A novel single‐base deletional mutation of MIP impairs protein distribution and cell‐to‐cell adhesion in autosomal dominant cataracts in a Chinese family

Abstract

AbstractCongenital cataracts are the leading cause of irreversible visual disability in children, and genetic factors play an important role in their development. In this study, targeted exome sequencing revealed a novel single‐base deletional mutation of MIP (c.301delG; p.Ala101Profs*16) segregated with congenital punctate cataract in a Chinese family. The hydrophobic properties, and secondary and tertiary structures for truncated MIP were predicted to affect the function of protein by bioinformatics analysis. When MIP‐WT and MIP‐Ala101fs expression constructs were singly transfected into HeLa cells, it was found that the mRNA level showed no significant difference, while the protein level of the mutant was remarkably reduced compared to that of the wild‐type MIP. Immunofluorescence images showed that the MIP‐WT was principally localized to the plasma membrane, whereas the MIP‐Ala101fs protein was aberrantly trapped in the cytoplasm. Furthermore, the cell‐to‐cell adhesion capability and the cell‐to‐cell communication property were both significantly reduced for MIP‐Ala101fs compared to the MIP‐WT (all *p < 0.05). This is the first report of the c.301delG mutation in the MIP gene associated with autosomal dominant congenital cataracts. We propose that the cataract is caused by the decreased protein expression and reduced cell‐to‐cell adhesion by the mutant MIP. The impaired trafficking or instability of the mutant protein, as well as compromised intercellular communication is probably a concurrent result of the mutation. The results expand the genetic and phenotypic spectra of MIP and help to better understand the molecular basis of congenital cataracts.