatgt aacat gtatc aaata gtcaa tatgc aatgt tatta acaca atgat catta atatt ttcgt tgatc gtgtc ataca ttgta catag tttat cagtt atacg ttaca ataat tgtgt tacta gtaat ctatt aataa cggta attaa gcaaa ctata gattt aataa agtta ttgat tatta tcacc ttctc tcatt aggta gataa ttatt gccat taatt cgttt gatat ctaaa ttatt tcaat aacta ataat agtgg aagag agtaa tccat

insT (7) del (6) 2850 | 2865 2880 |--| 2895 2910 last update: 29.08.2004 TT GCA AAT GCT GTT TTT AAT GGA CAA AGC GGT CAA ATA TTA TTC AGA AGC AAT GGG AAT ATT ACC AA CGT TTA CGA CAA AAA TTA CCT GTT TCG CCA GTT TAT AAT AAG TCT TCG TTA CCC TTA TAA TGG Ile Ala Asn Ala Val Phe Asn Gly Gln Ser Gly Gln Ile Leu Phe Arg Ser Asn Gly Asn Ile Thr I A N A V F N G Q S G Q I L F R S N G N I T EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 949 950 955 960 965 970

2925 2940 2955 2970 AGA GAA CTC ACC AAT ATC ACA TTT GGT TTC AGA ACA AGG GAT GCA AAT GTA ATA ATA TTG CAT GCA TCT CTT GAG TGG TTA TAG TGT AAA CCA AAG TCT TGT TCC CTA CGT TTA CAT TAT TAT AAC GTA CGT Arg Glu Leu Thr Asn Ile Thr Phe Gly Phe Arg Thr Arg Asp Ala Asn Val Ile Ile Leu His Ala R E L T N I T F G F R T R D A N V I I L H A EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE L03LLLLLLLL 975 980 985 990

T=ter (1) | 3000 3015 3030 GAA AAA GAG CCT GAA TTT CTT AAT ATT AGC ATT CAA GAT TCC AGA TTA TTC TTT CAA TTG CAA AGT CTT TTT CTC GGA CTT AAA GAA TTA TAA TCG TAA GTT CTA AGG TCT AAT AAG AAA GTT AAC GTT TCA Glu Lys Glu Pro Glu Phe Leu Asn Ile Ser Ile Gln Asp Ser Arg Leu Phe Phe Gln Leu Gln Ser E K E P E F L N I S I Q D S R L F F Q L Q S LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 995 1000 1005 1010

T=Ile (7) 3045 3060 | 3090 3105 GGC AAC AGC TTT TAT ATG CTA AGT CTG ACA AGT TTG CAG TCA GTG AAT GAT GGC ACA TGG CAC GAA CCG TTG TCG AAA ATA TAC GAT TCA GAC TGT TCA AAC GTC AGT CAC TTA CTA CCG TGT ACC GTG CTT Gly Asn Ser Phe Tyr Met Leu Ser Leu Thr Ser Leu Gln Ser Val Asn Asp Gly Thr Trp His Glu G N S F Y M L S L T S L Q S V N D G T W H E LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 1015 1020 1025 1030 1035

C=Thr (1) (3) T=Asn 3120 | 3135 3150 3165 | GTG ACC CTT TCC ATG ACA GAC CCA CTG TCC CAG ACC TCC AGG TGG CAA ATG GAA GTG GAC AAC GAA CAC TGG GAA AGG TAC TGT CTG GGT GAC AGG GTC TGG AGG TCC ACC GTT TAC CTT CAC CTG TTG CTT Val Thr Leu Ser Met Thr Asp Pro Leu Ser Gln Thr Ser Arg Trp Gln Met Glu Val Asp Asn Glu V T L S M T D P L S Q T S R W Q M E V D N E LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 1040 1045 1050 1055

