ABCMdb

PMID: 12192456

Gerth C, Andrassi-Darida M, Bock M, Preising MN, Weber BH, Lorenz B
Phenotypes of 16 Stargardt macular dystrophy/fundus flavimaculatus patients with known ABCA4 mutations and evaluation of genotype-phenotype correlation.
Graefes Arch Clin Exp Ophthalmol. 2002 Aug;240(8):628-38. Epub 2002 Jul 4., [PubMed]

Sentences

No. Mutations Sentence Comment

2 ABCA4 p.Gly1961Glu Results: The homozygous 5917delG mutation resulted in the earliest disease manifestation (at 5 years) and a general cone-rod dysfunction, whereas the compound heterozygous mother (5917delG, G1961E) exhibited a very mild phenotype. Login to comment 3 ABCA4 p.Tyr362* ABCA4 p.Tyr362* ABCA4 p.Cys1488Tyr ABCA4 p.Cys1488Tyr Compound heterozygotes for the IVS40+5G→A and the C1488Y or Y362X mutation showed also an early age of onset but only a central dysfunction. Login to comment 4 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro The effect of the 2588G→C mutation, the G1961E mutation, and the complex mutation L541P-A1038V depended on the mutation in the second allele. Login to comment 29 ABCA4 p.Gly1961Glu [17] identified three different phenotypes among 49 STGD patients associated with single heterozygous (16 patients) or compound heterozygous (13 patients) ABCA4 mutations and suggested that there is an association between the heterozygous ABCA4 mutation (Gly1961Glu change, exon 42) in one allele and a certain phenotype (fundus: small macular lesion; visual acuity: well preserved; angiography: no dark choroid; Ganzfeld ERG: normal). Login to comment 30 ABCA4 p.Gly1961Glu [17] identified three different phenotypes among 49 STGD patients associated with single heterozygous (16 patients) or compound heterozygous (13 patients) ABCA4 mutations and suggested that there is an association between the heterozygous ABCA4 mutation (Gly1961Glu change, exon 42) in one allele and a certain phenotype (fundus: small macular lesion; visual acuity: well preserved; angiography: no dark choroid; Ganzfeld ERG: normal). Login to comment 76 ABCA4 p.Tyr362* ABCA4 p.Cys1488Tyr Patients with the splice site mutation IVS40+5GA Two patients were compound heterozygous for this splice site mutation and a missense mutation (patient 2, C1488Y) or a nonsense mutation (patient 3, Y362X). Login to comment 81 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Tyr362* ABCA4 p.Tyr362* ABCA4 p.Arg681* ABCA4 p.Arg681* ABCA4 p.Trp855* ABCA4 p.Trp855* ABCA4 p.Cys1488Tyr ABCA4 p.Cys1488Tyr ABCA4 p.Tyr2203* ABCA4 p.Tyr2203* ABCA4 p.Tyr2203* ABCA4 p.Tyr2203* ABCA4 p.Ser765Arg ABCA4 p.Ser765Arg ABCA4 p.Arg1097Cys ABCA4 p.Arg1097Cys ABCA4 p.Cys764Tyr Patient 2 had a Table 2 Identified mutations in the ABCR alleles in the 16 patients (ND not tested) Patient ABCA4 allele 1 ABCA4 allele 2 no./sex (1*) Nucleotide changes Effects Nucleotide changes Effects 1a/F (139) 5917delG Frameshift 5917delG Frameshift 1b/F(139b) 5917delG Frameshift 5882G→A G1961E 2/M (167) IVS 40+5G→A Splice 4463G→;A C1488Y 3/F (108) IVS 40+5G→A Splice 1086T!92;A Y362X 4/M (109) 1622T!92;C- L541P-A1038V 2564G→A W855X 3113C→T 5/F (113) 1622T→C- L541P-A1038V 2588G→C Splice 3113C→T 6/M (50) 2588G→C Splice 3113C→T A1038V 7b/M (138) 2588G→C Splice IVS13+1G→A Splice 7a/F Not tested Splice Not tested Splice 8/F (111) 5882G→A G1961E 2292delT-2295T192;G Frameshift-S765R 9/F (147) 5882G→A G1961E IVS36+1G→A Splice 10/F (41) 5882G→A G1961E 2041C→T R681X 11a/F (114) 5882G→A G1961E 6609C→A Y2203X 11b/M ND ND 12/F (148) 3292C→;T R1097C 6609C→A Y2203X 13/M (107) 3528insTGCA Frameshift 2291G→A C764Y* Refers to the patients` ID in [42] Table3Demographicdataandclinicalfeaturesofthe16patients(NDtestnotdone,Aabnormal,Nnormal,RreducedArdenratio,NRnotreliable,NAmfERGnotanalyz- able,+present,-absent,DCdarkchoroid,DDdiscdiameter) Pat.aAgeDiseaseVisualacuityColorFun-GanzfeldERGEOGmfERGStatictwo-colorKineticperimetryAngio-FundusAF