Abstract
Autosomal dominant congenital cataracts (ADCC) are clinically and genetically heterogeneous diseases. The present study recruited two Chinese families with bilateral nuclear cataract or zonular pulverulent phenotype. Direct sequencing of candidate genes identified two novel missense mutations of Cx50, Cx50P59A (c.175C > G) and Cx50R76H (c.227G > A), both co-segregated well with all affected individuals. Bioinformatics analysis predicted deleterious for both mutations. Functional and cellular behaviors of wild type and mutant Cx50 examined by stably transfecting recombinant systems revealed similar protein expression levels. Protein distribution pattern by fluorescence microscopy showed that Cx50R76H localized at appositional membranes forming gap junctions with enormous cytoplasmic protein accumulation, whereas the Cx50P59A mutation was found inefficient at forming detectable plaques. Cell growth test by MTT assay showed that induction of Cx50P59A decreased cell viability. Our study constitutes the first report that the Cx50P59A and Cx50R76H mutations are associated with ADCC and expands the mutation spectrum of Cx50 in association with congenital cataracts. The genetic, cellular, and functional data suggest that the altered intercellular communication governed by mutated Cx50 proteins may act as the molecular mechanism underlying ADCC, which further confirms the role of Cx50 in the maintenance of human lens transparency.
Highlights
Congenital cataracts are defined as opacities of the lens that are present from birth, and are the leading cause of visual disability in children
The present study was designed to characterize the cellular and functional properties of two novel Cx50 mutations that we identified in Chinese pedigrees associated with Autosomal dominant congenital cataracts (ADCC), and to gain further insights into the pathogenesis of inherited cataracts
The proband (IV:2) was a three-year-old boy with bilateral congenital nuclear cataracts, which are characterized as a central, dense nuclear opacity involving the embryonic and fetal nucleus of the lens (Fig. 1B)
Summary
Congenital cataracts are defined as opacities of the lens that are present from birth, and are the leading cause of visual disability in children. Of the disease-causing mutations reported, about half are located in crystallins and a quarter in gap junctions. Gap junctions (GJs) play an important role in the formation of the extensive intercellular communication system for maintaining lens metabolic homeostasis, and transparency[4,5]. A connexon, in turn, consists of six connexin (Cx) subunits, which can cluster at appositional membranes and form gap junction plaques between adjacent cells[8]. The mechanisms proposed to account for the role of these mutations in the development of congenital cataracts include inefficiency in forming gap junction channels or impaired trafficking www.nature.com/scientificreports/. The present study was designed to characterize the cellular and functional properties of two novel Cx50 mutations that we identified in Chinese pedigrees associated with ADCC, and to gain further insights into the pathogenesis of inherited cataracts
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