C=Pro (1) 3180 3195 3210 | 3225 3240 ACA CCT TTT GTG ACC AGC ACA ATT GCT ACT GGA AGC CTC AAC TTT TTG AAG GAT AAT ACA GAT ATT TGT GGA AAA CAC TGG TCG TGT TAA CGA TGA CCT TCG GAG TTG AAA AAC TTC CTA TTA TGT CTA TAA Thr Pro Phe Val Thr Ser Thr Ile Ala Thr Gly Ser Leu Asn Phe Leu Lys Asp Asn Thr Asp Ile T P F V T S T I A T G S L N F L K D N T D I LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 1060 1065 1070 1075 1080

C=Thr (6) G=Arg (2) 3255 3270 3285 | TAT GTG GGA GAC AGA GCT ATT GAC AAT ATA AAG GGC CTG CAA GGG TGT CTA AGT ACA ATA GAA ATC ATA CAC CCT CTG TCT CGA TAA CTG TTA TAT TTC CCG GAC GTT CCC ACA GAT TCA TGT TAT CTT TAG Tyr Val Gly Asp Arg Ala Ile Asp Asn Ile Lys Gly Leu Gln Gly Cys Leu Ser Thr Ile Glu Ile Y V G D R A I D N I K G L Q G C L S T I E I LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL 1085 1090 1095 1100

|-- del (5)-| A=Arg (7) G=Arg (7) T=ter (2) | del (7) | | 3315 | 3330 | | | | 3360 GGA GGC ATT TAT CTC TCT TAC TTT GAA AAT GTT CAT GGT TTC ATT AAT AAA CCT CAG GAA GAG CAA CCT CCG TAA ATA GAG AGA ATG AAA CTT TTA CAA GTA CCA AAG TAA TTA TTT GGA GTC CTT CTC GTT Gly Gly Ile Tyr Leu Ser Tyr Phe Glu Asn Val His Gly Phe Ile Asn Lys Pro Gln Glu Glu Gln last update: 29.08.2004 G G I Y L S Y F E N V H G F I N K P Q E E Q LLLLLLL E15EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 1105 1110 1115 1120

3375 3390 3405 3420 3435 TTT CTC AAA ATC TCT ACC AAT TCA GTG GTC ACT GGC TGT TTG CAG TTA AAT GTC TGC AAC TCC AAC AAA GAG TTT TAG AGA TGG TTA AGT CAC CAG TGA CCG ACA AAC GTC AAT TTA CAG ACG TTG AGG TTG Phe Leu Lys Ile Ser Thr Asn Ser Val Val Thr Gly Cys Leu Gln Leu Asn Val Cys Asn Ser Asn F L K I S T N S V V T G C L Q L N V C N S N EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 1125 1130 1135 1140 1145

3450 3465 3480 3495 CCC TGT TTG CAT GGA GGA AAC TGT GAA GAC ATC TAT AGC TCT TAT CAT TGC TCC TGT CCC TTG GGA GGG ACA AAC GTA CCT CCT TTG ACA CTT CTG TAG ATA TCG AGA ATA GTA ACG AGG ACA GGG AAC CCT Pro Cys Leu His Gly Gly Asn Cys Glu Asp Ile Tyr Ser Ser Tyr His Cys Ser Cys Pro Leu Gly P C L H G G N C E D I Y S S Y H C S C P L G EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 1150 1155 1160 1165

C=Arg (2) 3510 3525 3540 | 3555 3570 TGG TCA GGG AAA CAC TGT GAA CTC AAC ATC GAT GAA TGC TTT TCA AAC CCC TGT ATC CAT GGC AAC ACC AGT CCC TTT GTG ACA CTT GAG TTG TAG CTA CTT ACG AAA AGT TTG GGG ACA TAG GTA CCG TTG Trp Ser Gly Lys His Cys Glu Leu Asn Ile Asp Glu Cys Phe Ser Asn Pro Cys Ile His Gly Asn W S G K H C E L N I D E C F S N P C I H G N EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE E16EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 1170 1175 1180 1185 1190

