ABCMdb

PMID: 11818392

Bernstein PS, Leppert M, Singh N, Dean M, Lewis RA, Lupski JR, Allikmets R, Seddon JM
Genotype-phenotype analysis of ABCR variants in macular degeneration probands and siblings.
Invest Ophthalmol Vis Sci. 2002 Feb;43(2):466-73., [PubMed]

Sentences

No. Mutations Sentence Comment

14 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn We reported that 16% of an initial cadre of patients with AMD (26/167) had heterozygous ABCR variants that resulted in non-conservative amino acid substitutions, frameshifts, or splice-site changes that were found in less than 1% of a general population control cohort.14 Two variants, G1961E and D2177N, accounted for half of the reported disease-associated variants, whereas the others were rare variants found in one or two affected individuals.14 Two groups subsequently reported much lower rates of potential disease-associated ABCR variants in their cohorts of patients with AMD,15-17 but their selected populations, clinical criteria, and mutation detection rates differed substantially from the initial study.18 More recently, however, a large multicenter international consortium confirmed that G1961E and D2177N variants of ABCR are indeed found in patients with AMD at a significantly higher frequency relative to control subjects.19 The two variants were found in 3.4% of patients with AMD (40/1189) versus 0.95% of control subjects (12/ 1258; P Ͻ 0.0001).19 We postulate that relatives of patients with Stargardt disease and of patients with AMD who are heterozygous carriers of the same variant ABCR alleles as the family proband may have an increased risk of development of AMD under some circumstances. Login to comment 52 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Leu1970Phe ABCA4 p.Ile1562Thr ABCA4 p.Arg1898His ABCA4 p.Glu471Lys ABCA4 p.Thr1428Met ABCA4 p.Arg1517Ser ABCA4 p.Gly1578Arg AMD Grade of Probands Carrying Heterozygous ABCR Variants ABCR Variant Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 E471K 0 0 1 1 0 P940R* 0 0 0 1 0 T1428M 0 0 1 0 0 R1517S 0 0 0 1 0 I1562T 0 0 1 1 0 G1578R 0 0 1 0 0 5196ϩ1G3A 0 0 1 0 0 R1898H 0 0 0 1 0 G1961E 0 0 2 4 0 L1970F 0 0 1 0 0 6519⌬11bp 0 0 0 1 0 D2177N 0 1 3 3 0 6568⌬C 0 0 0 0 1 Data are number of probands at each grade. Login to comment 53 ABCA4 p.Arg1129Leu * The patient reported to have the R1129L ABCR variant in Table 1 of the original study14 actually had Stargardt disease and should have been reported in the STGD column. Login to comment 54 ABCA4 p.Pro940Arg Subsequent to the publication of the initial study, one of the original 167 patients was found to have a P940R ABCR variant that was not present in the STGD or general-population cohorts. Login to comment 66 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn Statistical analysis becomes even more challenging if individual ABCR variants are examined, because the number of subjects becomes quite small, but two variants, G1961E and D2177N, deserve special attention. Login to comment 67 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Not only are they more common than other AMD-associated variants,14 but their association with risk of AMD has been confirmed in a large consortium study,19 and they alter ABCR adenosine triphosphatase (ATPase) activity in vitro in a manner similar to the majority of Stargardt- and AMD-associated ABCR variants analyzed so far.28 Three of four siblings of G1961E probands who also carried the variant G1961E allele had grade 2 or greater maculopathy, whereas both siblings who did not carry the variant allele had grade 4 disease. Login to comment 68 ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn Four of seven siblings of D2177N probands who also carried the variant allele had grade 2 or greater maculopathy, whereas four of five siblings who did not carry the variant D2177N allele had grade 2 or greater maculopathy. Login to comment 70 ABCA4 p.Ile1562Thr For example, all three living siblings in kindred K4495 share the proband`s I1562T ABCR allele (Fig. 2), and all four had virtually identical severe bilateral geographic atrophy of the macula (grade 4 AMD) with onset late in the seventh or early in the eighth decade of life in each individual (Fig. 3). Login to comment 74 ABCA4 p.Asp2177Asn segregation of the family`s D2177N ABCR allele with AMD phenotype (Fig. 4). Login to comment 75 ABCA4 p.Asp2177Asn The eldest sibling had moderate (grade 3) AMD, but did not carry the family proband`s D2177N ABCR variant. Login to comment 76 ABCA4 p.Asp2177Asn Two siblings (one older and one younger than the proband) carried the D2177N variant and exhibited mild to moderate AMD, whereas two others (one older and one younger than the proband) carried the variant but exhibited no signs of AMD. Login to comment 115 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn Our study of the D2177N and G1961E mutations in age-matched ophthalmoscopically examined control subjects confirms that an ABCR variant does not by itself confer an AMD phenotype in all cases, but may increase susceptibility to the complex trait when large populations are examined.19 The fact that many siblings have AMD without the same ABCR variant as the family proband is not unexpected, especially because there are likely to be other inherited and environmental risk factors that have not yet been identified that may act alone or in concert with ABCR alleles to enhance susceptibility to AMD. Login to comment 129 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn This is a recurring problem facing investigators studying other complex adult-onset multifactorial diseases, such as breast cancer and prostate cancer.46,47 Statistical power analysis indicates that we would need 144 siblings to achieve an 80% power of detecting a statistically significant elevated risk at P ϭ 0.05 if the study population prevalence of AMD is assumed to be 10% and the elevated risk of AMD conferred by any AMD-associated ABCR variant is comparable to the approximately threefold elevation in AMD risk found for the G1961E and D2177N ABCR variants in the International ABCR Consortium Study.19 Although there is mounting evidence that heterozygous variants in ABCR contribute to AMD susceptibility, we should not expect consistent concordance of variant alleles with AMD phenotype, because it is a complex trait influenced by a multitude of other hereditary and environmental risk factors. Login to comment 131 ABCA4 p.Ile1562Thr For example, all four siblings in kindred K4495 carried the same I1562T mutation, and all four had severe geographic atrophy in their eighth decade. Login to comment