ABCMdb

PMID: 15161829

September AV, Vorster AA, Ramesar RS, Greenberg LJ
Mutation spectrum and founder chromosomes for the ABCA4 gene in South African patients with Stargardt disease.
Invest Ophthalmol Vis Sci. 2004 Jun;45(6):1705-11., [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCA4 p.Cys1490Tyr ABCA4 p.Arg602Trp ABCA4 p.Leu2027Phe ABCA4 p.Arg152* The most common variants identified included the C1490Y, L2027F, R602W, V256splice, R152X, and 2588G3C mutations. Login to comment 8 ABCA4 p.Cys1490Tyr The C1490Y variant was the most common disease-associated variant identified (19/64 subjects) and was absent in 392 control chromosomes. Login to comment 10 ABCA4 p.Cys1490Tyr Two of these haplotypes, which carried the C1490Y mutation, were identified in three unrelated families. Login to comment 15 ABCA4 p.Cys1490Tyr ABCA4 p.Arg602Trp There seems to be at least two different origins for the common C1490Y mutation, as well as two for the R602W mutation, thereby suggesting several founder effects for STGD in SA. Login to comment 56 ABCA4 p.Cys1490Tyr Restriction Fragment Length Polymorphism Analysis Restriction fragment length polymorphism (RFLP) analyses were performed by using the RsaI restriction endonuclease enzyme to screen for the C1490Y mutation. Login to comment 71 ABCA4 p.Gly863Ala ABCA4 p.Arg212Cys ABCA4 p.Cys1490Tyr ABCA4 p.Arg602Trp ABCA4 p.Arg2038Trp ABCA4 p.Val989Ala ABCA4 p.Arg2030* ABCA4 p.Leu2027Phe ABCA4 p.Arg1443His ABCA4 p.Arg1443His ABCA4 p.Arg152* ABCA4 p.Arg152Gln ABCA4 p.Phe1440Ser List of 16 Different Potential Disease-Associated Sequence Variants Identified in 64 SA Subjects with arSTGD Nucleotide Change Amino Acid Change Families (N ‫؍‬ 64) Exon Reference C454T R152X 4 5 3,33 G455A R152Q 1 5 35 C634T R212C 1 6 16,27 G768T (Splice donor) V256splice 5 6 15 C1885T R602W 6 13 9 2588G3C G863A 4 17 8 T3047C V989A 1 20 11 T4319C F1440S 1 29 9 G4328A* R1443H 1 29 This study G4469A C1490Y 19 30 15,9 G5077A V16931 1 36 36 C6079T L2027F 8 44 8 C6088A R2030X 1 44 9,37 C6112T R2038W 2 44 5 IVS45ϩ7G3A Splice donor 1 45 26 6352⌬A* Frameshift 1 46 This study No individuals positive for the R1443H variant were identified in 47 control individuals of Indian ancestry. Login to comment 72 ABCA4 p.Cys1490Tyr The C1490Y variant was absent in 146 control individuals. Login to comment 76 ABCA4 p.Arg1443His The remaining two disease-associated variants, R1443H and 6352⌬A (nucleotide position), have not been previously reported. Login to comment 77 ABCA4 p.Arg1443His The R1443H variant was identified in a sporadic individual of Asian-Indian ancestry and was not observed in 47 unaffected, unrelated, ethnically matched control subjects. Login to comment 78 ABCA4 p.Cys1490Tyr The 6352⌬A sequence variant, which introduces a frameshift mutation that results in a premature termination codon, was identified in an individual of Afrikaner descent. The C1490Y sequence variant was the most frequently observed mutation in this study (19/64; 30%) but was absent in ethnically matched, unrelated, unaffected control individuals representative of the SA white (n ϭ 116), indigenous black (n ϭ 40), and mixed-ancestry (n ϭ 40) populations. Login to comment 82 ABCA4 p.Cys1490Tyr In a large proportion of the individuals with the C1490Y variant, the AO was under the age of 20 years. Login to comment 83 ABCA4 p.Cys1490Tyr The mean age of onset for individuals with the C1490Y mutation was 11.1 years with a standard deviation of 5.2. Login to comment 84 ABCA4 p.Cys1490Tyr ABCA4 p.Leu2027Phe Of note, individual 209.1 and 113.3 were compound heterozygotes for the C1490Y and L2027F variations; however, their AOs differ considerably (18 and 10 years, respectively). Login to comment 85 ABCA4 p.Arg1443His The novel sequence variant R1443H was associated with a late AO of 31 years (individual 372.1). Login to comment 90 ABCA4 p.Arg152* Individual 