Identification of Mutations in Myocilin and Beta-1,4-galactosyltransferase 3 Genes in a Chinese Family with Primary Open-angle Glaucoma

Abstract

Background:Glaucoma is a major cause of irreversible blindness worldwide. There is evidence showing that a subset of the disease is genetically determined. In this study, we screened for mutations in chromosome 1q-linked open-angle glaucoma (GLC1A) in a Chinese family with primary open-angle glaucoma (POAG).Methods:A total of 23 members from five generations of a family were enrolled and underwent thorough ophthalmologic examinations. In addition, 200 unrelated healthy Chinese controls were also recruited as normal control. GLC1A gene was amplified by polymerase chain reaction, and DNA sequencing was performed to screen for mutations.Results:Six members were diagnosed as POAG, with severe clinical manifestations, and history of high intraocular pressures. The mean age of disease onset was 26.3 years. However, the others were asymptomatic. In six affected and three asymptomatic members, gene sequencing revealed a mutation c.C1456T in exon 3 of myocilin gene (MYOC). Furthermore, we also identified a novel mutation c.G322A in beta-1,4-galactosyltransferase 3 (B4GALT3) gene in all six affected and three asymptomatic members, which was not reported previously in POAG patients. The two newly identified variants were absent in other family members as well as controls.Conclusion:The mutations c.1456C<T (p.L486F) in MYOC and c.322G<A (p.V108I) in B4GALT3 are likely responsible for the pathogenesis of POAG in this family.

Glaucoma Pathogenesis and Neurotrophins: Focus on the Molecular and Genetic Basis for Therapeutic Prospects

“…Recently, a mutation C1456_T in MYOC gene was identified in a Chinese family. Beta-1, 4-galactosyltransferase 3 ( B4GALT3 ) gene also showed mutation at G322_A in this POAG family [ 137 ]. In a transgenic mouse model of POAG, MYOC mutation Y437_H shows a significant increase in IOP with abnormal extracellular matrix accumulation that potentially reduces aqueous outflow [ 136 ].…”

Analysis of glaucoma genes in Finnish patients with juvenile open‐angle glaucoma

“…This variant has a relatively high frequency in gnomAD (0.00002) for a rare autosomal dominant disease, and we speculate that it might have reduced penetrance. Two other MYOC missense variants, p.(Leu486Phe) and p.(Val402Ile), have been previously reported in non‐Finnish patients with glaucoma (Fingert et al, 1999; Huang et al, 2014; Liao et al, 2016), while the MYOC p.(Asp378Asn) is a novel variant, although a different pathogenic missense change at the same amino acid residue has been reported before in a Chinese patient with sporadic JOAG (Huang et al, 2014). JG059 and JG060, father and son, harboured this novel variant and were diagnosed with JOAG at the age of 15 and 29, respectively.…”

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

“…It has been demonstrated that MYOC Q368X constitutes the most frequent variation responsible for late-onset POAG development, with an average age of 59 years at the date of diagnosis, whereas the Y437H mutation is responsible for early-onset glaucoma with an average age of onset of 20 years [115]. Besides, it has been reported that C1456T mutation in MYOC was responsible for the POAG pathogenesis in the Chinese family [123].…”