SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome

Alejandro Horga, Pedro J. Tomaselli, Michael A. Gonzalez, Matilde Laurà, Francesco Muntoni, Adnan Y. Manzur, Michael G. Hanna, Julian C. Blake, Henry Houlden, Stephan L Zuchner, Mary M. Reilly

Research output: Contribution to journalArticle

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Abstract

Objective: To describe the genetic and clinical features of a simplex patient with distal hereditary motor neuropathy (dHMN) and lower limb spasticity (Silver-like syndrome) due to a mutation in the sigma nonopioid intracellular receptor-1 gene (SIGMAR1) and review the phenotypic spectrum of mutations in this gene. Methods: We used whole-exome sequencing to investigate the proband. The variants of interest were investigated for segregation in the family using Sanger sequencing. Subsequently, a larger cohort of 16 unrelated dHMN patients was specifically screened for SIGMAR1 mutations. Results: In the proband, we identified a homozygous missense variant (c.194T>A, p.Leu65Gln) in exon 2 of SIGMAR1 as the probable causative mutation. Pathogenicity is supported by evolutionary conservation, in silico analyses, and the strong phenotypic similarities with previously reported cases carrying coding sequence mutations in SIGMAR1. No other mutations were identified in 16 additional patients with dHMN. Conclusions: We suggest that coding sequence mutations in SIGMAR1 present clinically with a combination of dHMN and pyramidal tract signs, with or without spasticity, in the lower limbs. Preferential involvement of extensor muscles of the upper limbs may be a distinctive feature of the disease. These observations should be confirmed in future studies.

Original languageEnglish (US)
Pages (from-to)1607-1612
Number of pages6
JournalNeurology
Volume87
Issue number15
DOIs
StatePublished - Oct 11 2016

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Mutation
Lower Extremity
Exome
Pyramidal Tracts
Spastic paraplegia 17
Upper Extremity
Computer Simulation
Genes
Virulence
Exons
Muscles

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Horga, A., Tomaselli, P. J., Gonzalez, M. A., Laurà, M., Muntoni, F., Manzur, A. Y., ... Reilly, M. M. (2016). SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome. Neurology, 87(15), 1607-1612. https://doi.org/10.1212/WNL.0000000000003212

SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome. / Horga, Alejandro; Tomaselli, Pedro J.; Gonzalez, Michael A.; Laurà, Matilde; Muntoni, Francesco; Manzur, Adnan Y.; Hanna, Michael G.; Blake, Julian C.; Houlden, Henry; Zuchner, Stephan L; Reilly, Mary M.

In: Neurology, Vol. 87, No. 15, 11.10.2016, p. 1607-1612.

Research output: Contribution to journalArticle

Horga, A, Tomaselli, PJ, Gonzalez, MA, Laurà, M, Muntoni, F, Manzur, AY, Hanna, MG, Blake, JC, Houlden, H, Zuchner, SL & Reilly, MM 2016, 'SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome', Neurology, vol. 87, no. 15, pp. 1607-1612. https://doi.org/10.1212/WNL.0000000000003212
Horga A, Tomaselli PJ, Gonzalez MA, Laurà M, Muntoni F, Manzur AY et al. SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome. Neurology. 2016 Oct 11;87(15):1607-1612. https://doi.org/10.1212/WNL.0000000000003212
Horga, Alejandro ; Tomaselli, Pedro J. ; Gonzalez, Michael A. ; Laurà, Matilde ; Muntoni, Francesco ; Manzur, Adnan Y. ; Hanna, Michael G. ; Blake, Julian C. ; Houlden, Henry ; Zuchner, Stephan L ; Reilly, Mary M. / SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome. In: Neurology. 2016 ; Vol. 87, No. 15. pp. 1607-1612.
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