Localization Of The Disease-associated Gene Of Autosomal Dominant Congenital Y-suture Cataract

[Objective] Congenital cataract is the leading cause of visual impairment in children and it was reported that about8.3-25%of congenital cataracts are inherited, with autosomal dominant transmission the most common mode of inheritance, although autosomal recessive and X-linked traits of inheritance exist. To date, more than25represent genes and35independent loci have been identified for congenital cataracts. Our study is to localization the disease-causing mutation of a typical Y-suture cataract pedigree.[Methods] A four-generation Chinese family from a remote mountain region of Guizhou province with autosomal dominant congenital cataract (ADCC) was recruited.16individuals participated in the study:8unaffected and8affected of whom2were male and6were female. All family members underwent history and ophthalmological examinations, including visual acuity, slit lamp, and fundus examinations with dilated pupils. The affected status was determined by a history of cataract extraction or ophthalmological examinations. Genomic DNA samples were extracted from the peripheral blood leukocytes of the family members. All the exons and flanking intronic sequences of candidate genes were amplified by polymerase chain reaction (PCR) and screened for mutation by direct bidirectional DNA sequencing. We used the online SWISS-MODEL and DEEP VIEW/SWISS-Pdb tool to analyze both the mutant and wild-type version of the structure of the MIP protein. For hydropathy analysis, we used Compute pI/MW to predict the isoelectric point (pI) and the molecular weight (MW) of the wild-type and mutant protein. Furthermore, online Mutation Taster software was used to distinguish between functionally neutral and deleterious mutations.[Results]The phenotype was a typical bilateral Y-sutural cataract, combined with punctuate cortical opacities by slit lamp photography. The family inherited model was identified as autosomal dominant according to the genealogy. Sequencing of the candidate genes detected a heterozygous C.337C>T change in the coding region of the MIP gene, leading to the replacement of a wild-type arginine with a stop codon at the113th amino acid position (p.R113X), which produced a shortened protein contained only112amino acids rather than the normal263. It co-segregated well with all8affected individuals and was not found in unaffected family members or in the100unrelated normal controls. The automated homology protein of human MIP was modeled in three dimensions by the Swiss-Model and DEEP VIEW/SWISS-Pdb tool, which indicated a severely truncated protein that lacks important functional domains on the C-terminal region. The theoretical pI of mutant MIP was increased to9.18compared to the wild-type pI of8.62. The MW of the mutant (11956Da) was significantly reduced compared to the MW of the wild-type MIP (28121Da), as predicted by Compute pI/MW. Results obtained with the online bioinformatics software Mutation Taster showed that the mutation was predicted to be "probably damaging"[Conclusions] We identified a novel mutation of MIP (p.R113X) in a Chinese cataract family, which co-segregated well with the presence of Y-sutural cataract. This mutation is probably the causative lesion for the observed phenotype in this family. This study confirmed that the congenital cataract were genetially heterogeneous. This is the first nonsense mutation of MIP identified thus far and the results add to the list of mutations of the M/P-linked cataracts, further supporting the notion that MIP play an important role in humall lens development and cataract formation.