Abstract
Congenital cataracts are major cause of visual impairment and blindness in children and previous studies have shown about 1/3 of non-syndromic congenital cataracts are inherited. Major intrinsic protein of the lens (MIP), also known as AQP0, plays a critical role in transparency and development of the lens. To date, more than 10 mutations in MIP have been linked to hereditary cataracts in humans. In this study, we investigated the genetic and functional defects underlying a four-generation Chinese family affected with congenital progressive cortical punctate cataract. Mutation screening of the candidate genes revealed a missense mutation at position 448 (c.448G>C) of MIP, which resulted in the substitution of a conserved aspartic acid with histidine at codon 150 (p.D150H). By linkage and haplotype analysis, we obtained positive multipoint logarithm of odds (LOD) scores at microsatellite markers D12S1632 (Zmax = 1.804 at α = 1.000) and D12S1691 (Zmax = 1.806 at α = 1.000), which flanked the candidate locus. The prediction results of PolyPhen-2 and SIFT indicated that the p.D150H mutation was likely to damage to the structure and function of AQP0. The wild type and p.D150H mutant AQP0 were expressed in HeLa cells separately and the immunofluorescence results showed that the WT-AQP0 distributed at the plasma membrane and in cytoplasm, while AQP0-D150H failed to reach the plasma membrane and was mainly retained in the Golgi apparatus. Moreover, protein levels of AQP0-D150H were significantly lower than those of wide type AQP0 in membrane-enriched lysates when the HEK-293T cells were transfected with the same amount of wild type and mutant plasmids individually. Taken together, our data suggest the p.D150H mutation is a novel disease-causing mutation in MIP, which leads to congenital progressive cortical punctate cataract by impairing the trafficking mechanism of AQP0.
Highlights
According to WHO criteria, there are estimated 1.4 million children affected by irreversible blindness worldwide [1]
We investigated the genetic and functional defects underlying a four-generation Chinese family affected with congenital progressive cortical punctate cataract
Through direct sequencing the candidate genes, we identified a mutation in Major intrinsic protein of the lens (MIP), a genes revealed a heterozygous change (G>C) heterozygous transversion at position 448, which was predicted to replace the conserved aspartic acid with a histidine (p.D150H) in AQP0
Summary
According to WHO criteria, there are estimated 1.4 million children affected by irreversible blindness worldwide [1]. Childhood blindness is mainly caused by congenital cataracts, which severely impair the normal visual development of children. Previous reports have shown that about 1/3 of non-syndromic congenital cataracts are inherited [2]. There are at least 20 genes having been identified and mutations in these genes have been linked to autosomal dominant inherited cataracts. These include genes encoding crystallins, membrane proteins (such as gap junction protein alpha-3 [GJA3], gap junction protein alpha-8 [GJA8] and MIP), cytoskeletal proteins (beaded filament structural protein 2 [BFSP2]), and some growth and transcription factors (including heat shock transcription factor 4 [HSF4], Maf-like protein [MAF] and paired-like homeodomain 3 [PITX3]) [3]
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