A=Arg (3) 3585 3600 | 3630 TGC TCT GAC AGA GTT GCA GCC TAC CAC TGC ACA TGT GAG CCT GGA TAC ACT GGT GTG AAC TGT GAA ACG AGA CTG TCT CAA CGT CGG ATG GTG ACG TGT ACA CTC GGA CCT ATG TGA CCA CAC TTG ACA CTT Cys Ser Asp Arg Val Ala Ala Tyr His Cys Thr Cys Glu Pro Gly Tyr Thr Gly Val Asn Cys Glu C S D R V A A Y H C T C E P G Y T G V N C E EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 1195 1200 1205 1210

3645 3660 3675 3690 GTG GAT ATA GAC AAC TGC CAG AGT CAC CAG TGT GCA AAT GGA GCC ACC TGC ATT AGT CAT ACT AAT CAC CTA TAT CTG TTG ACG GTC TCA GTG GTC ACA CGT TTA CCT CGG TGG ACG TAA TCA GTA TGA TTA Val Asp Ile Asp Asn Cys Gln Ser His Gln Cys Ala Asn Gly Ala Thr Cys Ile Ser His Thr Asn V D I D N C Q S H Q C A N G A T C I S H T N EEE E17EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 1215 1220 1225 1230

3705 3720 3735 3749 GGC TAT TCT TGC CTC TGT TTT GGA AAT TTT ACA GGA AAA TTT TGC AG gtgag cataa agtcc atatg CCG ATA AGA ACG GAG ACA AAA CCT TTA AAA TGT CCT TTT AAA ACG TC cactc gtatt tcagg tatac Gly Tyr Ser Cys Leu Cys Phe Gly Asn Phe Thr Gly Lys Phe Cys Arg G Y S C L C F G N F T G K F C R EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 1235 1240 1245 1250 aagct tggtc tttga agcta tactc tgcat cactg ttctt gtcaa attgg aaagc tctct cctca aggta tacat ttcga accag aaact tcgat atgag acgta gtgac aagaa cagtt taacc tttcg agaga ggagt tccat atgta atata ctgtg ctgaa caggg tgaca ctggt agctt ctgtc acaat ttggt catgt tcaga tggga tctca cttac tatat gacac gactt gtccc actgt gacca tcgaa gacag tgtta aacca gtaca agtct accct agagt gaatg cagga tattc tacag gtcag aaagg tagtg tttaa atcag atttt cagca aaata ttttc tcagt catct gtgtg gtcct ataag atgtc cagtc tttcc atcac aaatt tagtc taaaa gtcgt tttat aaaag agtca gtaga cacac aaaat atgtc tcatg aactg tagcc ccagg gtcta acagt ttcaa ggcct cggga aacaa atgca tttac aataa tttta tacag agtac ttgac atcgg ggtcc cagat tgtca aagtt ccgga gccct ttgtt tacgt aaatg ttatt atgca aaagc tgaaa tgtag tattg ttagg gaagg catga cttct attgc taaaa taatg ccttg agcta tttca last update: 29.08.2004 tacgt tttcg acttt acatc ataac aatcc cttcc gtact gaaga taacg atttt attac ggaac tcgat aaagt

IVS 9 (+ 2,164 bp) cctgg ccttt ataga gatgc aattt tccta tggcc tttat tgatt tatta gcaaa gcagc agcaa atcta gttat ggacc ggaaa tatct ctacg ttaaa aggat accgg aaata actaa ataat cgttt cgtcg tcgtt tagat caata agcaa gttct tttcc aaccc aaaat ttatt gccac cccat ggcat agatc ttatc tcaca aacga aaact gtgta tcgtt caaga aaagg ttggg tttta aataa cggtg gggta ccgta tctag aatag agtgt ttgct tttga cacat gaaat ggaag atgta tagcc atgct tgtca cagaa ccctc cagca ggagc ttttt actgg agaaa gtgat tcttg cttta ccttc tacat atcgg tacga acagt gtctt gggag gtcgt cctcg aaaaa tgacc tcttt cacta agaac cataa tgcag cacaa ttaag cattt gtagc tcctc cagcc tgagt actta attag cttgg cattg actac ataca gtatt acgtc gtgtt aattc gtaaa catcg aggag gtcgg actca tgaat taatc gaacc gtaac tgatg tatgt tgaat ttatc agaaa acttt tcttg aatga gatga acaag atgaa cagct gtggc tcttg ctttt atctc tctag actta aatag tcttt tgaaa agaac ttact ctact tgttc tactt gtcga caccg agaac gaaaa tagag agatc

3750 3765 3780 3795 3810 A CAG AGC AGA TTA CCC TCA ACA GTC TGT GGG AAT GAG AAG ACA AAT CTC ACT TGC TAC AAT GGA T GTC TCG TCT AAT GGG AGT TGT CAG ACA CCC TTA CTC TTC TGT TTA GAG TGA ACG ATG TTA CCT Arg Gln Ser Arg Leu Pro Ser Thr Val Cys Gly Asn Glu Lys Thr Asn Leu Thr Cys Tyr Asn Gly R Q S R L P S T V C G N E K T N L T C Y N G EEEEE E18EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 1250 1255 1260 1265 1270

(7) ter=A 3825 3840 3855 3870 | GGC AAC TGC ACA GAG TTC CAG ACT GAA TTA AAA TGT ATG TGC CGG CCA GGT TTT ACT GGA GAA TGG CCG TTG ACG TGT CTC AAG GTC TGA CTT AAT TTT ACA TAC ACG GCC GGT CCA AAA TGA CCT CTT ACC Gly Asn Cys Thr Glu Phe Gln Thr Glu Leu Lys Cys Met Cys Arg Pro Gly Phe Thr Gly Glu Trp G N C T E F Q T E L K C M C R P G F T G E W EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 1275 1280 1285 1290

t (2) 3880| T gagtc acatt agagc cttct ggaag agaat tctga gctaa agaat gatgg gatta ctcaa agttc atttt A ctcag tgtaa tctcg gaaga ccttc tctta agact cgatt tctta ctacc ctaat gagtt tcaag taaaa Cys E C 1294 ctcct ctaat ttttt atctc agttc ccata ggaaa atcta tgctg aaata gaggt tcaga cagaa tgaaa caata gagga gatta aaaaa tagag tcaag ggtat ccttt tagat acgac tttat ctcca agtct gtctt acttt gttat aaaaa gaaga aaaac tacag tttag gtcaa agggg agaac atttt attag acaaa acttc aaata gggaa aaatg ttttt cttct ttttg atgtc aaatc cagtt tcccc tcttg taaaa taatc tgttt tgaag tttat ccctt tttac atttt taaaa aatgt ataat gtgct atttt tcttt cttat aagta cttct gaatt catgt ctctt ttttg ttgct taaaa atttt ttaca tatta cacga taaaa agaaa gaata ttcat gaaga cttaa gtaca gagaa aaaac aacga aactc taata catga tgcaa atatg gttgc tgtcg aggta aaata aatta caact aaaag attgc ctcat agaat ttgag attat gtact acgtt tatac caacg acagc tccat tttat ttaat gttga ttttc taacg gagta tctta tgcct acaac ccaaa agtat atata cctta tccat atgag tctac ttttc ccaga gaaac tcttc aactg ttctt acgga tgttg ggttt tcata tatat ggaat aggta tactc agatg aaaag ggtct ctttg agaag ttgac aagaa

