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CRYGD p.(Ala159ProfsTer9) 增加疏水性：一个大型中国家族先天性白内障的疑似病因。

Increased hydrophobicity of CRYGD p.(Ala159ProfsTer9): Suspected cause of congenital cataracts in a large Chinese family.

机构信息

NHC Key Laboratory of Reproductive Health and Medical Genetics, Liaoning Research Institute of Family Planning, The Affiliated Reproductive Hospital of China Medical University, Shenyang, China.

出版信息

Mol Genet Genomic Med. 2020 Oct;8(10):e1436. doi: 10.1002/mgg3.1436. Epub 2020 Jul 23.

DOI:10.1002/mgg3.1436
PMID:33460241
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7549552/
Abstract

OBJECTIVE

This study aimed to identify the disease-causing mutation of congenital cataract disease in a large northeastern Chinese family.

MATERIALS AND METHODS

The subjects' peripheral blood was collected, their genomic DNA was extracted, mutation screening of candidate genes was performed using polymerase chain reaction, and the amplified products were sequenced. Recombinant C-terminal enhanced green fluorescent protein-tagged wild-type or mutant CRYGD was expressed in HEK293T cells, and the expression pattern was observed under a fluorescence microscope. The CRYGD protein mutation was analyzed via bioinformatics analysis.

RESULTS

c.475delG, a novel frameshift mutation in CRYGD, was identified in the affected family members. This mutation causes premature termination of the polypeptide, resulting in truncated p.(Ala159ProfsTer9). According to the bioinformatics analysis results, compared with wild-type CRYGD, p.(Ala159ProfsTer9) exhibits significantly decreased hydrophilicity. Fluorescence microscopy revealed that p.(Ala159ProfsTer9) aggregates in the cell in the form of granular deposits.

CONCLUSION

In this study, the novel frameshift mutation c.475delG, p.(Ala159ProfsTer9) in CRYGD was identified to cause congenital cataracts in a large Chinese family; increased hydrophobicity of p.(Ala159ProfsTer9) protein may be the underlying mechanism.

摘要

目的

本研究旨在鉴定一个大型中国东北家族先天性白内障疾病的致病突变。

材料与方法

采集受试者外周血，提取其基因组 DNA，采用聚合酶链反应对候选基因进行突变筛查，并对扩增产物进行测序。在 HEK293T 细胞中表达重组 C 端增强型绿色荧光蛋白标记的野生型或突变 CRYGD，在荧光显微镜下观察表达模式。通过生物信息学分析对 CRYGD 蛋白突变进行分析。

结果

在受影响的家族成员中发现了 CRYGD 中的一个新的移码突变 c.475delG。该突变导致多肽提前终止，导致截短的 p.(Ala159ProfsTer9)。根据生物信息学分析结果，与野生型 CRYGD 相比，p.(Ala159ProfsTer9)的亲水性显著降低。荧光显微镜显示，p.(Ala159ProfsTer9)以颗粒状沉积物的形式在细胞中聚集。

结论

本研究在中国一个大家庭中发现了 CRYGD 的新型移码突变 c.475delG，p.(Ala159ProfsTer9)导致先天性白内障；p.(Ala159ProfsTer9)蛋白亲水性增加可能是其潜在机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef19/7549552/c87e2391cdbb/MGG3-8-e1436-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef19/7549552/3e7744f52be6/MGG3-8-e1436-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef19/7549552/7153b2e5b58a/MGG3-8-e1436-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef19/7549552/c87e2391cdbb/MGG3-8-e1436-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef19/7549552/3e7744f52be6/MGG3-8-e1436-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef19/7549552/7153b2e5b58a/MGG3-8-e1436-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef19/7549552/c87e2391cdbb/MGG3-8-e1436-g003.jpg

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A novel frameshift mutation in CX46 associated with hereditary dominant cataracts in a Chinese family.在中国一个家族中，与遗传性显性白内障相关的CX46基因新的移码突变。
Int J Ophthalmol. 2017 May 18;10(5):684-690. doi: 10.18240/ijo.2017.05.04. eCollection 2017.
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Rapid detection of pathological mutations and deletions of the haemoglobin beta gene (HBB) by High Resolution Melting (HRM) analysis and Gene Ratio Analysis Copy Enumeration PCR (GRACE-PCR).通过高分辨率熔解曲线分析（HRM）和基因比例分析拷贝数定量PCR（GRACE-PCR）快速检测血红蛋白β基因（HBB）的病理性突变和缺失
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The human W42R γD-crystallin mutant structure provides a link between congenital and age-related cataracts.
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Increased hydrophobicity and decreased backbone flexibility explain the lower solubility of a cataract-linked mutant of γD-crystallin.γD-晶体蛋白相关白内障突变体的溶解度降低，原因是疏水性增加和主链柔韧性降低。
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High-resolution X-ray crystal structures of human gammaD crystallin (1.25 A) and the R58H mutant (1.15 A) associated with aculeiform cataract.与尖形白内障相关的人γD晶状体蛋白（分辨率1.25埃）和R58H突变体（分辨率1.15埃）的高分辨率X射线晶体结构。
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