A Novel Cx50 Insert Mutation from a Chinese Congenital Cataract Family Impairs Its Cellular Membrane Localization and Function

Abstract

Mutations in GJA8 are associated with hereditary autosomal dominant and recessive cataract formation. In this study, a novel insert mutation in GJA8 was identified in a Chinese congenital cataract family and cosegregated with the disease in this pedigree. This insert mutation introduces five additional amino acid residues YAVHY after histidine at the 95 site (p.H95_A96insYAVHY) within the second transmembrane (TM2) domain of Cx50 protein (Cx50-insert). Ectopic expression of Cx50-insert protein impairs the hemichannel functions and gap junction activity compared to wild-type Cx50 protein in human lens epithelial cells. Cx50-insert proteins were mislocated from cytoplasmic membrane to endoplasmic reticulum and lysosome. In mouse lens tissue, our results showed that Cx50 predominant expresses in epithelial cells and fiber cells at the transition zone of lens hinting its roles in lens differentiation. Taken together, these data suggest that the novel insert mutation in the TM2 domain of Cx50 protein, which impairs its trafficking to the cell membrane and gap-junction function, is associated with the cataract formation in this Chinese pedigree.

A novel missense mutation of CRYBA1 in a northern Chinese family with inherited coronary cataract with blue punctate opacities

“…Among them, around 50% of the variations occurred in crystallin genes (α, β, and γ). [9][10][11][12][13] Mutations in the crystalline genes may have negative influences in the stabilization, solvability, and oligomerize characteristics of these proteins, obstruct the sequential and spatial sequence of crystallin and lead to lens opacity. 1,24 The β-crystallin family is composed of βA-3/1, βA-2, βA-4, βB-1, βB-2, and βB-3 crystallins, encoded by the CRYBA1, CRYBA2, CRYBA4, CRYBB1, CRYBB2, and CRYBB3 genes separately.…”

“…8 According to previous reports, crystallin genes associated with congenital cataracts accounted for around half of the known genetic patterns of cataract. [9][10][11][12][13] The water-soluble lens crystallin are separated into α, β, and γ, representing around 90% of all lens proteins. 14 With the vigorous innovation of sequencing technique, Next Generation Sequencing (NGS) has been increasingly utilized to find the genetic defects of inherited cataract, 15 such as genome sequencing, whole exome sequencing, 16 sureselect target enrichment, 16,17 and targeted exome sequencing.…”

Evaluating gap junction variants for a role in pediatric cataract: an overview of the genetic landscape and clinical classification of variants in the GJA3 and GJA8 genes

“…In-frame insertion-deletion variants were only observed with AD inheritance in both genes. There were four reports of this variant type in GJA8: p.(Gly8_Leu11del) [110], p.(His95_Ala96insYAVHY) [111], p. (Lys131del) [20], and p.(Glu144_Leu148del) [112,113]. All of these variants are located in the C-terminal cytoplasmic tail or central cytoplasmic loop of the GJA8 protein.…”

A novel missense mutation of CRYBB1 causes congenital cataract in a Chinese family

“…With the rapid development of molecular diagnostic techniques, more than 40 genes have been associated with congenital cataract, including crystallin genes, which account for about half of the known genetic forms of cataract, membrane proteins genes, structural proteins genes, transcription factors genes, and so on. [2][3][4][5][6][7] In the present study, we investigated the genetic basis of cataract in a Chinese family with three members exhibiting congenital nuclear cataract. By using the targeted exome sequencing, we indentified a novel missense mutation in exon 3 of CRYBB1 as the pathogenic factor for the congenital nuclear cataracts in our family and the results broadened the spectrum of CRYBB1 mutations associated with congenital nuclear cataract.…”