Novel mutations in CRYGD are associated with congenital cataracts in Chinese families

Yang, Guo‐Yu; Chen, Zhimin; Zhang, Wulin; Liu, Zhiqiang; Zhao, Jialiang

doi:10.1038/srep18912

Cited by 12 publications

(15 citation statements)

References 14 publications

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“…(Leu45Pro)2nd Greek keyD, D, D-PRef [12]F#6FBirthTotal cataract, strabismus, nystagmus-AD CRYGD NM_006891.3 c.309dupp. (Glu104Argfs*4)---PRef [36]S#3FBirthTotal cataract, nystagmus-Sporadic->new AD CRYGD NM_006891.3 c.418C>Tp. (Arg140*)---PRef [37]F#7F2 monthsUnknown type, nystagmus-AD MIP NM_012064.3 c.494G>Ap.…”

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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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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“…Because the heterozygous c.70C>T (p.P24T) in CRYGD has been recognized as the cataract-causing gene mutation, [2,[19][20][21][22][23][24] we performed functional prediction only for WFS1 c.1514G>C. In our results, 19 of the 24 functional prediction programs in VarCards showed that c.1514G>C in WFS1 was possibly harmful (Table 1).…”

Section: Bioinformatics Analysismentioning

confidence: 86%

“…Literature review shows that cataracts caused by the mutation in CRYGD had been reported in many published articles since the 1990s and that the biological function of the mutant protein was deeply and meticulously researched in many papers [2,21,22,[25][26][27]. e p.P24T mutation in CRYGD has been widely reported as the cause of congenital cataract, especially in the East Asian population [2,[19][20][21][22][23][24].…”

Section: Discussionmentioning

confidence: 99%

“…e last two of the "Greek key" modules form a domain joined by connecting fragments [30,31]. At least eight mutations related to congenital cataract have been reported in the lens protein gene CRYGD [2,21,22,26,27,32]. ese mutations can change the structure or three-dimensional conformation of lens protein, affecting its solubility, stability, or orderliness, leading to cataracts [2,21,22,26,27].…”

Section: Discussionmentioning

confidence: 99%

“…At least eight mutations related to congenital cataract have been reported in the lens protein gene CRYGD [2,21,22,26,27,32]. ese mutations can change the structure or three-dimensional conformation of lens protein, affecting its solubility, stability, or orderliness, leading to cataracts [2,21,22,26,27]. In this study, we analyzed the structure of p.P24T and another six mutation sites in the first "Greek Key" module domain of the CRYGD protein, that is, p.R15C, p.R15S, p.P24S, p.A36P, p.R37S, and p.R37P, which have been reported as being associated with cataract.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Two Pathogenic Gene Mutations Identified Associating with Congenital Cataract and Iris Coloboma Respectively in a Chinese Family

Lü

Guo

et al. 2020

Journal of Ophthalmology

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Purpose. To screen out pathogenic genes in a Chinese family with congenital cataract and iris coloboma. Material and Methods. A three-generation family with congenital cataract and iris coloboma from a Han ethnicity was recruited. DNA was extracted from peripheral blood samples collected from all individuals in the family. Whole exon sequencing was employed for screening the disease-causing gene mutations in the proband, and Sanger sequencing was used for other members of the family and a control group of 500 healthy individuals. Bioinformatics analysis and three-dimensional structure predictions were used to predict the impact of amino acid changes on protein structure and function. Results. The candidate genes of cataract and iris coloboma were successfully screened out. A heterozygote mutation, CRYGD c.70C>A (p.P24T), was identified as cosegregating with congenital cataracts, while another heterozygous mutation, WFS1 c.1514G>C (p.C505S), which had not been reported previously, cosegregated with congenital iris coloboma. Bioinformatic analyses and three-dimensional structure prediction proved that the three-dimensional structures of WFS1 p.C505S and CRYGD p.P24T changed markedly and may contribute significantly to iris coloboma and congenital cataract, respectively. Conclusions. We report a novel mutation, WFS1 p.C505S, and a known mutation, CRYGD p.P24T, that cosegregate with iris coloboma and congenital cataract, respectively, in a Chinese family. This is the first time the association of WFS1 p.C505S with iris coloboma has been demonstrated, although CRYGD p.P24T has been widely reported as being associated with congenital cataract, especially in the Eastern Asian population. These findings may have future therapeutic benefit for the diagnosis of iris coloboma and congenital cataract. The results may also be relevant in further studies aiming to investigate the molecular pathogenesis of iris coloboma and congenital cataract.

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Effects of Mutating Trp42 Residue on γD-Crystallin Stability

Aguayo‐Ortiz

Domı́nguez

2019

J. Chem. Inf. Model.

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Oligomerization and aggregation of γD-crystallins (HγDC) in the eye lens is one of the main causes of cataract development. To date, several congenital mutations related to this protein are known to promote the formation of aggregates. Previous studies have demonstrated that mutations in W42 residue of HγDC lead to the generation of partially unfolded intermediates that are more prone to aggregate. To understand the role of W42 in the stability of HγDC, we performed alchemical free-energy calculations and all-atom molecular dynamics simulations of different W42 mutant models. Our results suggest that substitution of W42 by small size and/or polar residues promotes HγDC denaturation due to the entry of water molecules into the hydrophobic core of the N-terminal domain. Similar behavior was observed in the C-terminal domain of HγDC when mutating the W130 residue located in a homologous position. Moreover, the exposure of the hydrophobic core residues could lead to the formation of aggregation-prone partially unfolded species. Overall, this study takes a step toward understanding the role of HγDC in cataract development.

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Novel mutations in CRYGD are associated with congenital cataracts in Chinese families

Cited by 12 publications

References 14 publications

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

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

Two Pathogenic Gene Mutations Identified Associating with Congenital Cataract and Iris Coloboma Respectively in a Chinese Family

Effects of Mutating Trp42 Residue on γD-Crystallin Stability

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