An MIP/AQP0 mutation with impaired trafficking and function underlies an autosomal dominant congenital lamellar cataract

Kumar, Ganesan Senthil; Kyle, John W.; Minogue, Peter J.; Kumar, K. Dinesh; Vasantha, K; Berthoud, Viviana M.; Beyer, Eric C.; Santhiya, S.

doi:10.1016/j.exer.2012.10.010

Cited by 31 publications

(31 citation statements)

References 25 publications

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“…Similarly, Prior studies of mutant MIP proteins have shown a loss of water permeability function and impaired trafficking in expression systems [43], [44]. Our findings were consistent with the results of Senthil Kumar et al [43], who identified the G165D MIP mutation and confirmed that this mutant was involved in congenital lamellar cataracts in a South Indian family. In addition, the expression of MIP and G165D-MIP in Xenopus oocytes and Hela cells suggested that substitution of the conserved glycine residue leads to improper trafficking of AQP0 and destruction of water channel function.…”

Section: Discussionsupporting

confidence: 92%

A Novel MIP Gene Mutation Analysis in a Chinese Family Affected with Congenital Progressive Punctate Cataract

et al. 2014

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Congenital cataracts are one of the leading causes of visual impairment and blindness in children, and genetic factors play an important role in their development. This study aimed to identify the genetic defects associated with autosomal dominant congenital progressive punctate cataracts in a Chinese family and to explore the potential pathogenesis. Detailed family history and clinical data were recorded, and all the family members’ blood samples were collected for DNA extraction. Linkage analysis was performed by microsatellite markers that are associated with punctate cataracts, and logarithm (base 10) of odds (LOD) scores were calculated using the LINKAGE program. Positive two-point LOD scores were obtained at markers D12S1622 (Zmax = 2.71 at θ = 0.0), D12S1724 (Zmax = 2.71 at θ = 0.0), and D12S90 (Zmax = 2.71 at θ = 0.0), which flank the major intrinsic protein of lens fiber (MIP) gene on chromosomal region 12q13. Direct sequencing of the encoding region of the MIP gene revealed a novel mutation (G>D) in exon 4 at nucleotide 644, which caused a substitution of glycine to aspartic acid at codon 215 (p.G215D) for the MIP protein. The mutation cosegregated with all patients with congenital progressive punctate cataracts, but it was absent in the healthy members. Bioinformatics analysis predicted that the mutation affects the function of the MIP protein. The wild type (WT) and G215D mutant of MIP were transfected with green fluorescent protein (GFP) into Hela cells separately, and it was found that the G215D mutant was aberrantly located in the cytoplasm instead of in the plasma membrane. In summary, our study presented genetic and functional evidence linking the new MIP mutation of G215D to autosomal dominant congenital cataracts, which adds to the list of MIP mutations linked to congenital progressive punctate cataracts.

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Section: Discussionsupporting

confidence: 92%

A Novel MIP Gene Mutation Analysis in a Chinese Family Affected with Congenital Progressive Punctate Cataract

et al. 2014

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“…(Arg140*)---PRef [37]F#7F2 monthsUnknown type, nystagmus-AD MIP NM_012064.3 c.494G>Ap. (Gly165Asp)Aquaporin-likeD, D, D-PRef [17]S#4F3 monthsTotal cataract, nystagmus-Sporadic->new AD MIP NM_012064.3 c.530A>Gp. (Tyr177Cys)Aquaporin-likeT, D, D-PRef [18]F#8FBirthUnknown type, nystagmus-AD MIP NM_012064.3 c.612C>Gp.…”

Section: Resultsmentioning

confidence: 99%

“…Two variants were familial and the third was a sporadic case of pediatric cataract. While the two missenses mutations, c.530A > G; p.(Tyr177Cys) and c.494G > A; p.(Gly165Asp), have been previously described [17, 18], the nonsense mutation c.612C > G; p.(Tyr204 * ) in family #8 is a novel variant (Fig. 4d), it might prevent MIP protein transport and reduce the formation of available water channels as well as p.(Lys228Glufs*4), which recently reported by Long X [19].…”

