SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome
Authors:
- Alejandro HorgaAlejandro Horga
- Pedro J. TomaselliPTPedro J. Tomaselli
- Michael A. GonzalezMGMichael A. Gonzalez
- Matilde LauràMLMatilde Laurà
- Francesco MuntoniFMFrancesco Muntoni
- Adnan Y. ManzurAMAdnan Y. Manzur
- Michael G. HannaMHMichael G. Hanna
- Julian C. BlakeJBJulian C. Blake
- Henry HouldenHHHenry Houlden
- Stephan ZüchnerSZStephan Züchner
- Mary M. ReillyMary M. Reilly
Open Access
- 11 October 2016
- journal article
- research article
- Published by Wolters Kluwer Health in Neurology
- Vol. 87 (15) , 1607-1612
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.Keywords
This publication has 17 references indexed in Scilit:
- Exome Sequencing Identifies a REEP1 Mutation Involved in Distal Hereditary Motor Neuropathy Type VThe American Journal of Human Genetics, 2012
- The distal hereditary motor neuropathiesJournal of Neurology, Neurosurgery & Psychiatry, 2011
- Reliability of the CMT neuropathy score (second version) in Charcot‐Marie‐Tooth diseaseJournal of the Peripheral Nervous System, 2011
- A mutation in sigma‐1 receptor causes juvenile amyotrophic lateral sclerosisAnnals of Neurology, 2011
- REEP1 mutations in SPG31: Frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunctionHuman Mutation, 2011
- Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration–motor neuron diseaseAnnals of Neurology, 2010
- The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons. An anatomical and behavioral studyNeuroscience, 2010
- Sigma-1 Receptor Chaperones at the ER- Mitochondrion Interface Regulate Ca2+ Signaling and Cell SurvivalCell, 2007
- Phenotypes of the N88S Berardinelli–Seip congenital lipodystrophy 2 mutationAnnals of Neurology, 2005
- The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type VBrain, 2004