Biallelic loss-of-function variants inNEMFcause central nervous system impairment and axonal polyneuropathy
Biallelic loss-of-function variants inNEMFcause central nervous system impairment and axonal polyneuropathy
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NEMF 的双等位基因功能丧失变异导致中枢神经系统损伤和轴突多发性神经病
DOI：
10.1007/s00439-020-02226-3
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发表时间：
2020-10-13
期刊：
影响因子：
5.3
通讯作者：
Hu, Zhengmao
中科院分区：
文献类型：
--
作者：
Ahmed, Ashfaque;Wang, Meng;Hu, Zhengmao
我们的目的是检测5个无亲缘关系的隐性遗传型神经系统疾病家系中的致病基因，以及NEMF基因在中枢神经系统中的潜在功能。外显子组测序（ES）应用于所有的家庭和连锁分析进行家庭1。使用小基因测定来验证相关发现的变体的剪接效应。采用免疫荧光（IF）实验研究致病基因在神经元发育中的作用。通过ES分析，该家系证实了与纯合移码突变体（NM_004713. 6：c.2618del）的表型致病关系。家系连锁分析显示单点LOD为4.5个位点。通过在GeneMatcher中的合作，随后鉴定了另外四个不相关家族的可能对一系列中枢神经系统疾病具有致病性的NEMF变体，两种纯合剪接位点变体（NM_004713.6：c.574+1G>T和NM_004713.6：c.807-2A>C）和一种纯合移码变体（NM_004713.6：c.1234_1235insC），并与所有受影响的个体隔离。我们进一步发现，敲低（KD）的Nemf导致损伤的轴突生长和突触发育在培养的小鼠原代皮层神经元。我们的研究表明，致病性双等位基因NEMF变异导致中枢神经系统损伤和其他可变特征。NEMF在哺乳动物神经元发育中起重要作用。
We aimed to detect the causative gene in five unrelated families with recessive inheritance pattern neurological disorders involving the central nervous system, and the potential function of theNEMFgene in the central nervous system. Exome sequencing (ES) was applied to all families and linkage analysis was performed on family 1. A minigene assay was used to validate the splicing effect of the relevant discovered variants. Immunofluorescence (IF) experiment was performed to investigate the role of the causative gene in neuron development. The large consanguineous family confirms the phenotype-causative relationship with homozygous frameshift variant (NM_004713.6:c.2618del) as revealed by ES. Linkage analysis of the family showed a significant single-point LOD of 4.5 locus. Through collaboration in GeneMatcher, four additional unrelated families' likely pathogenic NEMF variants for a spectrum of central neurological disorders, two homozygous splice-site variants (NM_004713.6:c.574+1G>T and NM_004713.6:c.807-2A>C) and a homozygous frameshift variant (NM_004713.6: c.1234_1235insC) were subsequently identified and segregated with all affected individuals. We further revealed that knockdown (KD) ofNemfleads to impairment of axonal outgrowth and synapse development in cultured mouse primary cortical neurons. Our study demonstrates that disease-causing biallelicNEMFvariants result in central nervous system impairment and other variable features.NEMFis an important player in mammalian neuron development.