Section: Resultsmentioning

confidence: 99%

Clinical and genetic characteristics of Chinese patients with familial or sporadic pediatric cataract

Leng

Han

et al. 2018

Orphanet J Rare Dis

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BackgroundPediatric cataract is a clinically and genetically heterogeneous disease which is a significant cause of lifelong visual impairment and treatable blindness. Our study aims to investigate the genotype spectrum in a group of Chinese patients with pediatric cataract.MethodsWe enrolled 39 families with pediatric cataract from October 2015 to April 2016. DNA samples of the probands were analyzed by target next-generation sequencing. Variants were validated using Sanger sequencing in the probands and available family members.ResultsIn our cohort of 39 cases with different types of pediatric cataract, 23 cases were found to harbor putative pathogenic variants in 15 genes: CRYAA, CRYBA1, CRYBA4, CRYBB1, CRYGC, CRYGD, MIP, GCNT2, IARS2, NHS, BCOR, BFSP2, FYCO1, MAF, and PAX6. The mutation detection rates in the familial and sporadic cases were 75 and 47.8%, respectively. Of the 23 causative variants, over half were novel.ConclusionsThis is a rare report of systematic mutation screening analysis of pediatric cataract in a comparably large cohort of Chinese patients. Our observations enrich the mutation spectrum of pediatric cataract. Next-generation sequencing provides significant diagnostic information for pediatric cataract cases, especially when considering sporadic and subtle syndromal cases.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0828-0) contains supplementary material, which is available to authorized users.

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“…To date, 16 mutations in the MIP gene have been reported to be associate with autosomal dominant cataracts, including 10 missense mutations81315161718192021; one acceptor splice-site mutation22; one donor splice-site mutation23; one deletion that causes a frameshift at 638delG14; one initiation codon mutation24; and two nonsense mutations2526. The cataract phenotypes are significantly different among the MIP mutation families.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel missense mutation of MIP in a Chinese family with congenital cataracts by target region capture sequencing

Jiang

Chen

et al. 2017

Sci Rep

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Congenital cataract is both clinically diverse and genetically heterogeneous. To investigate the underlying genetic defect in three-generations of a Chinese family with autosomal dominant congenital cataracts, we recruited family members who underwent comprehensive ophthalmic examinations. A heterozygous missense mutation c.634G > C (p.G212R) substitution was identified in the MIP gene through target region capture sequencing. The prediction results of PolyPhen-2 and SIFT indicated that this mutation was likely to damage the structure and function of MIP. Confocal microscopy images showed that the intensity of the green fluorescent signal revealed much weaker signal from the mutant compared to the wild-type MIP. The expressed G212R-MIP was diminished and almost exclusively cytoplasmic in the HeLa cells; whereas the WT-MIP was stable dispersed throughout the cytoplasm, and it appeared to be in the membrane structure. Western blot analysis indicated that the protein expression level of the mutant form of MIP was remarkably reduced compared with that of the wild type, however, the mRNA levels of the wild-type and mutant cells were comparable. In conclusion, our study presented genetic and functional evidence for a novel MIP mutation of G212R, which leads to congenital progressive cortical punctate with or without Y suture.

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An MIP/AQP0 mutation with impaired trafficking and function underlies an autosomal dominant congenital lamellar cataract

Cited by 31 publications

References 25 publications

A Novel MIP Gene Mutation Analysis in a Chinese Family Affected with Congenital Progressive Punctate Cataract

A Novel MIP Gene Mutation Analysis in a Chinese Family Affected with Congenital Progressive Punctate Cataract

Clinical and genetic characteristics of Chinese patients with familial or sporadic pediatric cataract

Identification of a novel missense mutation of MIP in a Chinese family with congenital cataracts by target region capture sequencing

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