Mutation Database
Mutations of the RPE65 Gene

Recent update from: 18.02.2007


Phenotype Mutation Basechange Nucleotide Exon Restriction Site Classification
& Remarks
Mutation Database OMIM Reference
Sequence





The sequence data are adjusted to a sequence given in a WORD file which can be downloaded here. Nucleotides are counted from the translation start site since RPE65 does not contain an untranslated first exon.

Patients:



Retinal Degeneration UPD Duplication of maternal allele with loss of paternal allele



Markers used:
  • D1S2667
  • D1S199
  • D1S2697
  • D1S234
  • D1S2803
  • D1S1665
  • D1S488
  • D1S206
  • D1S2726
  • D1S498
  • D1S305
  • D1S2878
  • D1S218
  • D1S413
  • D1S306
  • D1S2785
  • D1S2836


      Patients: 1723


(25)
LCA2, ARRP Met 1 Thr ATG>ACG c.0002 01 +MaeII
Homozygous
Compound:
  • R91W


Patients: 048-040, arRP192
goto HGMD
(15)
(23)
Polymorphism IVS1+34t/a ccttc/ccatc c.0011 IVS 01




Patients:


(20)
LCA2, ARRP IVS1+5g>a gtaag>gtaaa c.0011 IVS 01 +SspI (by ASO)
Homozygous
Compound:
  • G436V
  • 90insT
  • E102X
  • 669delCA
  • T457N/114delA
  • Y368H
Homozygous/UPD

Patients: arRP181
arRP341
arRP697
arRP713
arRP850
LCA821
LCA826
1723
2711
57
goto HGMD
(5)
(16)
(11)
(25)
(20)
(4)
(3)
Polymorphism Phe 16 Phe TTT/TTC c.0048 02




Patients:


(15)
LCA 57delGG GTG GAG>GT_ _AG c.0057 02




Patients:


(2)
LCA Leu 22 Pro CTG>CCG c.0065 02

Heterozygous
Compound
  • H68Y


Patients:
goto HGMD
(14)
(6)
LCA 90insT GTA ACA>GTT AAC A c.0090 02 +MseI
Previously reported as 144insT
Compound:
  • IVS1+5g-a


Patients: arRP341
goto HGMD
(5)
(23)
Microarray Gly 32 Val cacag GC>cacag TC c.0095 03 TaaI+


Patients:


(21)
LCA IVS2-2a>t cacag GC>cactg GC c.0095 IVS 02



Patients:
goto HGMD
(8)
Microarray 106delCTCTGGCTC CCCCTCTGGCTCACC>CCCACC c.0106 03



Patients:
goto HGMD
(21)
LCA Gly 40 Ser GGC>AGC c.0118 03

Compound:
  • H182Y
  • <2% of WT activity


Patients: 048-017
35
goto HGMD
(15)
(20)
(4)
(3)
LCA Arg 44 Gln CGA>CAA c.0131 03

Compound:
  • N321K
  • <2% of WT activity


Patients: 35
goto HGMD
(20)
LCA 136delG GGG>_GG c.0136 03

Previously reported as 187delG
Heterozygous Compound:
  • E102X


Patients:


(11)
(4)
(3)
LCA Gln 64 ter CAA>TAA c.0189 03

Homozygous

Patients:
goto HGMD
(16)
Retinal dystrophy 201delGC insTT CTC CTG CAC>CTC CTT TAC c.0201 03

Heterozygous

Patients:
goto HMGD
(14)
LCA His 68 Tyr CAC>TAC c.0202 03

Heterozygous
Compound:
  • L22P
  • <2% of WT activity


Patients:


(14)
Microarray Phe 70 Val TTT>TGG c.0208 03



Patients:


Polymorphism Val 77 Val GTC/GTA c.0231 03

Heterozygous

Patients:


(20)
ARRP Tyr 79 His TAC>CAC c.0235 03

Compound:
  • E95Q


Patients: arRP76


(23)
ARRP Arg 85 His CGC>CAC c.0254 03 +MslI
Heterozygous

Patients: arRP870


(23)
LCA2, ARRP Arg 91 Trp CGG>TGG c.0271 04 -RsaI
Homozygous
Compound:
  • V452G
  • Y368H


