ABCMdb

PMID: 23329738

Burke TR, Allikmets R
Author response: Retinal phenotypes in patients homozygous for the G1961E mutation in the ABCA4 gene.
Invest Ophthalmol Vis Sci. 2013 Jan 17;54(1):521. doi: 10.1167/iovs.12-11528., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Letters Author Response: Retinal Phenotypes in Patients Homozygous for the G1961E Mutation in the ABCA4 Gene We appreciate the interest and comments of Burton et al.1 relating to our recent publication ''Retinal phenotypes in patients homozygous for the G1961E mutation in the ABCA4 gene.``2 In our report of 12 patients homozygous for the G1961E mutation, six patients had ''milder`` and six had more ''severe`` retinal disease phenotypes (as suggested by the extent of retinal changes present). Login to comment 1 ABCA4 p.Gly1961Glu Of the six patients in the latter group, five had additional mutations detected in cis with G1961E on either one or both chromosomes (i.e., complex alleles), clearly exacerbating protein dysfunction and, consequently, disease severity. Login to comment 2 ABCA4 p.Gly1961Glu We concluded that the G1961E mutation causes disease in homozygosity and that these patients exhibit a wide range of retinal phenotypes. Login to comment 3 ABCA4 p.Gly1961Glu Therefore, our findings were consistent with the authors` statement that ''there may not be a meaningful difference in the phenotype`` between patients homozygous and (compound) heterozygous for the G1961E mutation. Login to comment 4 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu The publications that they cited, together with other reports (both from our group as well as that from others), have shown that G1961E, in either compound heterozygous or homozygous state, tends to be associated with a localized retinal disease phenotype, including bull`s eye maculopathy, the absence of a ''silent`` choroid on fluorescein angiogram, and a normal full-field electroretinogram.3-5 The cumulative evidence suggests that even in cases of a ''severe`` second mutation (those resulting in a nonfunctional protein, such as nonsense mutations and frameshift-generating variants), G1961E tends to yield a ''milder`` phenotype, although variation in phenotype has also been reported in such patients.6 With regard to age of onset of visual symptoms in ABCA4 disease, the severity of phenotype may also be affected by environmental or genetic (other than ABCA4) modifying factors and their effects on ABCA4 protein function. Login to comment 7 ABCA4 p.Gly1961Glu Nonetheless, trends in age of onset emerge from the studies of patient cohorts that carry at least one mutation, which is the same for the entire cohort, and these have suggested that this is generally later for patients with the G1961E mutation. Login to comment 8 ABCA4 p.Gly1961Glu In summary, patients homozygous and heterozygous for the G1961E mutation in the ABCA4 gene tend to demonstrate a milder phenotype, including a later age of onset of visual symptoms. Login to comment 13 ABCA4 p.Gly1961Glu Retinal phenotypes in patients homozygous for the G1961E mutation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2013;54:520. Login to comment 14 ABCA4 p.Gly1961Glu 2. Burke TR, Fishman GA, Zernant J, et al. Retinal phenotypes in patients homozygous for the G1961E mutation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2012;53:4458-4467. Login to comment 23 ABCA4 p.Gly1961Glu Cella W, Greenstein VC, Zernant-Rajang J, et al. G1961E mutant allele in the Stargardt disease gene ABCA4 causes bull`s eye maculopathy. Login to comment