Recessive distal motor neuropathy with pyramidal signs in an Omani kindred: underlying novel mutation in the SIGMAR1 gene

Eur J Neurol. 2018 Feb;25(2):395-403. doi: 10.1111/ene.13519. Epub 2017 Dec 12.

Abstract

Background and purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Omani kindred; SIGMAR1 mutation; autosomal recessive inheritance; distal hereditary motor neuropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Codon, Nonsense
  • Consanguinity
  • Female
  • Genes, Recessive
  • Humans
  • Male
  • Muscular Atrophy, Spinal / genetics*
  • Muscular Atrophy, Spinal / physiopathology*
  • Oman
  • Pedigree
  • Receptors, sigma / genetics*
  • Respiratory Distress Syndrome, Newborn / genetics*
  • Respiratory Distress Syndrome, Newborn / physiopathology*

Substances

  • Codon, Nonsense
  • Receptors, sigma
  • sigma-1 receptor

Supplementary concepts

  • Spinal muscular atrophy with respiratory distress 1