Patients: 048-054, 003-179, arRPL, arRP192, LCA820
goto HMGD 180069-000006 (15)
(23)
Microarray 272insA GTA CGG GCA>GTA CAG GGC A c.0272 04



Patients:


LCA Arg 91 Gln CGG>CAG c.0272 04 +SunI
Homozygous
Heterozygous
Compound:
  • Single
  • IVS7+4a-g


Patients: 1024
91
goto HGMD

(23)
(20)
(4)
(3)
Microarray Arg 91 Pro CGG>CCG c.0272 04



Patients:


ARRP Glu 95 Gln GAG>CAG c.0283 04 +HinfI
Compound:
  • Y79H


Patients: arRP76


(23)
LCA 290del20bp AAA AGG ATC GTC ATA ACA GAA TTT GGC>AAA A__ ___ ___ ___ ___ ___ ___ GGC c.0290 04

Previously reported as 344del20bp
Homozygous

Patients: 1348
goto HGMD
(11)
(17)
(23)
LCA2, ARRP Glu 102 Lys GAA>AAA c.0304 04 -ApoI
Homozygous
Compound:
  • IVS1+5g-a
  • 136delG


Patients: 048-011, arRP849, arRP697
goto HMGD
(2)
(15)
(23)
(4)
(3)
LCA2, ARRP Glu 102 ter GAA>TAA c.0304 04 -ApoI
Homozygous
modified by RetGC1 I539V

Patients:
goto HMGD
(19)
Microarray Gly 104 Val GGC>GTC c.0311 04



Patients:


LCA IVS4+1g>t AG gtt>AG ttt c.0353 IVS 04




Patients:


(2)
LCA Arg 124 ter CGA>TGA c.0370 05 -TaqI
Compound:
  • R234X
  • 962insA


Patients: arRP114
goto HGMD
(23)
(4)
(3)
ARRP Ala 132 Thr GCC>ACC c.0394 05

Homozygous
Compound:
  • single


Patients: 003-119, arRP95
goto HGMD 180069-000005 (15)
(23)
Polymorphism Leu 133 Leu CTT/CTC c.0399 05




Patients:


(15)
LCA Tyr 144 Asp TAC>GAC c.0430 05

Homozygous

Patients: 84
goto HGMD
(20)
Polymorphism Tyr 144 Tyr TAC/TAT c.0432 05




Patients:


(15)
LCA Glu 148 Asp GAG>GAT c.0444 05



Patients:
goto HGMD
(8)
Microarray IVS5+1insg CAG gtgg>CAG ggtgg c.0495 IVS 05



Patients:


ARRP Asp 167 Tyr GAT>TAT c.0499 06 -MboI
Compound:
  • 777del8bp


Patients: arRP188


(23)
LCA His 182 Asn CAC>AAC c.0544 06



Patients:
goto HGMD
(8)
LCA His 182 Tyr CAC>TAC c.0544 06

Compound:
  • G40S
  • ~10% of WT activity


Patients: 048-017
76
goto HGMD
(15)
(20)
(4)
(3)
Polymorphism Tyr 190 Tyr TAC/TAT c.0570 05

Heterozygous

Patients: 33


(20)
Polymorphism Ala 203 Ala GCC/GCT c.0609 05




Patients:


(20)
Rare Variant Asn 205 Ser AAC>AGC c.0614 06




Patients:


(15)
LCA2, ARRP 615delCA AAC ATT>AA_ _TT c.0615 06 +MunI
Compound:
  • IVS1+5g-a
  • G528V


Patients: arRP713
goto HGMD
(23)
LCA IVS6+1g>c G gtgag>G ctgag c.0643 IVS 06




Patients:


(22)
ARRP IVS6+5g>a gtgag>gtgaa c.0643 IVS 06

Heterozygous

Patients: arRP476


(23)
LCA IVS6-2a>t ttcag>ttctg c.0643 IVS 06

Homozygous

Patients: 048-041
goto HGMD
(15)
Microarray Asp 215 Gly ttcag AG>ttcag GG c.0644 07



Patients:


Microarray IVS6-1g>t ttcag AC>ttcat AC c.0644 IVS 06



Patients:


