Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies
Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies
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SLC5A7 截短突变是一系列显性遗传性运动神经病的基础
DOI：
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
A. Crosby
中科院分区：
文献类型：
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作者：
Claire G. Salter;Danique Beijer;H. Hardy;Katy Barwick;Matthew Bower;I. Mademan;P. de Jonghe;T. Deconinck;M. Russell;M. McEntagart;B. Chioza;R. Blakely;J. Chilton;J. D. De Bleecker;J. Baets;E. Baple;D. Walk;A. Crosby
目的探讨2个未报道的远端遗传性运动神经病（dHMNs）家系的遗传学病因。方法第一个家族包括受dHMN V型影响的个体，其缺乏在第二个家族中观察到的dHMN-VII的声带麻痹特征的主要临床特征。对每个家族的先证者进行下一代测序。对变异体进行注释和筛选，最初集中在与神经病变相关的基因上。通过双脱氧序列分析和共分离研究进一步研究和确认候选变体。完成了全面的患者表型分型，包括临床病史、检查和神经系统检查。结果dHMNs是一组异质性的周围运动神经元疾病，其特征是长度依赖性神经病和进行性肢体远端肌无力和消瘦。我们以前报告了一个显性负移码突变位于SLC 5A 7基因编码的胆碱转运蛋白（CHT）的最后一个外显子，导致蛋白质截短，作为显性遗传dHMN-VII在一个扩展的英国家庭的可能原因。在这项研究中，我们的遗传学研究确定了位于SLC 5A 7最后一个编码外显子中的不同杂合移码突变，预测会导致CHT C-末端的截短，这可能是每个家族中病情的原因。结论本研究证实C端CHT截短是常染色体显性dHMN的一个原因，证实了上肢比下肢受累占主导地位，并扩大了CHT功能障碍引起的临床谱。
Objective To identify the genetic cause of disease in 2 previously unreported families with forms of distal hereditary motor neuropathies (dHMNs). Methods The first family comprises individuals affected by dHMN type V, which lacks the cardinal clinical feature of vocal cord paralysis characteristic of dHMN-VII observed in the second family. Next-generation sequencing was performed on the proband of each family. Variants were annotated and filtered, initially focusing on genes associated with neuropathy. Candidate variants were further investigated and confirmed by dideoxy sequence analysis and cosegregation studies. Thorough patient phenotyping was completed, comprising clinical history, examination, and neurologic investigation. Results dHMNs are a heterogeneous group of peripheral motor neuron disorders characterized by length-dependent neuropathy and progressive distal limb muscle weakness and wasting. We previously reported a dominant-negative frameshift mutation located in the concluding exon of the SLC5A7 gene encoding the choline transporter (CHT), leading to protein truncation, as the likely cause of dominantly-inherited dHMN-VII in an extended UK family. In this study, our genetic studies identified distinct heterozygous frameshift mutations located in the last coding exon of SLC5A7, predicted to result in the truncation of the CHT C-terminus, as the likely cause of the condition in each family. Conclusions This study corroborates C-terminal CHT truncation as a cause of autosomal dominant dHMN, confirming upper limb predominating over lower limb involvement, and broadening the clinical spectrum arising from CHT malfunction.
影响因子：
14.5
作者：
Wang, Haicui;Salter, Claire G.;Crosby, Andrew H.
通讯作者：
Crosby, Andrew H.
DOI：
10.1006/bbrc.2000.3561
发表时间：
2000-10-05
影响因子：
3.1
作者：
Apparsundaram, S;Ferguson, SM;Blakely, RD
通讯作者：
Blakely, RD