Extension of the mutation spectrum of PAX6 from three Chinese congenital aniridia families and identification of male gonadal mosaicism

Abstract

BackgroundCongenital aniridia is a severe autosomal dominant binocular developmental disorder, the primary feature of which is congenital absence or hypoplasia of the iris. PAX6 is the main disease‐causing gene of congenital aniridia; inheritance is autosomal dominant. But the current mutations do not fully explain this disorder.MethodsWe investigated the mutation profile of genes related in three Chinese families with congenital aniridia through targeted sequencing technology. And we validated the candidate variants by PCR‐based Sanger sequencing. Different degree impairments of islet function were observed in the patients with aniridia by carbohydrate tolerance butter and insulin release tests in our study.ResultsWe identified four novel mutations of PAX6 from three Chinese families with congenital aniridia, which included heterozygous double mutation c.879_880delCA (p.S294Cfs*46) and c.1124C>G (p.P375R) in Family 1 with three patients, heterozygous frameshift mutation c.308delG (p.P103Qfs*21) in Family 2 with one patient, and c.1192delT (p.S398Pfs*126) in Family 3 with two patients. The three frameshift mutations of PAX6 are co‐segregated with the aniridia from controls in the families, but the novel missense mutation is not co‐segregated with the phenotype. The frameshift mutations in Family 1 and Family 2 have effects to truncate the protein, but the frameshift mutation in Family 3 will prolong it. We confirmed the phenomenon of male gonadal mosaicism of PAX6 by the sequencing of two linked novel mutations in Family 1. Most of the patients with isolated aniridia have different degrees of islet damage through related clinical tests.ConclusionIt is therefore noteworthy that we found different types of pathogenic mutation, which have effects of truncating or prolonging protein leaded by frameshift mutation. Our results of this study extended the pathogenic mutation spectrum of PAX6 for congenital aniridia and demonstrated the male germline chimerism by molecular experiments.

The Spectrum of PAX6 Mutations and Genotype-Phenotype Correlations in the Eye

“…Quantitative analysis of parental PAX6 gene showed that all of the proband's fathers have mutant allele fractions that range from 13 to 29%, depending on the tissue analysed, and have mild or no ocular features as compared to their affected offspring. Similarly, Bai et al reported the presence of male gonadal mosaicism in a Chinese family with aniridia caused by PTC-inducing mutation c.879_880delCA, p.Ser294Cysfs*46 [109].…”

“…Recent studies reported that the rate of mosaicism could be as high as 17.5% among apparent de novo cases for different dominant disorders [83,107]. Indeed, several reports have suggested mosaicism as the cause for the variable phenotypes seen in some sporadic PAX6-affected patients [83,93,108,109]. A recent study from Tarilonte et al proved the existence of post-zygotic parental mosaicism in three unrelated Spanish families with variable aniridia or microphthalmia phenotypes caused by heterozygous nonsense (c.771G>A, p.Trp257* and c.120C>A, p.Cys40*) or missense (c.178T>C, p.Tyr60His) PAX6 mutations, respectively [110].…”

“…MAC is a group of developmental eye disorders characterised by reduced size orabsence of the ocular globe and it is caused by mutations in more than 90 genes, including PAX6 (Figure 4) [91]. Of the 13 different mutations that are associated with microphthalmia in the PAX6 Mutation Database, the vast majority (8) are missense, although PTC-inducing mutations have been reported (two nonsense and two frameshifts) ( Figure 5) [107,109,134,135]. Bilateral microphthalmia in a patient with WAGR syndrome was also identified [136].…”

The Genetic and Endoplasmic Reticulum-Mediated Molecular Mechanisms of Primary Open-Angle Glaucoma

“…It has been demonstrated that occurrence of PAX6 mutations may result in the development of aniridia, which constitutes a severe panocular eye disease associated with iris hypoplasia [177][178][179][180]. There are several research data confirming a direct correlation of PAX6 gene mutation with aniridia occurrence [181][182][183][184]. Interestingly, it has been reported that aniridia is frequently correlated with glaucoma and glaucoma associated with aniridia may trigger a progressive loss of vision [185].…”