Novel MIP gene mutation causes autosomal-dominant congenital cataract

To identify disease-causative mutations in families with congenital cataract. Two Chinese families with autosomal-dominant congenital cataract (ADCC) were recruited and underwent comprehensive eye examinations. Gene panel next-generation sequencing of common pathogenic genes of congenital cataract was performed in the proband of each family. Sanger sequencing was used to valid the candidate gene mutations and sequence the other family members for co-segregation analysis. The effect of sequence changes on protein structure and function was predicted through bioinformatics analysis. Major intrinsic protein (MIP)-wildtype and MIP-G29R plasmids were constructed and microinjected into zebrafish single-cell stage embryos. Zebrafish embryonic lens phenotypes were screened using confocal microscopy. A novel heterozygous mutation (c.85G>A; p.G29R) in the gene was identified in the proband of one family. A known heterozygous mutation (c.97C>T; p.R33C; rs864309693) in was found in the proband of another family. prediction indicated that the novel mutation might affect the MIP protein function. Zebrafish embryonic lens was uniformly transparent in both wild-type PCS2+MIP and mutant PCS2+MIP. Two missense mutations in the gene in Chinese cataract families are identified, and one of which is novel. These findings expand the genetic spectrum of mutations associated with cataracts. The functional studies suggest that the novel mutation might not be a gain-of-function but a loss-of-function mutation.