Identification of p.S50P Mutation in a Chinese Family with Autosomal Dominant Congenital Cataract and Its Underlying Pathogenesis.

Congenital cataract refers to a lens opacity caused by multiple etiological factors, including genetic mutation, abnormal metabolism of the lens, and infection. Currently, there are >100 known disease-causing genes as well as 60 known mutations in the Cx46 gene (Gap junction alpha-3, ) associated with congenital cataracts. Dysfunction of gap junctions impairs homeostasis in lens cells, thereby inducing cataract pathogenesis. This study aims to identify the disease-causing mutation in a family with congenital cataract, and to further explore the possible pathogenic mechanism resulting from this mutation. We identified that a recurrent heterozygous missense mutation c.T148C (p.S50P) in was the pathogenic mutation in this family. Previously, this mutation was found in a British family causing bilateral congenital cataract. We further demonstrated that CX46 wild type (WT) was coupled through functional gap junctions in HeLa cells, while mutant Cx46 S50P lost this ability. Moreover, the half-life of Cx46 S50P was longer than that of Cx46 WT, Cx46 S50P protein was also localized to the endoplasmic reticulum and induced more reactive oxygen species compared to Cx46 WT, which may lead to dysregulation of Cx46-formed gap junction. Collectively, our study defines the genetics basis of a congenital cataract family as well as the cellular mechanisms of mutant Cx46 S50P, and provides useful information for further studies of the pathogenesis and therapeutic strategy for treating congenital cataract.