GNPTAB基因新变异致黏脂贮积症Ⅲα/β型的临床表现和遗传学分析

doi:10.3969/j.issn.1006-5725.2024.24.022

实用医学杂志 ›› 2024, Vol. 40 ›› Issue (24): 3575-3581.doi: 10.3969/j.issn.1006-5725.2024.24.022

• 疑难病例研讨 • 上一篇

GNPTAB基因新变异致黏脂贮积症Ⅲα/β型的临床表现和遗传学分析

王丽¹,石聪聪²,严学勤¹,唐家彦³,李思涛²,郝虎²,肖昕²()

^1.中山市博爱医院儿童保健科（广东中山 528403 ）
^3.中山市博爱医院儿科（广东中山 528403 ）
^2.山大学附属第六医院儿科，广州市黄埔区中六生物医学创新研究院（广东广州 510655 ）

收稿日期:2024-11-18 出版日期:2024-12-25 发布日期:2024-12-23
通讯作者: 肖昕 E-mail:xiaoxin2@mail.sysu.edu.cn
基金资助:
广东省科技计划项目(2020A1414010111);广州市科技计划项目(2024B03J0191)

Study on the clinical characteristics and genetic mechanisms of mucolipidosis Ⅲα/β caused by a novel mutation in the GNPTAB gene

Li WANG¹,Congcong SHI²,Xueqin YAN¹,Jiayan TANG³,Sitao LI²,Hu HAO²,Xin. XIAO²()

^*.Department of Child Healthcare，Boai Hospital of Zhongshan，Zhongshan 528403，Guangdong，China

Received:2024-11-18 Online:2024-12-25 Published:2024-12-23
Contact: Xin. XIAO E-mail:xiaoxin2@mail.sysu.edu.cn

摘要/Abstract

摘要：

目的探讨GNPTAB基因变异引起的黏脂贮积症Ⅲα/β型患者的临床特征及遗传机制。方法对1例确诊的黏脂贮积症Ⅲα/β型患儿的临床资料及基因检测结果进行回顾性分析，并通过多种蛋白质预测工具，生成GNPTAB蛋白野生型和突变型的蛋白质模型，利用计算机生物学工具阐明野生型和突变型蛋白结构和功能的差异。结果本例患儿主要表现为关节畸形、身材矮小，基因测序结果提示GNPTAB基因发生c.2715 + 1G > A、c.1582T > C复合杂合变异；其中错义突变c.1582T > C在文献中未见报道。通过对突变体进行三维模型构建和结构分析，发现c.2715 + 1G > A位点变异会改变蛋白整体结构而导致蛋白功能丧失，c.1582T > C位点变异则会影响N-乙酰氨基葡萄糖-1-磷酸转移酶亚基和配体的相互作用。结论本例黏脂贮积症Ⅲα/β型是由GNPTAB基因变异所致，其中错义突变c.1582T > C未见报道，其增加了该基因的致病突变谱。通过对GNPTAB基因变异的蛋白质变体进行计算机分析，阐释了其结构-功能关系的认知，并初步探索了黏脂贮积症Ⅲα/β型疾病发病的分子机制。

关键词: 黏脂贮积症, 错义突变, GNPTAB基因, 计算机生物学

Abstract:

Objective To explore the clinical characteristics and genetic mechanisms of patients with Mucolipidosis Ⅲα/β caused by GNPTAB gene mutations. Methods A retrospective analysis was conducted on the clinical data and genetic tests of a confirmed case of Mucolipidosis Ⅲα/β. Various protein prediction tools were used to generate protein models of the wild type and mutant GNPTAB proteins， and computational biology tools were employed to elucidate the differences in protein structure and function between the wild type and mutant variants. Results The patient in this case mainly presented with joint deformities and short stature. Genetic sequencing revealed compound heterozygous mutations in the GNPTAB gene， c.2715 + 1G > A and c.1582T > C； the missense mutation c.1582T > C has not been reported in the literature. By constructing and analyzing three-dimensional models of the mutants， it was found that the c.2715 + 1G > A mutation alters the overall structure of the protein， leading to the loss of protein function， while the c.1582T > C mutation affects the interaction between the subunit of N-acetylglucosamine-1-phosphate transferase and its ligand. Conclusions This case of MLⅢα/β results from a mutation in the GNPTAB gene， including a missense mutation c.1582T > C that has not been previously reported， which expands the spectrum of pathogenic mutations of this gene. Through computational analysis of the protein variants resulting from the GNPTAB gene mutation， the understanding of their structure-function relationship has been elaborated， revealing the molecular mechanisms behind the onset of ML Ⅲα/β disease.

Key words: mucolipidosis, missense mutation, GNPTAB gene, Computational Biology

中图分类号:

S856.1

王丽,石聪聪,严学勤,唐家彦,李思涛,郝虎,肖昕. GNPTAB基因新变异致黏脂贮积症Ⅲα/β型的临床表现和遗传学分析[J]. 实用医学杂志, 2024, 40(24): 3575-3581.

Li WANG,Congcong SHI,Xueqin YAN,Jiayan TANG,Sitao LI,Hu HAO,Xin. XIAO. Study on the clinical characteristics and genetic mechanisms of mucolipidosis Ⅲα/β caused by a novel mutation in the GNPTAB gene[J]. The Journal of Practical Medicine, 2024, 40(24): 3575-3581.

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核苷酸改变	氨基酸改变	临床意义	致病性预测
核苷酸改变	氨基酸改变	临床意义	MutPred2	PolyPhen-2
c.1582T > C	p.C528R	VUS	0.976	1
c.2715 + 1G > A	p.E906Ifs*24	VUS	0.556	None
	p.D538Gfs*14	VUS	0.586	None

突变		ΔΔG/（Kcal·mol-1）				稳定性
突变		mCSM	SDM	DUET	DynaMut2	稳定性
c.1582T>C	p.C528R	-1.575	-0.57	-1.297	-1.2	Destabilising

序号	突变位点		蛋白-配体结合自由能（kcal/mol）
1	Wild-type		-4.79
2	c.1582T>C	p.C528R	2.11
3	c.2715+1G>A	p.E906Ifs*24	0.35
4	c.2715+1G>A	p.D538Gfs*14	-2.44

GNPTAB基因新变异致黏脂贮积症Ⅲα/β型的临床表现和遗传学分析

Study on the clinical characteristics and genetic mechanisms of mucolipidosis Ⅲα/β caused by a novel mutation in the GNPTAB gene

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