Department of Medicine - Neurology Unit, Sultan Qaboos University Hospital, Muscat, Oman.
Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat, Oman.
Eur J Neurol. 2018 Feb;25(2):395-403. doi: 10.1111/ene.13519. Epub 2017 Dec 12.
Distal hereditary motor neuropathy (dHMN) due to sigma non-opioid intracellular receptor 1 (SIGMAR1) gene mutation (OMIM 601978.0003) is a rare neuromuscular disorder characterized by prominent amyotrophic distal limb weakness and co-existing pyramidal signs initially described in a Chinese family recently. We report an extended consanguineous Omani family segregating dHMN with pyramidal signs in an autosomal recessive pattern and describe a novel mutation in the SIGMAR1 gene underlying this motor phenotype. We also provide an update on the reported phenotypic profile of SIGMAR1 mutations.
We utilized homozygosity mapping and whole-exome sequencing of leucocyte DNA obtained from three affected members of an Omani family who manifested with a length-dependent motor neuropathy and pyramidal signs.
We identified a novel C>T transition at nucleotide position 238 (c.238C>T) in exon 2 of the SIGMAR1 gene. Sanger sequencing and segregation analysis confirmed the presence of two copies of the variant in the affected subjects, unlike the unaffected healthy parents/sibling who carried, at most, a single copy. The T allele is predicted to cause a truncating mutation (p.Gln80*), probably flagging the mRNA for nonsense-mediated decay leading to a complete loss of function, thereby potentially contributing to the disease process.
Our finding expands the spectrum of SIGMAR1 mutations causing recessive dHMN and indicates that this disorder is pan-ethnic. SIGMAR1 mutation should be included in the diagnostic panel of a dHMN, especially if there are co-existing pyramidal signs and autosomal recessive inheritance.
由于 sigma 非阿片类细胞内受体 1（SIGMAR1）基因突变（OMIM 601978.0003）导致的远端遗传性运动神经病（dHMN）是一种罕见的神经肌肉疾病，其特征为明显的远端肢体无力和肌萎缩，最初在最近的一个中国家族中描述。我们报道了一个扩展的阿曼近亲家族，其表现为常染色体隐性遗传方式的伴有锥体束征的 dHMN，并描述了该运动表型的 SIGMAR1 基因中的一个新突变。我们还提供了 SIGMAR1 突变报告表型谱的更新。
我们利用白细胞 DNA 的同源性作图和外显子组测序，对来自一个表现出长度依赖性运动神经病和锥体束征的阿曼家族的三个受影响成员进行了分析。
我们在 SIGMAR1 基因的外显子 2 中发现了一个新的 C>T 转换，位于核苷酸位置 238（c.238C>T）。Sanger 测序和分离分析证实，受影响的个体存在两个变异体的副本，而未受影响的健康父母/兄弟姐妹则最多携带一个副本。T 等位基因预计会导致截断突变（p.Gln80*），可能会标记 mRNA 进行无意义介导的衰变，导致完全失去功能，从而可能导致疾病过程。
我们的发现扩展了导致隐性 dHMN 的 SIGMAR1 突变谱，并表明这种疾病是泛种族的。SIGMAR1 突变应包含在 dHMN 的诊断面板中，特别是如果存在共存的锥体束征和常染色体隐性遗传。