IVS 10 (+2,670 bp) ctct ccttg tgccc ctaat aaact gaaca tttat ataag gtggc aacca cacta atgct cttga gcatt gacac last update: 29.08.2004 gaga ggaac acggg gatta tttga cttgt aaata tattc caccg ttggt gtgat tacga gaact cgtaa ctgtg tggtg taggc atggc ccact tttct cttgg tttct aaata tttgc atcta ttttc tcatt ctaat taatt ccgtg accac atccg taccg ggtga aaaga gaacc aaaga tttat aaacg tagat aaaag agtaa gatta attaa ggcac tgtat atgta tatat atgtg tacag attat ttcca ttaaa cccca aatgt gttaa agaaa tttta agaaa catct acata tacat atata tacac atgtc taata aaggt aattt ggggt ttaca caatt tcttt aaaat tcttt gtaga ccgac attat caagt atgta taaag tatgt gtgga tgggt agata agact gtgct gttcc agaga gataa ggcaa ggctg taata gttca tacat atttc ataca cacct accca tctat tctga cacga caagg tctct ctatt ccgtt acttt ttctt cccat ttcac aacca atgta ttcaa caggg acctg ggttt ctgct gttct gttta ttttg aaggt tgaaa aagaa gggta aagtg ttggt tacat aagtt gtccc tggac ccaaa gacga caaga caaat aaaac ttcca

3882 3900 3915 3930 3945 GT GAA AAG GAC ATT GAT GAG TGT GCC TCT GAT CCG TGT GTC AAT GGA GGT CTG TGC CAG GAC TTA CA CTT TTC CTG TAA CTA CTC ACA CGG AGA CTA GGC ACA CAG TTA CCT CCA GAC ACG GTC CTG AAT Cys Glu Lys Asp Ile Asp Glu Cys Ala Ser Asp Pro Cys Val Asn Gly Gly Leu Cys Gln Asp Leu C E K D I D E C A S D P C V N G G L C Q D L EEEEEEEEEE E19EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 1294 1300 1305 1310 1315

del (7) | A=His (2,3) A=Gly (7) | | A=ter (3) IVS Start C=His (3) A=Ser (5) | | | T=ter (2,3) a (7) | 3960 | 3975 | | | | 4005 | CTC AAC AAA TTC CAG TGC CTC TGT GAT GTT GCC TTT GCT GGC GAG CGC TGC GAG GTG GAC GTA AGC GAG TTG TTT AAG GTC ACG GAG ACA CTA CAA CGG AAA CGA CCG CTC GCG ACG CTC CAC CTG CAT TCG Leu Asn Lys Phe Gln Cys Leu Cys Asp Val Ala Phe Ala Gly Glu Arg Cys Glu Val Asp Val Ser L N K F Q C L C D V A F A G E R C E V D V S EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE 1320 1325 1330 1335

IVS11 (+34921 bp)

4020 4035 4050 4065 AGC CTC TCC TTT TAT GTC TCT CTC TTA TTC TGG CAG AAT CTT TTT CAG CTT CTT TCT TAC CTC ATT TCG GAG AGG AAA ATA CAG AGA GAG AAT AAG ACC GTC TTA GAA AAA GTC GAA GAA AGA ATG GAG TAA Ser Leu Ser Phe Tyr Val Ser Leu Leu Phe Trp Gln Asn Leu Phe Gln Leu Leu Ser Tyr Leu Ile S L S F Y V S L L F W Q N L F Q L L S Y L I 1340 1345 1350 1355

4080 4095 4110 4125 4128 4138 TTG CGT ATG AAT GAC GAG CCA GTT GTT GAG TGG GGT GAA CAG GAA GAT TAT TAA catac atttg aacat AAC GCA TAC TTA CTG CTC GGT CAA CAA CTC ACC CCA CTT GTC CTT CTA ATA ATT gtatg taaac ttgta Leu CGT Met Asn Asp Glu Pro Val Val Glu Trp Gly Glu Gln Glu Asp Tyr ter L R M N D E P V V E W G E Q E D Y X 1360 1365 1370 1376

4148 4158 4168 4178 4188 4198 4208 4218 tccca aatga aaaaa aaagc cattg aattt caaga aatgc cttga ttcat tttag atctc tgggg aagaa aaagg agggt ttact ttttt tttcg gtaac ttaaa gttct ttacg gaact aagta aaatc tagag acccc ttctt tttcc