atdurationvisiondusbthresholdperimetrygraphy onset/(years)ODOSRodMaximalConePeakResponseCentralCon-CentralCircularPeri- examresponseresponseresponsetimesdensitiesMeanRSLMeanCSLscotomacentricAFAFmacular/ b-wavecb-wavec30Hzab-abnormalc(dB)e(dB)efortargetcon-AF flickerdnormaldstriction <=13°>13°<=13°>13° 1a5/10520/250*20/250NDIfNDNANAND-ND-NRNRND+-- 1b32/32020/30*20/30NDINDNNNDN5-10°ND-ND-NDNDND+-- 27/15820/10020/200*AIINNNND5-15°5-25°2120--ND+-+ 39/13420/250*20/250AIINNNN5-15°5-25°0030I-2e-ND+++ 47/12520/25020/250*AIIINNNN5-25°5-25°ND-ND-I-4e-ND>1DD-- 520/4525<20/400<20/400*AIIINNNNNANA194143II-3e+ND>1DD-+ 614/19520/200*20/200AIINDNNNR5-10°5-25°1080I-4e-ND+-+ 7b16/23720/25020/250*AIINDNNR20°5-25°101113I-3e-ND+-+ 7a6/272120/20020/200NDIINDNDNDNDND-ND-ND-NDNDNDND 815/18320/100*20/100AINNND5-10°5-25°2010I-2e-N++- 921/23220/40*20/200AINDNNN10-15°5°0060NDNDN+++ 1024/31720/400*20/400AIINNNN5°5-15°3270I-2e-ND+-+ 11a16/331720/200*20/200AIINDNNNN5-15°81140I-2e-NDND 11b26/28220/20020/200*AINNNN5-10°,5-10°0010I-2e-ND+++ 20-25° 1238/571920/22*20/250NDIII(OD)ND5-25°5-25°35/3835/39ND-III/4e-NDND 1314/16220/100*20/100AIINDNNNN5-25°1120ND-DC+-+ aOnenumberindicatesonefamily bReferredtoTable1 cResults<5thpercentile dResults>95thpercentile eRSL(rodsensitivityloss;500nm,darkadapted)andCSL(conesensitivityloss; 600nm,lightadapted)comparedtothe10thpercentileofnormals;mfERGrespons- eswereanalyzedforallbutthecentral(1°inradius)responseduetohighnoise fRetinalvesselattenuation *EyetestedformfERG/staticperimetry CSL within 13° and a more widespread RSL over the 30° test field. Login to comment 84 ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Leu541Pro ABCA4 p.Trp855* Patients with the complex mutation L541P-A1038V Two patients were compound heterozygous for this complex mutation and a nonsense mutation (W855X, patient 4) as well as a mutation with bipartite outcome [2588G→C (G863A/G863del), patient 5]. Login to comment 91 ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro Patients with the missense mutation 2588G→C Four patients were compound heterozygous for this missense mutation and an alteration in the donor splice site of exon 13 (IVS13+1G→A, siblings 7a and 7b), a complex mutation [L541P-A1038V (patient 5, results described above)] or a missense mutation (A1038V, patient 6). Login to comment 94 ABCA4 p.Gly1961Glu AF Fig. 1 Fundus photographs, AF images, and mfERG trace arrays (from top to bottom) of patient 1a (homozygote for 5917delG) and her mother, patient 1b (compound heterozygote for 5917delG and G1961E) showed central hypofluorescence with surrounding perimacular hyper- and hypofluorescent spots in patients 6 and 7b. Login to comment 98 ABCA4 p.Gly1961Glu ABCA4 p.Arg681* ABCA4 p.Arg681* ABCA4 p.Tyr2203* ABCA4 p.Tyr2203* Patients with the missense mutation G1961E Four patients were compound heterozygous for this missense mutation and an alteration in the donor splice site of exon 36 (IVS36+1G→A, patient 9), a nonsense mutation (R681X, patient 10; Y2203X, patient 11a) or frameshift mutation [5917delG, patient 1b (results described above)] (Figs. 2, 3). Login to comment 99 ABCA4 p.Gly1961Glu ABCA4 p.Arg681* ABCA4 p.Arg681* ABCA4 p.Ser765Arg In patient 8 two alterations in the Fig. 2 Fundus photograph, AF images, rod and cone sensitivity in the static two-color threshold perimetry in the dark-adapted (500 nm; RSL) and the light-adapted (600 nm; CSL) state, and mfERG trace arrays (from top to bottom) of three patients with the G1961E mutation in one and the 2292delT-S765R mutation (patient 8), the IVS36+1G→A mutation (patient 9), or the R681X mutation (patient 10) in the second ABCA4 allele. Scale for mfERG shown in Fig. 1. Login to comment 100 ABCA4 p.Gly1961Glu ABCA4 p.Ser765Arg Static perimetry