ABSTRACT
PURPOSE: Stargardt disease type 1 (STGD1) is a recessively inherited retinal disorder that can cause severe visual impairment. ABCA4 mutations are the usual cause of STGD1. ABCA4 codes a transporter protein exclusively expressed in retinal photoreceptor cells. The genecontains 50 exons. Mutations are most frequent in exons 3, 6, 12, and 13, and exons 10 and 42 each contain two common variations. We aimed to screen these exons for mutations in Iranian STGD1 patients. METHODS: Eighteen STGD1 patients were recruited for genetic analysis. Diagnosis by retina specialists was based on standard criteria, including accumulation of lipofuscin. The six ABCA4 exons were PCR amplified and sequenced by the Sanger method. RESULTS: One or more ABCA4-mutated alleles were identified in 5 of the 18 patients (27.8%). Five different mutations including two splice site (c.1356+1G > A and c.5836-2A > G) and three missense mutations (p.Gly1961Glu, p.Gly1961Arg, and p.Gly550Arg) were found. The p.Gly1961Glu mutation was the only mutation observed in two patients. CONCLUSION: As ABCA4 mutations in exons 6, 12, 10, and 42 were identified in approximately 25% of the patients studied, these may be appropriate exons for screening projects. As in other populations, STDG1 causative ABCA4 mutations are heterogeneous among Iranian patients, and p.Gly1961Glu may be relatively frequent.
ABSTRACT
Purpose: Peters anomaly (PA) is a heterogeneous developmental disorder characterized by central corneal opacity and iridocorneal or corneolenticular adhesions. Although many causative genes have been identified, most screened patients do not have mutations in the known genes. We aimed to identify the genetic cause of Peters anomaly in a pedigree with three affected individuals. Methods: Slit-lamp biomicroscopy and ultrasound biomicroscopy were performed for definitive diagnosis. Exome sequencing was conducted on the DNA of all three patients. After identification of a candidate causative gene, expression of the gene was assessed with real-time PCR in various ocular tissues of three human embryos and three adults. Results: The patients were affected with isolated PA. The parents of the patients were related to one another. Inheritance of PA was autosomal recessive. After appropriate filtering of the exome data, a homozygous variation in DOP1B remained as the only candidate genetic cause of PA in the pedigree. The variant segregated with disease status in the pedigree and was absent among 800 control Iranians. The variant has been reported in various databases at frequencies of 0.006 or less only in the heterozygous state in some cohorts of African origin. The p.Val1660 amino acid affected by the mutation is completely conserved in mammals and birds during evolution. Expression of DOP1B was shown in all adult and embryonic lens, iris, cornea, sclera, and retina tissues that were tested. Conclusions: DOP1B that encodes DOP1 leucine zipper like protein B was identified as the putative PA-causing gene in pedigree PA-101. As DOP1B is positioned within the Down syndrome chromosomal region on chromosome 21, until now this gene has mostly been studied with respect to brain functions. However, members of the Dopey gene family have been shown to have roles in development in other organisms. Evidence of the expression of DOP1B in various PA-relevant eye tissues, which, to the best of our knowledge, is shown here for the first time, is to be noted. However, this finding does not necessarily implicate a specific role for DOP1B in eye development as the gene is expressed in many tissues. Ultimately, definitive assessment of the contribution of DOP1B to PA pathology awaits identification of mutations in the gene in unrelated patients with PA and functional studies.