4228 4238 4248 4258 4268 4278 4288 aaata aaaac catct caata attaa ggtaa attca aggct tattt taaac atatc agaag cactt tgtct gtgta tttat ttttg gtaga gttat taatt ccatt taagt tccga ataaa atttg tatag tcttc gtgaa acaga cacat

4298 4308 4318 4328 4338 4348 4358 4368 taaaa tattt tccta ttcta acttt aaata tgaaa aaagt gttct taata taact agaaa tatct cctta ttgtg atttt ataaa aggat aagat tgaaa tttat acttt tttca caaga attat attga tcttt ataga ggaat aacac

4378 4388 4398 4408 4418 4428 4438 tgtat ttagt acaaa catat tatca ttctc aacac ttcta tatgt gaatg accac tgcaa tttct tccca ctcca acata aatca tgttt gtata atagt aagag ttgtg aagat ataca cttac tggtg acgtt aaaga agggt gaggt

4448 4458 4468 4478 4488 4498 4508 4518 last update: 29.08.2004 tttct gggta ttttc acatt ttaag ttgcc ctcca tcact atgat tctat tttca tttct gttct ttcat tctta aaaga cccat aaaag tgtaa aattc aacgg gaggt agtga tacta agata aaagt aaaga caaga aagta agaat

4528 4538 4548 4458 4568 4578 4588 tctat tattt atgac acaaa aattg agaat tacag gccag gtgtg gtggt tcact cctat aatcc cagca ctatg agata ataaa tactg tgttt ttaac tctta atgtc cggtc cacac cacca agtga ggata ttagg gtcgt gatac

4598 4608 4618 4628 4638 4648 4658 4668 ggagg ctgaa gtggg cggaa cacct gaggc cagga gtttg agacc agcct agcca acgtg gtgaa aacct gtctc cctcc gactt caccc gcctt gtgga ctccg gtcct caaac tctgg tcgga tcggt tgcac cactt ttgga cagag

4678 4688 4698 4708 4728 4738 4748 tacta aaaat acaaa agtaa ctggg agtgg tggca catgc ctgta atccc agcta ctcag gaggg tgaag cagga atgat tttta tgttt tcatt gaccc tcacc accgt gtacg gacat taggg tcgat gagtc ctccc acttc gtcct

IVS 11 (+34180 bp) tttct ttcct ttccc aaagc aacaa aacaa aactg taaaa taacc atttc ttcag tccca aatta gaact tttgg aaaga aagga aaggg tttcg ttgtt ttgtt ttgac atttt attgg taaag aagtc agggt ttaat cttga aaacc caagg gagga aagag atcat gaata atacg tggct ataga tctag aatca tttta taaat ataag tgtgg gctca gttcc ctcct ttctc tagta cttat tatgc accga tatct agatc ttagt aaaat attta tattc acacc cgagt tcttt tgcct ttgtt gctac atgaa tcatc tcagt cactg agatt aagag actga gcaaa tatag taggt atttc agaaa acgga aacaa cgatg tactt agtag agtca gtgac tctaa ttctc tgact cgttt atatc atcca taaag atgcc atatt ttctg actgt agact ttaga ttcta gatat atgat tattt gtaaa tgatt tgaga ataag aaaat tacgg tataa aagac tgaca tctga aatct aagat ctata tacta ataaa cattt actaa actct tattc tttta ctgac tttct tttaa tacct tggtc ttttt acagt actga gtggt accag cttgc tctgg ttggt cttca ttcct gactg aaaga aaatt atgga accag aaaaa tgtca tgact cacca tggtc gaacg agacc aacca gaagt aagga gagta gttcc attgt cctga atatt tattt gcctt tgcta tagaa ttcgc atccc aatga tttca atctt tccag ctcat caagg taaca ggact tataa ataaa cggaa acgat atctt aagcg taggg ttact aaagt tagaa aggtc