results are shown as gray scales of sensitivity loss (normal sensitivity indicated by white, no stimulus detection by black, blind spot by two blank test squares) second ABCA4 allele (frameshift 2292delT and missense S765R mutation) were identified in addition to the missense G1961E mutation. Login to comment 108 ABCA4 p.Gly1961Glu ABCA4 p.Tyr2203* ABCA4 p.Arg1097Cys Patients with the nonsense mutation Y2203X Three patients were identified as compound heterozygous for this nonsense mutation and the missense mutations G1961E [siblings 11a and 11b (results described above)] or R1097C (patient 12) (Figs. 3, 4). Login to comment 109 ABCA4 p.Gly1961Glu ABCA4 p.Tyr2203* ABCA4 p.Tyr2203* ABCA4 p.Arg1097Cys Age at onset Fig. 3 Fundus photograph, RSL, CSL, and mfERG trace arrays (from top to bottom) of two siblings (patients 11a and 11b) with the Y2203X mutation in one and the G1961E mutation in the second ABCA4 allele. Scale for mfERG/perimetry shown in Fig. 1 Fig. 4 Fundus photograph, RSL, and mfERG trace arrays (from top to bottom) of patient 12 with the Y2203X mutation in one and the R1097C mutation in the second ABCA4 allele. Scale for mfERG/perimetry shown in Fig. 1 varied (Table 3). Login to comment 112 ABCA4 p.Cys764Tyr Patient with frameshift 3528insTGCA mutation Patient 13 was compound heterozygous for this frameshift mutation and the missense C764Y mutation. Login to comment 152 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu The milder phenotype in her mother (patient 1b), who was shown to be compound heterozygous for the 5917delG and G1961E mutation, is not unexpected since the G1961E mutation in her second allele is thought to result in partial activity of the ABCA4 transporter [49]. Login to comment 153 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Tyr362* ABCA4 p.Cys1488Tyr The milder phenotype in her mother (patient 1b), who was shown to be compound heterozygous for the 5917delG and G1961E mutation, is not unexpected since the G1961E mutation in her second allele is thought to result in partial activity of the ABCA4 transporter [49]. Login to comment 154 ABCA4 p.Tyr362* ABCA4 p.Cys1488Tyr The combination of the IVS40+5G→A splice site mutation and the C1488Y missense (patient 2) or the Y362X nonsense (patient 3) mutation resulted in an early age at onset but only a central cone and rod dysfunction at age 15 and 13. Login to comment 157 ABCA4 p.Tyr362* The slightly more advanced cone dysfunction in patient 3 could be caused by the more severe functional restrictions of the associated nonsense mutation (Y362X), which results in a nonfunctional gene product. Login to comment 158 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Tyr362* ABCA4 p.Trp855* The slightly more advanced cone dysfunction in patient 3 could be caused by the more severe functional restrictions of the associated nonsense mutation (Y362X), which results in a non-functional gene product. Login to comment 159 ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Trp855* The complex mutation L541P-A1038V was associated with an earlier onset and more rapid progression when occurring together with the W855X nonsense mutation (patient 4) than with the missense mutation 2588G→C (patient 5). Login to comment 160 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Trp855* Both mutations on their own, L541P and A1038V, have been associated with severely reduced but not abolished ATPase activity [49]. Login to comment 161 ABCA4 p.Trp855* The combination with W855X, which completely eliminates the ATPase activity, predicts a severe phenotype, which is supported by the functional data of patient 4. Login to comment 163 ABCA4 p.Ala1038Val The missense mutation 2588G࢐C resulted in a more advanced cone and rod dysfunction when associated with the IVS13+1G࢐A splice site (siblings 