105.1 was heterozygous for two different mutations, the V256splice variant and the R152X variant. Login to comment 93 ABCA4 p.Cys1490Tyr Individual 219.1 in whom a single disease-associated allele carrying the C1490Y variant was identified, was diagnosed with STGD at an early age (AO of 5 years); bilateral extensive RPE atrophy was noted 4 years later (Table 3). Login to comment 96 ABCA4 p.Leu2027Phe ABCA4 p.Arg152* ABCA4 p.Phe1440Ser A single STGD-associated haplotype was identified for the (1) L2027F sequence variant, in two unrelated families; (2) V256splice variant, in two unrelated families; (3) R152X variant, three unrelated families; (4) 2588G3C variant, in one family; (5) F1440S variant, in one family; and (6) IVS45ϩ7G3A variant, in one family. Login to comment 97 ABCA4 p.Cys1490Tyr Two disease-associated haplotypes were identified for the frequent C1490Y variant in three unrelated STGD families, suggesting several founder effects for STGD in SA (Fig. Login to comment 99 ABCA4 p.Arg602Trp Likewise, two STGD-associated haplotypes for the R602W variant were identified in two unrelated families. Login to comment 114 ABCA4 p.Arg943Gln ABCA4 p.Glu310Gln ABCA4 p.Pro1395Leu ABCA4 p.Gly330Asp ABCA4 p.Glu2119Lys The 14 Non-Disease-Causing Sequence Variants Identified in the Study Nucleotide Change Amino Acid Change Families (n ‫؍‬ 64) G1009C E310Q 2 G989A G330D 1 IVS18-38⌬G - 3 G2828A R943Q 6 C4184T P1395L 1 IVS27-71T3A - 1 IVS28-38G3A - 1 IVS38-10T3C - 1 IVS39-17T3A - 1 G5682C L1894L 1 TG5925CA L1984L 2 IVS43-16G3A - 3 C6329T 12083I 1 G6355A E2119K 2 other ABCA4 studies in which similar mutation screening methods were used.10,11,26 -28 Methods such as direct sequencing of all arSTGD probands in other studies have, however, identified approximately 66% to 80% of ABCA4-associated STGD chromosomes.13,14 The SSCP-HD mutation screening method used in this study has a reported sensitivity of 97%.17 It is possible that allelic mutations have been missed because (1) of the sensitivity of the method used, or (2) the unidentified mutations may reside in parts of the gene-for example, the promotor or regulatory regions that have not yet been screened. Login to comment 119 ABCA4 p.Cys1490Tyr ABCA4 p.Arg602Trp ABCA4 p.Leu2027Phe ABCA4 p.Arg152* The C1490Y sequence variant was the most common disease-associated variant identified in this study (19/64; 30%), followed by the L2027F (8/64; 13%), the R602W variant (6/64; 9%), the V256splice variant (5/64; 8%), and the 2588G3C and R152X sequence variants occurred at equal frequencies (4/64; 6%). Login to comment 121 ABCA4 p.Cys1490Tyr ABCA4 p.Arg602Trp ABCA4 p.Leu2027Phe ABCA4 p.Arg152* Five (C1490Y, L2027F, R602W, V256splice and R152X) of the six common sequence variants identified were at a higher frequency in the SA STGD cohort than in populations from Europe and the United States. Login to comment 122 ABCA4 p.Cys1490Tyr ABCA4 p.Arg602Trp ABCA4 p.Arg152* Of interest, the C1490Y, R602W, V256splice, and R152X variants were found to be some of the rarer ABCA4 mutations observed in populations of Europe. Login to comment 125 ABCA4 p.Arg212Cys ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Arg602Trp ABCA4 p.Arg602Trp ABCA4 p.Arg602Trp ABCA4 p.Arg602Trp ABCA4 p.Arg602Trp ABCA4 p.Arg602Trp ABCA4 p.Arg2038Trp ABCA4 p.Arg2038Trp ABCA4 p.Val989Ala ABCA4 p.Arg2030* ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Arg152* ABCA4 p.Arg152* ABCA4 p.Arg152* ABCA4 p.Arg152* ABCA4 p.Arg152Gln ABCA4 p.Phe1440Ser ABCA4 p.Val1693Ile AO (y) Phenotype Mutation 1 Mutation 2 224.1 9 STGD C1490Y R602W 170.2 10 STGD C1490Y R602W 241.1 9 STGD C1490Y 25883C 448.1 20 STGD C1490Y 2588G3C 113.3 10 STGD C1490Y L2027F 209.1 18 STGD C1490Y L2027F 165.4 10 STGD C1490Y V256splice 166.3 27 STGD C1490Y R152X 151.4 5 STGD C1490Y ND 219.1 5 (rapid clinical progression was observed by 9 years) STGD