G=Thr (2) 4008 4020 4035 4050 | 4065 TTG GCA GAT GAC TTG ATC TCC GAC ATT TTC ACC ACT ATT GGC TCA GTG ACT GTC GCC TTG TTA CTG AAC CGT CTA CTG AAC TAG AGG CTG TAA AAG TGG TGA TAA CCG AGT CAC TGA CAG CGG AAC AAT GAC Leu Ala Asp Asp Leu Ile Ser Asp Ile Phe Thr Thr Ile Gly Ser Val Thr Val Ala Leu Leu Leu L A D D L I S D I F T T I G S V T V A L L L TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT 1336 1340 1345 1350 1355

del (4,7) 4080 4095 4110 |------| ATC CTC TTG CTG GCC ATT GTT GCT TCT GTT GTC ACC TCC AAC AAA AGG GCA ACT CAG GGA ACC TAC TAG GAG AAC GAC CGG TAA CAA CGA AGA CAA CAG TGG AGG TTG TTT TCC CGT TGA GTC CCT TGG ATG Ile Leu Leu Leu Ala Ile Val Ala Ser Val Val Thr Ser Asn Lys Arg Ala Thr Gln Gly Thr Tyr I L L L A I V A S V V T S N K R A T Q G T Y TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC 1360 1365 1370 1375

4140 4155 4170 4185 4120 AGC CCC AGC CGT CAG GAG AAG GAG GGC TCC CGA GTG GAA ATG TGG AAC TTG ATG CCA CCC CCT GCA TCG GGG TCG GCA GTC CTC TTC CTC CCG AGG GCT CAC CTT TAC ACC TTG AAC TAC GGT GGG GGA CGT Ser Pro Ser Arg Gln Glu Lys Glu Gly Ser Arg Val Glu Met Trp Asn Leu Met Pro Pro Pro Ala S P S R Q E K E G S R V E M W N L M P P P A 1380 1385 1390 1395 1400

4135 4138 4148 4158 4168 4178 ATG GAG AGA CTG ATT TAG gagca ttgtg tccct tcgag atggg gatcc acaca ctgtg aatgt gatga ctgta TAC CTC TCT GAC TAA ATC ctcgt aacac aggga agctc taccc ctagg tgtgt gacac ttaca ctact gacat Met Glu Arg Leu Ile ter M E R L I X CCCCCCCCCCCCCCCCCCC 1405 last update: 29.08.2004

4188 4198 4208 4218 4228 4238 4248 4258 cttca ggtat ctctg acata cctga caatg ttaat ctgca actgg gatta cactg gaact acagg aatga ttcct gaagt ccata gagac tgtat ggact gttac aatta gacgt tgacc ctaat gtgac cttga tgtcc ttact aagga

4268 4278 4288 4298 4308 4318 4328 ttgac cacct taaaa acttt cacag tggtt ccgct cgaca ccatt gtttt attat attat atcag ccaat tgcaa aactg gtgga atttt tgaaa gtgtc accaa ggcga gctgt ggtaa caaaa taata taata tagtc ggtta acgtt

4338 4348 4358 4368 4378 4388 4398 4408 aaaaa gtctg tgcca gtaat ttcag cctta taatt agcaa aaaca tcttc cagag aataa agtct tctgt ggctt ttttt cagac acggt catta aagtc ggaat attaa tcgtt tttgt agaag gtctc ttatt tcaga agaca ccgaa

4418 4428 4438 4448 4458 4468 4478 tagtg gctat cactg aaact ctttc ctctt ttcaa cctgg gaaca aattt tagtt ttcat tttag gtttc tgtac atcac cgata gtgac tttga gaaag gagaa aagtt ggacc cttgt ttaaa atcaa aagta aaatc caaag acatg

4488 4498 4508 4518 4528 4538 4548 4558 tttct gtagt ttctg tgtaa actgc catat gttta catgg aaact acagg aaaaa attgg ctaca tttct cactt aaaga catca aagac acatt tgacg gtata caaat gtacc tttga tgtcc ttttt taacc gatgt aaaga gtgaa