7a and 7b) than with the missense mutation A1038V (patient 6) in the second allele. Login to comment 164 ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val The missense mutation 2588G→C resulted in a more advanced cone and rod dysfunction when associated with the IVS13+1G→A splice site (siblings 7a and 7b) than with the missense mutation A1038V (patient 6) in the second allele. Login to comment 165 ABCA4 p.Ala1038Val This difference is predictable since the A1038V showed a reduced ATPase activity of about 60% but a nearly wild-type-like yield [49]. Login to comment 166 ABCA4 p.Gly1961Glu ABCA4 p.Arg681* ABCA4 p.Tyr2203* ABCA4 p.Ser765Arg 636 The missense mutation G1961E (with a clearly reduced ATPase activity but wild-type-like yield [49]) associated with the splice donor mutation IVS36+1G࢐A (patient 9), the complex mutation 2292delT-S765R (patient 8), the nonsense R681X mutation (patient 10) or the Y2203X mutation (patient 11a) in the second allele resulted in different degrees of photoreceptor dysfunction. Login to comment 167 ABCA4 p.Gly1961Glu ABCA4 p.Arg681* ABCA4 p.Tyr2203* ABCA4 p.Ser765Arg 636 The missense mutation G1961E (with a clearly reduced ATPase activity but wild-type-like yield [49]) associated with the splice donor mutation IVS36+1G→A (patient 9), the complex mutation 2292delT-S765R (patient 8), the nonsense R681X mutation (patient 10) or the Y2203X mutation (patient 11a) in the second allele resulted in different degrees of photoreceptor dysfunction. Login to comment 170 ABCA4 p.Tyr2203* The Y2203X mutation is located beyond the second NBD and abolishes about 70 amino acids of the C-terminus. Login to comment 171 ABCA4 p.Arg681* ABCA4 p.Tyr2203* ABCA4 p.Ser765Arg The Y2203X mutation is located beyond the second NBD and abolishes about 70 amino acids of the C-terminus. Login to comment 172 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Arg681* ABCA4 p.Tyr2203* ABCA4 p.Ser765Arg Since ABCA4 is not prenylated, the loss of these amino acids may cause a less impaired protein function than the 2292delT-S765R and R681X mutations, which predict a loss of about three quarters of the gene product due to the location in the first TMD. Login to comment 173 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Tyr2203* By correlating the functional prediction to the clinical phenotype it is obvious that the patient with the G1961E- Y2203X mutation showed a more advanced rod dysfunction than the other patients with the G1961E mutation in one allele. Login to comment 174 ABCA4 p.Gly1961Glu ABCA4 p.Tyr2203* ABCA4 p.Arg1097Cys The Y2203X mutation associated with the missense mutation R1097C (NBD-1) in patient 12 resulted in a less severe phenotype than seen in patient 11a (G1961E). Login to comment 175 ABCA4 p.Gly1961Glu ABCA4 p.Tyr2203* ABCA4 p.Arg1097Cys ABCA4 p.Arg1097Cys The Y2203X mutation associated with the missense mutation R1097C (NBD-1) in patient 12 resulted in a less severe phenotype than seen in patient 11a (G1961E). Login to comment 176 ABCA4 p.Arg1097Cys R1097C is located within NBD-1 but does not directly contribute to the ABC domains. Login to comment 177 ABCA4 p.Tyr2203* Together with Y2203X, a milder phenotype may be predicted. Login to comment 178 ABCA4 p.Tyr2203* Together with Y2203X, a milder phenotype may be predicted. Login to comment 183 ABCA4 p.Cys764Tyr The functional role of the mutations found in patient 13 [3528insTGCA (NBD-1), C764Y (first TMD group)] is not yet known. Login to comment 184 ABCA4 p.Cys764Tyr ABCA4 p.Cys764Tyr The functional role of the mutations found in patient 13 [3528insTGCA (NBD-1), C764Y (first TMD group)] is not yet known. Login to comment 185 ABCA4 p.Cys764Tyr Looking at the protein structure, an influence of the C764Y mutation on the TMD integrity may be predicted. Login to comment