Polymorphism IVS6-33g/c tgttc/tcttc c.0644 IVS 06 +EarI



Patients:


(12)
Polymorphism IVS6-42del t ataag/a_aag c.0644 IVS 06




Patients:


(12)
Polymorphism IVS6-43del a ataag/a_taag c.0644 IVS 06




Patients:


(12)
LCA Arg 234 ter CGA>TGA c.0700 07 +AluNWI
Compound:
  • 1114delA
  • R124X


Patients:
goto HGMD 180069-000002 (13)
(16)
(23)
(6)
LCA Tyr 239 Asp TAC>GAC c.715 06

Heterozygous
Compound:
  • Single


Patients:


(4)
(3)
ARRP IVS7+4a>g gtaac>gtagc c.0725 IVS 07 +AluI
Compound:
  • R91Q


Patients: 1024
goto HGMD
(23)
(20)
LCA 777del8bp ATT AAC CTG TTC>AT_ ___ ___ _TC c.0777 08 +ApoI
Previously reported as 831del8bp
Compound:
  • D167Y


Patients: arRP188
goto HGMD
(5)
(23)
LCA IVS8+1g>a GG gta>GG ata c.0858 IVS 08

Heterozygous

Patients:
goto HGMD
(16)
LCA IVS8+1g>t GG gta>GG tta c.0858 IVS 08 +MseI
Homozygous

Patients: PMK18/1
goto HGMD
(5)
(23)
LCA IVS8+4a>g gtaag>gtagg c.0858 IVS 08




Patients:


(24)
LCA Val 287 Phe GTT>TTT c.0859 09




Patients:
goto HGMD
(11)
Rare Variant Lys 294 Thr AAA>ACA c.0881 09

Heterozygous
  • 16% of WT activity


Patients: 208, 858, 1369


(15)
(23)
LCA 889delA AGG AAA AAG>AGG _AA AAG c.0889 09

Heterozygous

Patients: 33


(20)
LCA 894delG AAG TAC>AA_ TAC c.0894 09

Previously reported as 948delG

Patients:
goto HGMD
(11)
LCA Lys 303 ter AAA>TAA c.907 09



Patients:
goto HGMD
(1)
Microarray Tyr 318 Asn TAT>AAT c.0952 09



Patients:


LCA 962insA AAT>AAA T c.0962 09

Previously reported as 1016insA
Compound:
  • R124X


Patients: 048-033
goto HGMD
(15)
(4)
(3)
LCA Asn 321 Lys AAT>AAA or AAG c.0963 09

Homozygous
Heterozygous
Compound:
  • R44Q


Patients: PMK29/1
35
Indian
goto HGMD
(20)
(11)
(23)
(9)
Polymorphism Val 326 Val GTG/GTT c.0978 09




Patients:


(15)
LCA Cys 330 Tyr TGC>TAC c.0989 09

Homozygous
  • reduced isomerization activity


Patients:
goto HGMD
(16)
(18)
ARRP Leu 341 Ser TTA>TCA c.1022 10

Compound:
  • E404 ins 4 bp


Patients: 003-117
goto HGMD 180069-000004 (15)
LCA 1047insTGG ACC TGG>ACC TGG TGG c.1047 10

Previously reported as 1101insTGG
Heterozygous

Patients:
goto HGMD
(14)
Polymorphism Glu 351 Glu GAA/GAG c.1053 10




Patients:


(13)
Polymorphism Glu 352 Glu GAG/GAA c.1056 10




Patients:


(15)
(20)
LCA 1060delA GTG AAA AAA GCC>GTG _AA AAA GCC c.1060 10

Previously reported as1114delA
Compound:
  • R234X
  • IVS1+5g>a
  • In cis: T457N


Patients:
goto HGMD 180069-000001 (16)
(23)
(13)
LCA 1069ins1bp GAT GCC>GAT NGC C c.1069 10

Previously reported as 1123ins1bp
Compound:
  • A393G


Patients:
goto HGMD
(11)
(4)
(3)
Microarray Ala 360 Pro GCT>CCT c.1078 10



Patients:


LCA Pro 363 Thr CCT>ACT c.1114 10 -BspMI
Homozygous

Patients: PMK30/265
goto HGMD 180069-000003 (5)
(23)
RCD, early onset Tyr 368 His TAT>CAT c.1102 10 +NlaIII
Compound:
  • IVS1+5g-a
  • R91W
  • <3% of WT activity


Patients: arRPL, 2711
goto HGMD
(10)
(23)
Microarray Tyr 368 Cys TAT>TGT c.1103 10



Patients:


LCA 1120delA AAT ATT>AAT _TT c.1120 10

Published as 1121delA
Heterozygous
Compound:
  • R234X


Patients:


(7)
(6)
Polymorphism Thr 385 Thr ACG/ACA c.1155 11




Patients:


(15)
(20)
LCA Ala 393 Gly GCA>GGA c.1178 12

Compound:
  • 1069ins1bp


Patients:
goto HGMD
(11)
(4)
(3)
ARRP 1207dupCTGG TGG CTG GAG>TGG CTG GCT GGA G c.1207 11

Previously reported as 1275insCTGG
Compound:
  • L341S


Patients: 003-117
goto HGMD
(15)
Microarray Leu 403 Pro CTG>CCG c.1208 10



Patients:


Rare Variant Val 407 Ala GTT>GCT c.1220 11




Patients:


(15)
Microarray Leu 408 Pro CTC>CCC c.1223 11



Patients:


LCA Glu 417 Gln GAG>CAG c.1249 12

Homozygous
  • Loss of isomerization activity


Patients: 38
goto HGMD
(20)
Microarray Tyr 431 Cys TAC>TGC c.1292 12



Patients:


LCA Ala 434 Val GCG>GTG c.1300 11

Rare Variant?
  • 55% of WT activity


Patients:
goto HGMD
(15)
(16)
Polymorphism Ala 434 Ala GCG/GCC c.1302 12




Patients:


(15)
LCA Tyr 435 Cys A>G c.1304 12 +Hpy8I


Patients:
goto HGMD
(21)
LCA Gly 436 Val GGA>GTA c.1307 12 +RsaI
Compound:
  • IVS1+5g-a


Patients: LCA821


(23)
Polymorphism IVS12+20a/c tacta/tactc c.1338 IVS12




Patients:


(15)
LCA Leu 450 Arg CTG>CTT c.1350 13




Patients:


(26)
ARRP Val 452 Gly GTC>GGC c.1355 13

Compound:
  • R91W


Patients: 003-179
goto HGMD 180069-0007 (15)
LCA Thr 457 Asn ACT>AAT c.1370 13 +Tsp509I
Compound:
  • IVS1+5a-g
  • allele in cis: 1060delA


Patients: arRP850


(10)
(23)
LCA Glu 462 ter GAG>TAG c.1384 13

Homozygous and VMD2: G222V

Patients:


(11)
LCA Val 473 Asp GTT>GAT c.1418 13

Homozygous
Compound:
  • P363T
  • Single


Patients: 048-008
goto HGMD
(15)
(16)
(4)
(3)
Microarray Gly 484 Asp aacag GT>aacag AT c.1451 14



Patients:


Polymorphism IVS13-22c/t gccta/gctta c.1451 IVS13




Patients:


(20)
LCA Arg 515 Trp CGG>TGG c.1543 13




Patients:


(26)
Microarray Ile 520 Thr ATT>ACT c.1559 14



Patients:


Microarray Gly 528 Val GGA>GAT c.1573 14



Patients:


Microarray 1590delC TTC AAA>TT_ AAA c.1590 14



Patients:


