[1]吕晨,肖婷婷,张兆辉.新复合杂合突变所致GNE肌病1例:临床特点及致病性研究[J].卒中与神经疾病杂志,2025,32(02):177-183.[doi:10.3969/j.issn.1007-0478.2025.02.012]
　Lv Chen,Xiao Tingting,Zhang Zhaohui..Identification of a novel compound heterozygous mutation of GNE in a Chinese patient with GNE myopathy[J].Stroke and Nervous Diseases,2025,32(02):177-183.[doi:10.3969/j.issn.1007-0478.2025.02.012]
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新复合杂合突变所致GNE肌病1例:临床特点及致病性研究()
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《卒中与神经疾病》杂志[ISSN:1007-0478/CN:42-1402/R]

卷:
第32卷
期数:
2025年02期
页码:
177-183
栏目:
论著
出版日期:
2025-04-20

文章信息/Info

Title:
Identification of a novel compound heterozygous mutation of GNE in a Chinese patient with GNE myopathy
文章编号:
1007-0478(2025)02-0177-07
作者:
吕晨; 肖婷婷; 张兆辉
430060 武汉大学人民医院神经内科[吕晨 肖婷婷(通信作者)张兆辉(通信作者)]
Author(s):
Lv Chen;  Xiao Tingting;  Zhang Zhaohui.
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 410000
关键词:
GNE 氨基葡萄糖(UDP-N-乙酰基)-2-差向异构酶/N-乙酰甘露糖胺激酶 GNE肌病 遗传性包涵体肌病 复合杂合突变
Keywords:
GNE UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase GNE myopathy Compound heterozygous mutation
分类号:
R746.9
DOI:
10.3969/j.issn.1007-0478.2025.02.012
文献标志码:
A
摘要:
目的 报道氨基葡萄糖(UDP-N-乙酰基)-2-差向异构酶/N-乙酰甘露糖胺激酶(GNE)基因新复合杂合突变所致GNE肌病1例,通过生物信息学分析、体外功能实验探索该复合杂合突变的致病性。方法 全面收集患者临床资料,提取患者外周血DNA行全外显子测序,对可疑致病位点进行sanger测序验证,通过生物信息分析对可疑致病位点进行保守性及有害性预测,在细胞水平探索突变位点对唾液酸生成的影响。结果 患者表现为进行性双下肢无力,肌肉活检提示肌纤维大小不等、部分肌纤维膜下可见不规则空泡; 全外显子测序提示该患者携带2个GNE基因错义突变:c.1642G>A(p.G548S),c.1892C>T(p.A631V),sanger测序证实该复合杂合突变分别来自于其父母,其中c.1892C>T为已报道的GNE肌病致病突变,而c.1642G>A为新发突变位点; 以上2个位点在不同物种中具有高度保守性,PolyPhen-2,Mutation Taster等软件预测以上2个位点均具有致病性; 过表达突变型GNE基因(c.1642G>A、c.1892C>T)可导致HEK293细胞唾液酸生成减少。结论 本研究扩大了GNE肌病的基因突变谱。
Abstract:
ObjectiveTo report a case of GNE myopathy caused by a novel compound heterozygous mutation of the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase(GNE)gene. The pathogenicity of this compound heterozygous mutation was explored through bioinformatics analysis and in vitro functional experiments.Methods Comprehensive clinical data of the patient were collected. Peripheral blood DNA of the patient was extracted for whole-exome sequencing. Suspected pathogenic loci were verified by Sanger sequencing. The conservation and harmfulness of the suspected pathogenic loci were predicted through bioinformatics analysis. The effects of the mutation loci on sialic acid generation were explored at the cellular level.Results The patient manifested progressive bilateral lower extremity weakness. Muscle biopsy indicated unequal muscle fiber size and irregular vacuoles under some muscle fiber membranes. Whole-exome sequencing suggested that the patient carried two missense mutations in the GNE gene: c.1642G>A(p.G548S)and c.1892C>T(p.A631V). Sanger sequencing confirmed that the compound heterozygous mutations were inherited from the patient's parents respectively. Among them, c.1892C>T was a reported pathogenic mutation of GNE myopathy, while c.1642G>A was a novel mutation site. These two sites were highly conserved among different species. Software such as PolyPhen-2 and Mutation Taster predicted the above two sites were pathogenic. Overexpression of the mutant GNE gene(c.1642G>A, c.1892C>T)could lead to a reduction in sialic acid generation in HEK293 cells.Conclusion This study expands the gene mutation spectrum of GNE myopathy.

参考文献/References:

[1] Pogoryelova O.Phenotypic stratification and genotype-phenotype correlation in a heterogeneous, international cohort of GNE myopathy patients:First report from the GNE myopathy disease monitoring program,registry portion[J].Neuromuscul Disord,2018,28(2):158-168.
[2] Slota C.Patient reported outcomes in GNE myopathy:incorporating a valid assessment of physical function in a rare disease[J].Disabil Rehabil,2018,40(10):1206-1213.
[3] Mori-Yoshimura M,Oya YSH,Hayashi YK,et al.Respiratory dysfunction in patients severely affected by GNE myopathy(distal myopathy with rimmed vacuoles)[J].Neuromuscul Disord,2013,23(1):84-88.
[4] Pogoryelova O.GNE myopathy:from clinics and genetics to pathology and research strategies[J].Orphanet J Rare Dis,2018,13(1):70.
[5] Carrillo N,Malicdan MC,Huizing M.GNE myopathy: etiology, diagnosis, and therapeutic challenges[J].Neurotherapeutics,2018,15(4):900-914.
[6] Sharma S. Functional characterization of GNE mutations prevalent in Asian subjects with GNE myopathy,an ultra-rare neuromuscular disorder[Z], 2022: 36-45.
[7] 张羽彤,蒲传强.遗传性包涵体肌病的基因研究进展[J].国际神经病学神经外科学杂志,2019,46(5):572-576.
[8] 陈琦.中国人遗传性包涵体肌病GNE基因突变分析[Z],2008.
[9] 陈阳.中国南方地区GNE肌病基因突变分析及临床特点研究[Z],2014.
[10] Lu X.Distal myopathy with rimmed vacuoles:clinical and muscle morphological characteristics and spectrum of GNE gene mutations in 53 Chinese patients[J].Neurol Res,2011,33(10):1025-1031.
[11] Richards S,Aziz N,Bale S,et al.Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology[J].Genet Med,2015,17(5):405-424.
[12] Paljarvi LKH.Kalimo altered muscle saccharide pattern in x-linked muscular dystrophy[J].Arch Neurol,1984,41(1):39-42.
[13] ParkYE.Pharmacokinetics and clinical efficacy of 6'-sialyllactose in patients with GNE myopathy:randomized pilot trial[Z],2023:115689.
[14] Mashangva F.Understanding pathophysiology of GNE myopathy and current progress towards drug development[Z],2024:49.
[15] Yoshioka WNS.Noguchi,recent advances in establishing a cure for GNE myopathy[J].Curr Opin Neurol,2022,35(5):629-636.
[16] Mori-Yoshimura M,Suzuki N,Katsuno M,et al.Efficacy confirmation study of aceneuramic acid administration for GNE myopathy in Japan[J].Orphanet J Rare Dis,2023,18(1):241.
[17] Carrillo N.Safety and efficacy of N-acetylmannosamine(ManNAc)in patients with GNE myopathy:an open-label phase 2 study[J].Genet Med,2021,23(11):2067-2075.
[18] Oswalia J.Altered autophagic flux in GNE mutant cells of Indian origin:potential drug target for GNE myopathy[J].Exp Cell Res,2024,440(1):114118.
[19] Noguchi S.Reduction of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase activity and sialylation in distal myopathy with rimmed vacuoles[J].J Biol Chem,2004,279(12):11402-11407.
[20] Yadav R.Role of HSP70 chaperone in protein aggregate phenomenon of GNE mutant cells:therapeutic lead for GNE myopathy[Z],2022:106258.

备注/Memo

备注/Memo:
基金项目:国家自然科学基金(8210050708)
更新日期/Last Update: 2025-04-20