Abstract
BackgroundThe major intrinsic protein gene (MIP), also known as MIP26 or AQP0, is a member of the water-transporting aquaporin family, which plays a critical role in the maintenance of lifelong lens transparency. To date, several mutations in MIP (OMIM 154050) have been linked to hereditary cataracts in humans. However, more pathogenic mutations remain to be identified. In this study, we describe a four-generation Chinese family with a nonsense mutation in MIP associated with an autosomal dominant congenital cataract (ADCC), thus expanding the mutational spectrum of this gene.MethodsA large four-generation Chinese family affected with typical Y-suture cataracts combined with punctuate cortical opacities and 100 ethnically matched controls were recruited. Genomic DNA was extracted from peripheral blood leukocytes to analyze congenital cataract-related candidate genes. Effects of the sequence change on the structure and function of proteins were predicted by bioinformatics analysis.ResultsDirect sequencing of MIP in all affected members revealed a heterozygous nucleotide exchange c.337C>T predicting an arginine to a stop codon exchange (p.R113X). The substitution co-segregated well in all the affected individuals in the family and was not found in unaffected members or in the 100 unrelated healthy controls. Bioinformatics analysis predicted that the mutation affects the secondary structure and function of the MIP protein.ConclusionsWe identified a novel mutation of MIP (p.R113X) in a Chinese cataract family. This is the first nonsense mutation of MIP identified thus far. This novel mutation is also the first disease-causing mutation located in the loop C domain of MIP. The results add to the list of mutations of the MIP linked to cataracts.
Highlights
The major intrinsic protein gene (MIP), known as MIP26 or AQP0, is a member of the water-transporting aquaporin family, which plays a critical role in the maintenance of lifelong lens transparency
The remainder are divided among the genes for heat shock transcription factor-4 (HSF4), major intrinsic protein (MIP), and beaded filament structural protein2 (BFSP2) [3,5,6]
Clinical evaluation We identified a four-generation Chinese family (8 affected and 8 unaffected) with a clear diagnosis of autosomal dominant congenital cataract (ADCC) (Figure 1)
Summary
The major intrinsic protein gene (MIP), known as MIP26 or AQP0, is a member of the water-transporting aquaporin family, which plays a critical role in the maintenance of lifelong lens transparency. Several mutations in MIP (OMIM 154050) have been linked to hereditary cataracts in humans. We describe a four-generation Chinese family with a nonsense mutation in MIP associated with an autosomal dominant congenital cataract (ADCC), expanding the mutational spectrum of this gene. It was reported that about 8.3–25% of congenital cataracts are inherited [3], with autosomal dominant transmission the most common mode of inheritance, autosomal recessive and X-linked traits of inheritance exist [4]. More than 35 independent loci have been identified for nonsyndromic cataract, segregating most often as an autosomal dominant trait, of which 25 represent identified genes [3,5]. Among the cataract mutations reported, about half involve crystallines, and a quarter involve connexins [3,5,6]. The remainder are divided among the genes for heat shock transcription factor-4 (HSF4), major intrinsic protein (MIP), and beaded filament structural protein (BFSP2) [3,5,6]
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