References

  1. Al Khayer,K., Hagstrom,S., Pauer,G., Zegarra,H., Sears,J., and Traboulsi,E.I. Thirty-year follow-up of a patient with leber congenital amaurosis and novel RPE65 mutations. 2004; Am.J.Ophthalmol. 137: 375-377. Link Goto Top
  2. Dharmaraj,S.R., Silva,E.R., Pina,A.L., Li,Y.Y., Yang,J.M., Carter,C.R., Loyer,M.K., El Hilali,H.K., Traboulsi,E.K., Sundin,O.K., Zhu,D.K., Koenekoop,R.K., and Maumenee,I.H. Mutational analysis and clinical correlation in Leber congenital amaurosis. 2000; Ophthalm.Genet. 21: 135-150. Link Goto Top
  3. Galvin,J.A., Fishman,G.A., Stone,E.M., and Koenekoop,R.K. Clinical phenotypes in carriers of Leber congenital amaurosis mutations. 2005; Ophthalmology. 112: 349-356. Link Goto Top
  4. Galvin,J.A., Fishman,G.A., Stone,E.M., and Koenekoop,R.K. Evaluation of genotype-phenotype associations in Leber congenital amaurosis. 2005; Retina. 25: 919-929. Link Goto Top
  5. Gu,S., Thompson,D.A., Srisailapathy Srikumari,C.R., Lorenz,B., Finckh,U., Nicoletti,A., Murthy,K.R., Rathmann,M., Kumaramanickavel,G., Denton,M.J., and Gal,A. Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy. 1997; Nat.Genet. 17: 194-197. Link Goto Top
  6. Hamel,C.P., Griffoin,J.M., Lasquellec,L., Bazalgette,C., and Arnaud,B. Retinal dystrophies caused by mutations in RPE65: assessment of visual functions in Retinal degenerative diseases and experimental therapy. Hollyfield,J.G.; Anderson,R.E.; LaVail,M.M. eds. 2001; Br.J.Ophthalmol. 85: 424-427. Link Goto Top
  7. Hamel,C.P., Marlhens,F., Griffoin,J.M., Bareil,C., Claustres,M., and Arnaud,B. Different mutations in RPE65 are associated with variability in the severity of retinal dystrophy. 1999; 27 Goto Top
  8. 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., and Kaplan,J. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. 2004; Hum Mutat. 23: 306-317. Link Goto Top
  9. Joseph,B., Srinivasan,A., Soumittra,N., Vidhya,A., Shetty,N.S., Uthra,S., and Kumaramanickavel,G. RPE65 gene: multiplex PCR and mutation screening in patients from India with retinal degenerative diseases. 2002; J Genet. 81: 19-23. Link Goto Top
  10. Lorenz,B., Gyürüs,P., Preising,M., Bremser,D., Gu,S., Andrassi,M., Gerth,C., and Gal,A. Early-onset severe rod-cone dystrophy in young children with RPE65 mutations. 2000; Invest.Ophthalmol.Vis.Sci. 41: 2735-2742. Link Goto Top
  11. Lotery,A.J., Namperumalsamy,P., Jacobson,S.G., Weleber,R.G., Fishman,G.A., Musarella,M.A., Hoyt,C.S., Heon,E., Levin,A., Jan,J., Lam,B., Carr,R.E., Franklin,A., Radha,S., Andorf,J.L., Sheffield,V.C., and Stone,E.M. Mutation analysis of 3 genes in patients with Leber congenital amaurosis. 2000; Arch.Ophthalmol. 118: 538-543. Link Goto Top
  12. Marcos,I., Ruiz,A., Borrego,S., Ayuso,C., Baiget,M., and Antinolo,G. [Molecular analysis of the RPE65 gene in 72 spanish families with autosomal recessive retinitis pigmentosa]. 2001; Med.Clin.(Barc.). 117: 121-123. Link Goto Top
  13. Marlhens,F., Bareil,C., Griffoin,J.M., Zrenner,E., Amalric,P., Eliaou,C., Liu,S.Y., Harris,E., Redmond,T.M., Arnaud,B., Claustres,M., and Hamel,C.P. Mutations in RPE65 cause Leber's congenital amaurosis. 1997; Nat.Genet. 17: 139-141. Link Goto Top
  14. Marlhens,F., Griffoin,J.M., Bareil,C., Arnaud,B., Claustres,M., and Hamel,C.P. Autosomal recessive retinal dystrophy associated with two novel mutations in the RPE65 gene. 1998; Eur.J Hum.Genet. 6: 527-531. Link Goto Top
