ABCMdb

PMID: 12824224

Schmidt S, Postel EA, Agarwal A, Allen IC Jr, Walters SN, De la Paz MA, Scott WK, Haines JL, Pericak-Vance MA, Gilbert JR
Detailed analysis of allelic variation in the ABCA4 gene in age-related maculopathy.
Invest Ophthalmol Vis Sci. 2003 Jul;44(7):2868-75., [PubMed]

Sentences

No. Mutations Sentence Comment

100 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn We did not detect the variants G1961E (5882G3A, exon 42) and D2177N (6529G3A, exon 48) reported as disease-associated16 in any of the 257 samples screened in this study. Login to comment 102 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn In agreement with the DHPLC results, we did not detect G1961E and D2177N in this patient population. Login to comment 103 ABCA4 p.Asp2177Asn In our earlier work,18 we had detected the D2177N variant in two of our sporadic patients with ARM. Login to comment 114 ABCA4 p.Glu1087Lys DHPLC Sensitivity The sequencing of 10% of the samples for those exons in which DHPLC did not detect the presence of sequence polymorphisms led to the detection of two additional variants: 3261G3A, a missense (Glu1087Lys) variant in exon 22, and 4848-16delAC in intron 34. Login to comment 123 ABCA4 p.Cys1490Tyr ABCA4 p.Leu2027Phe ABCA4 p.Arg212His ABCA4 p.Asn1868Ile ABCA4 p.Thr901Ala ABCA4 p.Pro1948Leu ABCA4 p.His423Arg ABCA4 p.Asp197Asn ABCA4 p.Ser1736Pro Polymorphisms and Rare Sequence Variants in Exons of the ABCA4 Gene Exon Nucleotide Change Effect Allele Frequency* P† P§ Referenceሻ Independent ARM (n ‫؍‬ 140) All ARM (n ‫؍‬ 330) Control Subjects (n ‫؍‬ 118) 6 589G3C Asp197Asn 0.000 0.000 0.009 0.46 0.12 - 6 635G3A Arg212His 0.030 0.026 0.000 0.13 0.11 W, R 10 1268A3G His423Arg 0.394 0.371 0.427 0.62‡ 0.34 W, R 10 1269C3T His423His(syn) 0.033 0.039 0.031 1.0 0.74 W 18 2701A3G Thr901Ala 0.000 0.003 0.000 NA 0.58 W, R 23 3495C3T Asn1165Asn(syn) 0.000 0.003 0.000 NA 0.75 - 30 4469G3A Cys1490Tyr 0.007 0.003 0.000 1.0 0.59 W 37 5206T3C Ser1736Pro 0.009 0.008 0.000 1.0 0.44 W 40 5603T3A Asn1868Ile 0.100 0.102 0.054 0.29 0.18 W 40 5682G3C Leu1894Leu(syn) 0.293 0.272 0.298 1.0 0.64 W 41 5814A3G Leu1938Leu(syn) 0.160 0.169 0.218 0.33 0.38 W 42 5843C3T Pro1948Leu 0.052 0.038 0.054 1.0 0.50 W 42 5844A3G Pro1948Pro(syn) 0.199 0.192 0.205 1.0 0.77 W 44 6069C3T Ile2023Ile(syn) 0.040 0.050 0.044 1.0 0.82 W 44 6079C3T Leu2027Phe 0.000 0.000 0.009 0.48 0.13 W * Actual n (number of chromosomes) varies, as frequencies were calculated relative to nonmissing data only. Login to comment 158 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn However, the fact that we did not detect a single copy of the only variants that have so far been reported as potentially disease associated, G1961E (5882G3A) and D2177N (6529G3A), in any of our 165 patients with ARM, suggests that their contribution to this phenotype is small at best. Login to comment 170 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn The frequency of potentially disease-associated variants has been consistently estimated to be no higher than 1% in a nonpatient population.11,12,16,20 Because of uncertainty about the true effect size, we have assumed three plausible relative risk values for an ABCA4 variant: 5, estimated for G1961E;16 3, estimated for D2177N;16 and 1.5, the lower confidence limit for G1961E.16 Power calculations using commercial software (nQuery-Advisor; Statistical Solutions, Saugus, MA) and DSTPLAN (http://odin. Login to comment 183 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn However, it is not clear that the two sequence variants proposed to be disease-associated in humans (G1961E, D2177N) are equivalent to a null mutation, even though they were shown to have some effect on the function of the ABCA4 protein.46 An animal model can be an invaluable tool for assessing the potential significance of sequence variation in a candidate gene; however, caution is necessary in inferring functional consequences in the context of complex human disease from data generated on mice. Login to comment 188 ABCA4 p.Gly1961Glu That said, several recent empiric studies have suggested that the impact of population stratification in reasonably well-designed genetic-epidemiologic studies may not be as large as initially suspected.47,48 Nevertheless, the report of a much higher prevalence of the G1961E allele in healthy individuals of Somali ancestry20 was illuminating, and, in the absence of high prevalences of either ARM or STGD in Somalia, certainly raised doubts about the potential disease association of this allele. Login to comment