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

Abstract

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.

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

“…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.…”

“…Each monomer is a water channel and can function independently2829. The first missense mutation in H6 of MIP (c.644G > A) was reported to be associated with punctate cataracst in 20148; this is the second substituation mutation in H6 that can cause ADCC.…”

“…To date, more than 20 genetic loci have been linked to autosomal dominant inherited cataracts. Among these, the identified genes encode crystallines, membrane transport and channel proteins, cytoskeletal proteins, and some growth and transcription factors68.…”

Inherited Congenital Cataract: A Guide to Suspect the Genetic Etiology in the Cataract Genesis

“…some cases with microphthalmia and microcornea constitute the major proteins of vertebrate eye lens Héon et al, 1999;Ren et al, 2000;Santhiya et al, 2002;Gonzalez-Huerta et al, 2007;Devi et al, 2008;Yao et al, 2008;Zhang et al, 2009b;Kumar et al, 2011;Guo et al, 2012;Li et al, 2012;Kondo et al, 2013;Reis et al, 2013;Gillespie et al, 2014;Prokudin et al, 2014;Li D et al, 2016; Geyer et al, 2006;Gu et al, 2007;Lin et al, 2007;Jiang et al, 2009;Wang et al 2011a;Xiao et al, 2011;Yang et al, 2011b;Reis et al, 2013;Senthil Kumar et al, 2013;Zeng et al, 2013;Ding et al, 2014;Sun et al, 2014;Yu et al, 2014;Shentu et al, 2015;Song et al, 2015;Qin et al, 2016 13q11q12 GJA3 AD nuclear, pulverulent, Y-sutural, lamellar, lamerllar sutural, pearl box, coralliform, punctate, Coppock-like gap junction protein alpha 3 Mackay et al, 1999;Rees et al, 2000;Jiang et al, 2003;Bennett et al, 2004;Burdon et al, 2004;Li et al, 2004;Devi et al, 2005;Ma et al, 2005;…”

A NovelCRYBB2Stopgain Mutation Causing Congenital Autosomal Dominant Cataract in a Chinese Family

“…were identified to be associated with congenital cataract [11–14]. Among these mutations, about half are in crystalline genes, mainly including CRYAA , CRYAB , CRYBA4 , CRYBB1 , CRYBB2 , and CRYGC [15]; one-quarter of mutations are in connexin genes, such as GJA3 and GJA [16, 17]; the remaining mutations are other genes which consist essentially of HSF4 [18], MIP [19], and EPHA2 [20]. Although autosomal dominant congenital cataract (ADCC) is the major inherited mode of congenital cataract, there were a few reports about autosomal recessive [21–23] and X-linked inheritance mode [24, 25].…”