ABCMdb

PMID: 18506364

Shastry BS
Evaluation of the common variants of the ABCA4 gene in families with Stargardt disease and autosomal recessive retinitis pigmentosa.
Int J Mol Med. 2008 Jun;21(6):715-20., [PubMed]

Sentences

No. Mutations Sentence Comment

8 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Arg943Gln In order to further understand the contribution of this gene to the susceptibility to STGD and RP, we analyzed three unrelated STGD families and one autosomal recessive RP family specifically for the more common variants (A1038V, G1961E, 2588G&#a1;C, R943Q or 2828G&#a1;A) in the ABCA4 gene. Login to comment 9 ABCA4 p.Arg943Gln Our analyses employing standard techniques such as polymerase chain reaction, restriction fragment length polymorphism, and direct DNA sequencing of amplified products were able to identify one common variant (R943Q) in all three STGD families but not in the RP family. Login to comment 49 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Arg943Gln To further extend the diagnostic and prognostic value of the molecular genetic study of STGD and to understand the genetic heterogeneity of RP, in this report we analyzed three unrelated STGD families and one AR RP family specifically for the more common variants (A1038V, G1961E, R943Q or 2828G&#a1;A and 2588G&#a1;C) of the ABCA4 gene which when mutated produce a broad spectrum of the retinal phenotypes including RP and age-related macular degeneration (AMD). Login to comment 79 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Arg943Gln The amplified product was subjected to restriction enzyme digestion with either 10 units of Alu I (2588G&#a1;C mutation in exon 17 of ABCA4 gene creates a site for Alu I), or Bse YI (A1038V mutation in exon 21 destroys a site for Bse YI), or Taq I (G1961E variation in exon 42 in ABCA4 creates a Taq I site), or Msp I (R943Q alteration in exon 19 destroys the Msp I site), or Nla III (Y402H mutation in exon 9 of the CFH gene creates a Nla III site) at 37da;C (Alu I, Bse YI, Msp I, Nla III) and 65da;C (Taq I) for 1 h. Login to comment 83 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Arg943Gln The finding that the variants A1038V (exon 21), G1961E (exon 42), 2588G&#a1;C (exon 17) and R943Q (exon 19) which is previously known as 2828G&#a1;A (4) are more common INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 21: 715-720, 2008 717 Figure 1. Login to comment 92 ABCA4 p.Gly1961Glu ABCA4 p.Arg943Gln The restriction enzyme digestion patterns for R943Q (Msp I) and G1961E (Taq I) changes are shown in Fig. 3A and B respectively. Login to comment 97 ABCA4 p.Arg943Gln This experiment demonstrated that three out of four patients were heterozygous for the R943Q alteration, but this mutation did not segregate in the family (family 1). Login to comment 98 ABCA4 p.Gly1961Glu Similar experiments with the Taq I enzyme for the G1961E mutation detected no alteration in any patient (Fig. 3B). Login to comment 99 ABCA4 p.Ala1038Val Additionally, we failed to detect the other two alterations (A1038V and 2588G&#a1;C). Login to comment 103 ABCA4 p.Gly1961Glu ABCA4 p.Arg943Gln Restriction digestion patterns of PCR-amplified products for R943Q (A) and G1961E (B) variants. Login to comment 104 ABCA4 p.Arg943Gln All three patients (patients II-1 in families 1-3) were heterozygous (lanes 3-8 in A) for the R943Q mutation whereas the affected individual I-3 in family 1 was completely normal (lanes 9-10). Login to comment 105 ABCA4 p.Gly1961Glu Similar experiments with Taq I enzyme for the G1961E mutation did not detect any alterations (B). Login to comment 109 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val Restriction digestion patterns of PCR-amplified products for variants 2588 G&#a1;C (A), A1038V (B), G1961E (C) and Y402H (D). Login to comment 114 ABCA4 p.Gly1961Glu Additionally, variants G1961E in the ABCA4 gene and Y402H in exon 9 of the CFH gene are associated with AMD at a statistically significant level. Login to comment 125 ABCA4 p.Arg943Gln Our analysis detected only one of the more common variants R943Q (also known as 2828G&#a1;A) located in exon 19 in all three STGD families (but not in RP), and three of the four affected individuals were heterozygous for this mutation. Login to comment 126 ABCA4 p.Arg943Gln The R943Q alteration results in a non-conservative amino acid substitution, and this variation was most often found to be in linkage disequilibrium with presumably a pathogenic variation 2588G&#a1;C in exon 17 in a western European population (4). Login to comment 128 ABCA4 p.Arg943Gln Additionally, as suggested by others, the R943Q variation may not be a pathogenic mutation by itself because it was not segregating in the family (STGD family 1), and the affected individual (I-3) had normal alleles (Fig. 3A, lanes 9-10). Login to comment 135 ABCA4 p.Arg943Gln We also cannot assess the functional consequences of the R943Q alteration in the affected individuals at present because there is no functional test for ABCA4 activity. Login to comment