DNM1L基因新变异致EMPF11例临床表型和遗传学分析  

Clinical phenotype and genetic analysis of a case of EMPF1 caused by a novel DNM1L mutation

作　　者：王炳辉 李晶 刘文淼 刘世国[3] 董继承[4] WANG Binghui;LI Jing;LIU Wenmiao;LIU Shiguo;DONG Jicheng(Qingdao University Medical College,Qingdao 266071,China)

机构地区：[1]青岛大学医学部,山东青岛266071 [2]青岛市妇女儿童医院儿童重症监护室 [3]青岛大学附属医院医学遗传科 [4]青岛市精神卫生中心精神一科

出　　处：《青岛大学学报（医学版）》2024年第2期184-189,共6页Journal of Qingdao University(Medical Sciences)

基　　金：国家自然科学基金项目(81371499);青岛市卫计委医药科研指导计划(2016-WJZD067)。

摘　　要：目的 探讨由DNM1L基因变异导致的线粒体和过氧化物酶体裂变缺陷型脑病1型(EMPF1)的临床表型和遗传学特点。方法 收集1例EMPF1病儿的临床资料和实验室检查结果。采用全外显子组测序(WES)检测EMPF1病儿及其父母的基因变异,并通过双脱氧测序法(Sanger法)测序对变异位点进行验证;使用生物信息学软件和氨基酸多序列对变异位点对比分析,以明确其致病性;利用蛋白三维结构模型模拟蛋白质结构和分子间作用力在变异前后的变化。结果 病儿主要表现为发育迟缓、肌张力减退和难治性癫痫。脑MRI显示双侧豆状核和背侧丘脑对称性异常信号,视频脑电图显示肌阵挛发作频繁呈持续状态。WES分析显示,病儿DNM1L基因存在c.1049G>C(p.G350A)新发杂合错义突变,而Sanger测序验证其父母均未检测到该变异;氨基酸多序列比对结果显示,Gly350在各种属间高度保守;蛋白三维结构建模分析显示,p.G350A蛋白构象变化导致蛋白结构稳定性降低,进而影响蛋白质的功能。该变异为疑似致病性变异(PS2+PM2+PP2+PP3)。结论 本文病儿的EMPF1是由DNM1L基因c.1049G>C(p.G350A)变异所致,EMPF1主要的临床表现为精神运动迟缓、肢体瘫痪、肌张力障碍和癫痫等,综合临床表型及基因检测结果有助于该病的早期诊断。Objective To investigate the clinical phenotype and genetic characteristics of encephalopathy due to defective mitochondrial and peroxisomal fission 1(EMPF1)caused by a variant in the[STBX]DNM1L[STBZ]gene.Methods The clinical data and laboratory findings of a child with EMPF1 were collected.Whole-exome sequencing(WES)was used to detect genetic mutation in the patient and her parents,and the mutation was verified by Sanger dideoxy sequencing.Variant pathogenicity was determined through bioinformatics analysis and multiple amino acid sequence alignment.A three-dimensional(3D)protein structure model was used to model changes in protein structure and intermolecular forces before and after mutation.Results The patient mainly presented with developmental delay,hypotonia,and refractory epilepsy,with symmetrical abnormal signals in bilateral lenticular nuclei and dorsal thalami on magnetic resonance imaging and frequent and persistent myoclonic seizures on video-electroencephalography.WES revealed a de novo heterozygous missense mutation,c.1049G>C(p.G350A),in the DNM1L gene of the child,and Sanger sequencing verified that this mutation was absent in her parents.Multiple amino acid sequence alignment results showed that Gly350 was highly conserved among various species and genera.The 3D protein structure modeling analysis predicted that conformational changes in p.G350A protein would lead to a less stable protein structure,thereby altering protein function.The c.1049G>C variant was considered likely pathogenic(PS2+PM2+PP2+PP3).ConclusionThis case of EMPF1 is caused by c.1049G>C(p.G350A)mutation in the DNM1L gene.EMPF1 is characterized by psychomotor retardation,limb paralysis,dystonia,and epilepsy,and the combination of clinical phenotyping and genetic testing is helpful for the early diagnosis of EMPF1.

关 键 词：动力蛋白质Ⅰ 线粒体脑肌病 突变 误义 遗传关联研究 基因检测 

分 类 号：R742[医药卫生—神经病学与精神病学]