ABCMdb

PMID: 23755871

Riveiro-Alvarez R, Lopez-Martinez MA, Zernant J, Aguirre-Lamban J, Cantalapiedra D, Avila-Fernandez A, Gimenez A, Lopez-Molina MI, Garcia-Sandoval B, Blanco-Kelly F, Corton M, Tatu S, Fernandez-San Jose P, Trujillo-Tiebas MJ, Ramos C, Allikmets R, Ayuso C
Outcome of ABCA4 disease-associated alleles in autosomal recessive retinal dystrophies: retrospective analysis in 420 Spanish families.
Ophthalmology. 2013 Nov;120(11):2332-7. doi: 10.1016/j.ophtha.2013.04.002. Epub 2013 Jun 4., [PubMed]

Sentences

No. Mutations Sentence Comment

42 ABCA4 p.Arg1129Leu ABCA4 p.Arg1129Leu ABCA4 p.Arg1129Leu Because of the existence of a prevalent disease-associated allele in the Spanish STGD patients, p.Arg1129Leu, 159 arSTGD patients were classified into 4 major categories: (1) those homozygous for p.Arg1129Leu (n &#bc; 8), (2) those compound heterozygous for this mutation (n &#bc; 58), (3) patients with complex alleles on at least 1 chromosome (n &#bc; 10), and (4) those harboring compound heterozygous mutations excluding the p.Arg1129Leu allele (n &#bc; 83). Login to comment 44 ABCA4 p.Arg1129Leu Patients who are homozygous for the p.Arg1129Leu allele (i.e., in the first group) always have an arSTGD phenotype at presentation, and the average age at onset of the disease was at the beginning of the third decade of life (20.6), ranging from 12 to 40 years of age. Login to comment 48 ABCA4 p.Arg1129Leu Finally, the largest group of patients was compound heterozygous for ABCA4 mutations and did not harbor the p.Arg1129Leu variant. Login to comment 60 ABCA4 p.Arg1129Leu In addition, the Spanish founder mutation p.Arg1129Leu was identified in only 3 families with arCRD (MD-0247, MD- 0390, and RP-0532; Table 2, available at http://aaojournal.org). Login to comment 75 ABCA4 p.Arg1129Leu The most prevalent p.Arg1129Leu allele, which accounts for 22.4% of the mutant alleles in the Spanish STGD population, is associated mainly with the arSTGD phenotype. Login to comment 78 ABCA4 p.Arg1129Leu Thus, p.Arg1129Leu could be considered a relatively moderate allele, and the severity of the phenotype is determined by the second mutation in compound heterozygotes (see below). Login to comment 86 ABCA4 p.Arg1129Leu This study has the advantage of the presence of a common missense mutation, p.Arg1129Leu, in the Spanish STGD population that accounts for almost one-fourth of all mutant alleles. Login to comment 87 ABCA4 p.Arg1129Leu ABCA4 p.Arg1129Leu As seen in Table 1 (available at http://aaojournal.org), 8 patients were homozygous for the p.Arg1129Leu variant and 58 were compound heterozygous, therefore reducing the variability in the patient pool and allowing comparison with other mutations that are found in the same patients with the p.Arg1129Leu variant (which is constant). Login to comment 88 ABCA4 p.Leu541Pro ABCA4 p.Thr1019Met ABCA4 p.Arg602Trp ABCA4 p.His1838Asp ABCA4 p.Leu1940Pro Based on our data, the likely severe ABCA4 missense mutations, resulting in an early disease onset and severe disease, include, among others: p.Leu541Pro, p.Arg602Trp, p.Thr1019Met, p.Leu1940Pro, and p.His1838Asp. Login to comment 90 ABCA4 p.Gly1961Glu ABCA4 p.Leu541Pro ABCA4 p.Arg602Trp ABCA4 p.His1838Asp ABCA4 p.Leu1940Pro These results are supported by previous findings that the p.Leu541Pro and p.Arg602Trp variants result in mislocalized protein,22 the p.Leu1940Pro and IVS38e10T/C variants confer much earlier onset of the disease,23 and the p.His1838Asp variant, in a complex allele with the p.Gly1961Glu mutation, results in an early-onset, severe disease.24 Although the above estimates are simplified because they do not take into account environmental factors and genetic variation at other loci in these patients, they serve as a good basis for association with disease onset and disease severity. Login to comment 91 ABCA4 p.Arg18Trp ABCA4 p.Leu11Pro ABCA4 p.Ala538Val Almost all disease-associated variants were found in both arSTGD and arCRD phenotypes in our cohort, with the exception of p.Leu11Pro, p.Arg18Trp, p.Ala538Val, and p.Val1973*, which were associated only with CRD. Login to comment