  15. Morimura,H., Fishman,G.A., Grover,S.A., Fulton,A.B., Berson,E.L., and Dryja,T.P. Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or Leber congenital amaurosis. 1998; Proc.Natl.Acad.Sci.U.S.A. 95: 3088-3093. Link Goto Top
  16. Perrault,I., Rozet,J.M., Gerber,S., Ghazi,I., Leowski,C., Ducroq,D., Souied,E., Dufier,J.L., Munnich,A., and Kaplan,J. Leber Congenital Amaurosis. 1999; Mol.Genet.Metab. 68: 200-208. Link Goto Top
  17. Poehner,W.J., Fossarello,M., Rapoport,A.L., Aleman,T.S., Cideciyan,A.V., Jacobson,S.G., Wright,A.F., Danciger,M., and Farber,D.B. A homozygous deletion in RPE65 in a small sardinian family with autosomal recessive retinal dystrophy. 2000; Mol.Vis. 6:192-8: 192-198. Link Goto Top
  18. Porto,F.B., Perrault,I., Hicks,D., Rozet,J.M., Hanoteau,N., Hanein,S., Kaplan,J., and Sahel,J.A. Prenatal human ocular degeneration occurs in Leber's congenital amaurosis (LCA2). 2002; J Gene Med. 4: 390-396. Link Goto Top
  19. Silva,E., Dharmaraj,S., Li,Y.Y., Pina,A.L., Carter,R.C., Loyer,M., Traboulsi,E., Theodossiadis,G., Koenekoop,R., Sundin,O., and Maumenee,I. A missense mutation in GUCY2D acts as a genetic modifier in RPE65-related Leber Congenital Amaurosis. 2004; Ophthalmic Genet. 25: 205-217. Link Goto Top
  20. Simovich,M.J., Miller,B., Ezzeldin,H., Kirkland,B.T., McLeod,G., Fulmer,C., Nathans,J., Jacobson,S.G., and Pittler,S.J. Four novel mutations in the RPE65 gene in patients with Leber congenital amaurosis. 2001; Hum.Mutat. 18: 164 Link Goto Top
  21. Sitorus,R.S., Lorenz,B., and Preising,M.N. Analysis of three genes in Leber congenital amaurosis in Indonesian patients. 2003; Vision Res. 43: 3087-3093. Link Goto Top
  22. Stockton,D.W., Lewis,R.A., Abboud,E.B., Al Rajhi,A., and Lupski,J.R. Genetic Heterogeneity Of Leber Congenital Amaurosis In The Saudi Arabian Population. 1999; Invest.Ophthalmol.Vis.Sci. 40: S471 Goto Top
  23. Thompson,D.A., Gyürüs,P., Fleischer,L.L., Bingham,E.L., McHenry,C.L., Apfelstedt-Sylla,E., Zrenner,E., Lorenz,B., Richards,J.E., Jacobson,S.G., Sieving,P.A., and Gal,A. Genetics and Phenotypes of RPE65 Mutations in Inherited Retinal Degeneration. 2000; Invest.Ophthalmol.Vis.Sci. 41: 4293-4299. Link Goto Top
  24. Thompson,D.A., Lorenz,B., Gyürüs,P., Gao,J., Hanna,D.B., and Andrassi,M. RPE65 Mutations In Childhood-Onset Severe Retinal Degenerations. 1999; Invest.Ophthalmol.Vis.Sci. 40: S575 Goto Top
  25. Thompson,D.A., McHenry,C.L., Li,Y., Richards,J.E., Othman,M.I., Schwinger,E., Vollrath,D., Jacobson,S.G., and Gal,A. Retinal Dystrophy Due to Paternal Isodisomy for Chromosome 1 or Chromosome 2, with Homoallelism for Mutations in RPE65 or MERTK, Respectively. 2001; Am.J.Hum.Genet. 70: Link Goto Top
  26. Wada,Y., Nakazawa,M., Abe,T., Fuse,N., and Tamai,M. Clinical variability of patients associated with gene mutations of visual cycle protein; Arrestin, RPE65 and RDH5 genes. 2000; Invest.Ophthalmol.Vis.Sci. 41: S617 Goto Top


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Contact the editor
This site is maintained and edited by
Dr. rer. medic. Markus Preising, Dipl.Biol.
Molecular Genetics Laboratory
Department of Paediatric Ophthalmology, Strabismology and Ophthalmogenetics
University of Regensburg
Head: Prof. Dr. med. Birgit Lorenz