C1490Y ND 223.1 9 STGD C1490Y ND 307.1 9 STGD C1490Y ND 319.3 9 STGD C1490Y ND 385.1 10 STGD C1490Y ND 226.1 10 STGD C1490Y ND 142.2 10 STGD C1490Y ND 273.1 11 STGD C1490Y ND 382.1 12 STGD C1490Y ND 449.1 14 STGD C1490Y ND 344.2 ND STGD C1490Y ND 374.1 10 STGD L2027F 6352⌬A† 305.1 18 STGD L2027F R2038W 377.1 25 STGD L2027F R2038W 276.1 27 STGD L2027F R212C 204.4 8 STGD L2027F ND 135.4 13 STGD L2027F ND 446.1 9 STGD R602W ND 109.3 11 STGD R602W ND 110.7 13 STGD R602W ND 438.3 12 STGD R602W ND 123.1 9 STGD V256splice R152X 105.1* 10 STGD AND atypical RP V256splice R152X 24 129.3* 10 (rapid clinical progression was observed) STGD V256splice ND 163.22 10 STGD V256splice ND 173.1 8 STGD 2588G3C ND 9.4 27 STGD 2588G3C R152X 330.2 29 STGD R152Q V989A 372.1 31 STGD R1443H† R2030X 141.3 11 STGD F1440S IVS45ϩ7G3A (splice site mutation) 206.3 ND STGD V1693I ND Rows are arranged according to the age of onset (AO) starting with the earliest AO for the most common sequence variant. Login to comment 132 ABCA4 p.Arg1443His Finally, variants R1443H and 6352⌬A identified in this SA study, had not been reported previously. Login to comment 133 ABCA4 p.Arg152* ABCA4 p.Arg152* This study presents further supporting evidence that mutations such as R152X and V256splice variants within ABCA4 can cause recessive panretinal degeneration, which is typified by changes in the clinical presentation from STGD to a more severe arRP phenotype over time.32 Individual 105.1 was heterozygous for two different mutations: the V256splice variant and the R152X sequence variant. Login to comment 134 ABCA4 p.Arg152* ABCA4 p.Arg152* The R152X change has been associated with a mild clinical phenotype of fundus flavimaculatus, which has a late AO and a slow progressive clinical phenotype.13,33 In this study, the R152X sequence variant is associated with an earlier AO (Ͻ28 years) than the published data of 70 and 52 years. Login to comment 136 ABCA4 p.Arg152* Without in vitro functional analyses of the effects of these two mutations (R152X and V256splice) on the ABCA4 protein, it is difficult to predict accurately whether both variants contribute TABLE 4. Login to comment 137 ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Arg602Trp ABCA4 p.Arg602Trp ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Arg152* ABCA4 p.Arg152* ABCA4 p.Arg152* ABCA4 p.Phe1440Ser The 10 ABCA4 Disease-Associated Haplotypes Identified in the 10 STGD Families Investigated Family D1S188 Marker ABCA4 MutationD1S406 D1S236 166 14 6 12 C1490Y 170 15 4 9 C1490Y 151 15 4 9 C1490Y 204 9 5 14 L2027F 135 9 5 14 L2027F 105 8 4 14 V256splice 129 8 4 14 V256splice 170 10 5 12 R602W 110 16 6 3 R602W 9 7 5 14 2588G3C 9 16 5 4 R152X 105 16 5 4 R152X 166 16 5 4 R152X 141 8 3 6 F1440S 141 9 5 14 IVS45ϩ7G3A The numbers in column 1 denote the identity number of the family. Login to comment 145 ABCA4 p.Cys1490Tyr Two haplotypes were identified for the C1490Y variant in three families: (a) 166, (b) 170, and (c) 151. equally to the severe clinical phenotype or whether the severity of the phenotype is determined by the effects of the V256splice mutation on the protein function. Login to comment 146 ABCA4 p.Arg152* However, the findings of the present investigation suggest that the V256splice variant and the R152X variant both affected the ABCA4 protein function severely and that this could explain the severe clinical phenotype. Login to comment 148 ABCA4 p.Arg1443His ABCA4 p.Arg1443His It has previously been hypothesized that two null mutations cause atypical RP and combinations of a null and a moderately severe mutation cause CRD.15 The novel R1443H involves a substitution of a conserved arginine residue with histidine, another basic amino acid, at position 1443 within extracellular domain 2 (ECD 2) of the ABCA4 protein.34 It is therefore predicted that R1443H does not have a dramatic functional effect within the intradiscal space of the photoreceptor cells where ECD-2 is localized. Login to comment 150 ABCA4 p.Arg2030* ABCA4 p.Arg1443His It has been suggested that mutations toward the 3Ј end of the gene may not have a significant effect on protein function and hence can be more often associated with milder phenotypes (referring specifically to AO).34 The novel R1443H and R2030X sequence variants, located toward the 3Ј end of the gene may therefore explain the milder phenotype (AO ϭ 31 years) observed in individual 372.1, who was heterozygous for these mutations. Login to comment 152 ABCA4 p.Leu2027Phe The severe phenotype noted in this patient was therefore attributed to the subject`s heterozygosity for the 6352⌬A and L2027F mutations, with the latter being the major contributor to the disease phenotype. Login to comment 153 ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe Further investigation into the AO reported to be associated with L2027F (data not presented), however, highlights a correlation between the L2027F variant with a milder clinical phenotype associated with a late AO (second and third decade of life). Login to comment 154 ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe It is therefore reasonable to hypothesize that regarding individual 374.1, who was heterozygous for the two mutations, L2027F and the novel mutation 6352⌬A, (1) both mutations contribute equally to the severity of the phenotype, (2) modifying sequences within ABCA4 or other genes modulate the effect of the compound heterozygous mutations 6352⌬A/L2027F on the ABCA4 protein, and hence the phenotype, or (3) environmental factors such as diet, smoking, and UV radiation may all contribute to the scenario in (2). Login to comment 155 ABCA4 p.Arg1443His This therefore suggests that the two novel mutations 6352⌬A and R1443H may have moderate and mild effects on ABCA4 protein function, respectively. Login to comment 157 ABCA4 p.Cys1490Tyr From the published data, the C1490Y mutation was noted to be present at a particularly low frequency (1%) in the European population.9 This is in contrast, to the notably high frequency (30%) observed in the SA Afrikaner population who are of Dutch, German, and French ancestry. Login to comment 159 ABCA4 p.Cys1490Tyr However, the C1490Y variant was absent in the 196 ethnically unrelated, unaffected control individuals investigated. Login to comment 160 ABCA4 p.Cys1490Tyr This absence in the control group and the high association with the affected cohort therefore suggests that the high frequency of the C1490Y sequence variant in the SA STGD cohort is due to a founder effect. Login to comment 162 ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr The 16 different disease-associated sequence variants identified together with the high association of C1490Y with STGD in SA and its absence in 392 control chromosomes suggests the presence of several ancestral haplotypes underlying STGD in SA and, possibly, several founder effects for the C1490Y in the SA cohort of subjects. Login to comment 164 ABCA4 p.Cys1490Tyr Of note, two disease-associated haplotypes were identified for the frequent C1490Y variant in three unrelated families with STGD, suggesting several founder effects for STGD in SA. Login to comment 165 ABCA4 p.Arg602Trp Likewise, two STGD-associated haplotypes for the R602W variant were identified in two unrelated families. Login to comment 166 ABCA4 p.Cys1490Tyr Recruitment of more subjects from SA families in whom the C1490Y variant has been identified will facilitate the interrogation of a founder effect for this mutation in the SA STGD cohort. Login to comment 169 ABCA4 p.Cys1490Tyr More important, there seems to be at least two different origins for the same "disease-predisposing" allele carrying the common C1490Y mutation in this study population. Login to comment