Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study
Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study
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DOI：
10.1093/brain/awn029
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发表时间：
2008-05-01
期刊：
影响因子：
14.5
通讯作者：
Timmerman, Vincent
中科院分区：
文献类型：
--
作者：
Dierick, Ines;Baets, Jonathan;Timmerman, Vincent
远端遗传性运动神经病（HMN）是一组影响脊髓α-运动神经元的临床和遗传异质性疾病。自2001年以来，已鉴定出常染色体显性遗传远端HMN的六种不同基因突变：甘氨酰-tRNA合成酶（加尔斯）、dynactin 1（DCTN 1）、小热休克27 kDa蛋白1（HSPB 1）、小热休克22 kDa蛋白8（HSPB 8）、Berardinelli-Seip先天性脂肪营养不良（BSCL 2）和senataxin（SETX）。此外，在巴西几个患有复杂和非典型形式的常染色体显性遗传运动神经元病的家族中发现了（VAMP）相关蛋白B和C（VAP B）的突变。我们研究了112例诊断为远端运动神经病的家族性和孤立性患者中这7个基因突变的分布，在17例患者中发现了HSPB 8、HSPB 1、BSCL 2和SETX中9种不同的致病突变，其中10例先前已报道。未发现加尔斯、DCTN 1和VAPB基因突变。具有HSPB 8、HSPB 1、BSCL 2和SETX突变的患者的表型特征符合远端HMN分类，只有一个例外; C末端HSPB 1突变与上运动神经元体征相关。此外，我们提供的证据遗传镶嵌在传输HSPB 1突变。这项研究，在一个大的队列的家族性和孤立的远端HMN患者，清楚地证实了远端HMN的遗传和表型异质性，并提供了一个基础的算法的开发诊断突变筛查这组疾病。
Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorders.