[1]覃梨,杨灿洪,吕田明,等.一个常染色体显性遗传腓骨肌萎缩症2K家系的GDAP1 基因突变分析[J].南方医科大学学报,2019,(01):63.[doi:10.12122/j.issn.1673-4254.2019.01.10]
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一个常染色体显性遗传腓骨肌萎缩症2K家系的GDAP1 基因突变分析()
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《南方医科大学学报》[ISSN:1673-4254/CN:44-1627/R]

卷:
期数:
2019年01期
页码:
63
栏目:
出版日期:
2019-01-26

文章信息/Info

Title:
Analysis of GDAP1 gene mutation in a pedigree with autosomal dominant Charcot- Marie-Tooth disease
作者:
覃梨杨灿洪吕田明李兰英宗丹丹伍月颖
关键词:
腓骨肌萎缩症2K型常染色体显性遗传神经节苷脂诱导分化相关蛋白1基因突变
Keywords:
Charcot-Marie-Tooth disease 2K autosomal dominance ganglioside-induced differentiation-associated protein 1 gene mutation
DOI:
10.12122/j.issn.1673-4254.2019.01.10
摘要:
目的探讨一个腓骨肌萎缩症(CMT)家系的分子遗传发病机制。方法抽取家系成员外周血基因组DNA,应用目标外显 子捕获及二代测序技术对先证者的65个候选基因进行基因突变筛查,并对可疑基因进行Sanger测序验证。采用多序列比对分 析基因序列的保守性,利用PolyPhen-2、PROVEAN和SIFT三种软件进行突变基因功能预测。用PyMOL-1软件对突变基因的 蛋白质结构进行分子模拟。结果先证者GDAP1基因第3外显子检测出1个未见报道的杂合错义突变[c.371A>G(p.Y124C)]。 先证者母亲及弟弟均检出该杂合突变,而其父亲未检测到该突变。多序列比对分析结果显示位于GDAP1蛋白的第124位的酪 氨酸具有高度保守性。三种预测软件预测该突变均为有害突变。分子结构模拟结果显示突变体在124位的氨基酸残基与周围 氨基酸残基的相互作用力减弱,影响蛋白整体的稳定性。结论GDAP1基因突变可能与该AD-CMT家系发病有关,新发现的 c.371A>G突变(p.Y124C)扩展了GDAP1基因的突变谱,但其确切发病机制仍需进一步研究。
Abstract:
Objective To investigate the molecular genetic mechanism of Charcot- Marie-Tooth (CMT) disease in a pedigree. Methods Genomic DNA was extracted from the peripheral blood of the family members of a pedigree with autosomal dominant CMT disease, and 65 candidate genes of the proband were screened using target exon capture and the next generation sequencing, and the suspicious genes were verified using Sanger sequencing. PolyPhen-2, PROVEAN and SIFT software were used to predict the function of the mutant genes, and PyMOL-1 software was used to simulate the mutant protein structure. Results A heterozygous missense mutation [c.371A>G (p.Y124C)] was detected in exon 3 of GDAP1 gene of the proband. This heterozygous mutation was also detected in both the proband’s mother and her brother, but not in her father. Multiple sequence alignment analysis showed that tyrosine at codon 124 of GDAP1 protein was highly conserved. All the 3 prediction software predicted that the mutation was harmful. Molecular structure simulation showed a weakened interaction force between the amino acid residues at codon 124 and the surrounding amino acid residues to affect the overall stability of the protein. Conclusion The mutation of GDAP1 gene may be related to the pathogenesis of autosomal dominant AD-CMT in this pedigree. The newly discovered c.371A>G mutation (p.Y124C) expands the mutation spectrum of GDAP1 gene, but further study is needed to clarify the underlying pathogenesis.
更新日期/Last Update: 1900-01-01