4568 4578 4588 4598 4608 4618 4628 ctcct atcat gtggt caaag ttatt gttgt atacc agcga tggga tgtat acttt tgtcc ttcat tcatg gattc gagga tagta cacca gtttc aataa caaca tatgg tcgct accct acata tgaaa acagg aagta agtac ctaag

4638 4648 4658 4668 agaga aagct ctggg aatga cttat ggtcc aaaaa tctct ttcga gaccc ttact gaata ccagg ttttt

175436 bp bis Ende AL136322

(1)=[1] (2)=[2] (3)=[3] (4)=[4] (5)=[5] (6)=[6] (7)=[7]

Literatur

1. den Hollander,A.I., ten Brink,J.B., de Kok,Y.J., van Soest,S., van den Born,L.I., van Driel,M.A., van de Pol,D.J.R., Payne,A.M., Bhattacharya,S.S., Kellner,U., Hoyng,C.B., Westerveld,A., Brunner,H.G., Bleeker Wagemakers,E.M., Deutman,A.F., Heckenlively,J.R., Cremers,F.P.M., Bergen,A.A.B., van de Pol,D.J., Bleeker-Wagemakers,E.M., Heckenlively,J.R., Cremers,F.P., Bergen,A.A. (1999) Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12). Nat.Genet. 23 (2): 217-221.

2. den Hollander,A.I., Heckenlively,J.R., van den Born,L.I., de Kok,Y.J., Velde-Visser,S.D., Kellner,U., Jurklies,B., van Schooneveld,M.J., Blankenagel,A., Rohrschneider,K., Wissinger,B., Cruysberg,J.R., Deutman,A.F., Brunner,H.G., Apfelstedt- Sylla,E., Hoyng,C.B., Cremers,F.P. (2001) Leber Congenital Amaurosis and Retinitis Pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene. Am.J.Hum.Genet. 69 (1): 198-203.

3. Lotery,A.J., Jacobson,S.G., Fishman,G.A., Weleber,R.G., Fulton,A.B., Namperumalsamy,P., Heon,E., Levin,A.V., Grover,S., Rosenow,J.R., Kopp,K.K., Sheffield,V.C., Stone,E.M. (2001) Mutations in the CRB1 gene cause Leber congenital amaurosis. Arch.Ophthalmol. 119 (3): 415-420.

4. Gerber,S., Perrault,I., Hanein,S., Shalev,S., Zlotogora,J., Barbet,F., Ducroq,D., Dufier,J., Munnich,A., Rozet,J., Kaplan,J. (2002) A novel mutation disrupting the cytoplasmic domain of CRB1 in a large consanguineous family of Palestinian origin affected with Leber congenital amaurosis. Ophthalm.Genet. 23 (4): 225-235.

5. Lotery,A.J., Malik,A., Shami,S.A., Sindhi,M. , Chohan,B., Maqbool,C., Moore,P.A., Denton,M.J., Stone,E.M. (2001) CRB1 mutations may result in retinitis pigmentosa without para-arteriolar RPE preservation. Ophthalmic Genet 22 (3): 163-169.

6. Bernal,S., Calaf,M., Garcia-Hoyos,M., Garcia-Sandoval,B., Rosell,J., Adan,A., Ayuso,C., Baiget,M. (2003) Study of the involvement of the RGR, CRPB1, and CRB1 genes in the pathogenesis of autosomal recessive retinitis pigmentosa. J.Med.Genet. 40 (7): e89 last update: 29.08.2004 7. Hanein,S., Perrault,I., Gerber,S., Tanguy,G., Barbet,F., Ducroq,D., Calvas,P., Dollfus,H., Hamel,C., Lopponen,T., Munier,F., Santos,L., Shalev,S., Zafeiriou,D., Dufier,J.L., Munnich,A., Rozet,J.M., Kaplan,J. (2004) Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. Hum Mutat. 23 (4): 306-317.