title: SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome.
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.
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (A.H., P.J.T., M.L., M.G.H., J.C.B., H.H., M.M.R.), UCL Institute of Neurology, Queen Square, London, UK; Department of Human Genetics and Hussman Institute for Human Genomics (M.A.G., S.Z.), Miller School of Medicine, University of Miami; The Genesis Project Foundation (M.A.G.), Miami, FL; The Dubowitz Neuromuscular Centre (F.M., A.Y.M.), UCL Institute of Child Health, London; and Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norwich, UK.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Horga
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (A.H., P.J.T., M.L., M.G.H., J.C.B., H.H., M.M.R.), UCL Institute of Neurology, Queen Square, London, UK; Department of Human Genetics and Hussman Institute for Human Genomics (M.A.G., S.Z.), Miller School of Medicine, University of Miami; The Genesis Project Foundation (M.A.G.), Miami, FL; The Dubowitz Neuromuscular Centre (F.M., A.Y.M.), UCL Institute of Child Health, London; and Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norwich, UK.
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Tomaselli
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (A.H., P.J.T., M.L., M.G.H., J.C.B., H.H., M.M.R.), UCL Institute of Neurology, Queen Square, London, UK; Department of Human Genetics and Hussman Institute for Human Genomics (M.A.G., S.Z.), Miller School of Medicine, University of Miami; The Genesis Project Foundation (M.A.G.), Miami, FL; The Dubowitz Neuromuscular Centre (F.M., A.Y.M.), UCL Institute of Child Health, London; and Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norwich, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gonzalez
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (A.H., P.J.T., M.L., M.G.H., J.C.B., H.H., M.M.R.), UCL Institute of Neurology, Queen Square, London, UK; Department of Human Genetics and Hussman Institute for Human Genomics (M.A.G., S.Z.), Miller School of Medicine, University of Miami; The Genesis Project Foundation (M.A.G.), Miami, FL; The Dubowitz Neuromuscular Centre (F.M., A.Y.M.), UCL Institute of Child Health, London; and Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norwich, UK.
authors.forename: Matilde
authors.initials: M
authors.lastname: Laurà
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (A.H., P.J.T., M.L., M.G.H., J.C.B., H.H., M.M.R.), UCL Institute of Neurology, Queen Square, London, UK; Department of Human Genetics and Hussman Institute for Human Genomics (M.A.G., S.Z.), Miller School of Medicine, University of Miami; The Genesis Project Foundation (M.A.G.), Miami, FL; The Dubowitz Neuromuscular Centre (F.M., A.Y.M.), UCL Institute of Child Health, London; and Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norwich, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (A.H., P.J.T., M.L., M.G.H., J.C.B., H.H., M.M.R.), UCL Institute of Neurology, Queen Square, London, UK; Department of Human Genetics and Hussman Institute for Human Genomics (M.A.G., S.Z.), Miller School of Medicine, University of Miami; The Genesis Project Foundation (M.A.G.), Miami, FL; The Dubowitz Neuromuscular Centre (F.M., A.Y.M.), UCL Institute of Child Health, London; and Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norwich, UK.
authors.forename: Adnan Y
authors.initials: AY
authors.lastname: Manzur
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (A.H., P.J.T., M.L., M.G.H., J.C.B., H.H., M.M.R.), UCL Institute of Neurology, Queen Square, London, UK; Department of Human Genetics and Hussman Institute for Human Genomics (M.A.G., S.Z.), Miller School of Medicine, University of Miami; The Genesis Project Foundation (M.A.G.), Miami, FL; The Dubowitz Neuromuscular Centre (F.M., A.Y.M.), UCL Institute of Child Health, London; and Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norwich, UK.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (A.H., P.J.T., M.L., M.G.H., J.C.B., H.H., M.M.R.), UCL Institute of Neurology, Queen Square, London, UK; Department of Human Genetics and Hussman Institute for Human Genomics (M.A.G., S.Z.), Miller School of Medicine, University of Miami; The Genesis Project Foundation (M.A.G.), Miami, FL; The Dubowitz Neuromuscular Centre (F.M., A.Y.M.), UCL Institute of Child Health, London; and Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norwich, UK.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Blake
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (A.H., P.J.T., M.L., M.G.H., J.C.B., H.H., M.M.R.), UCL Institute of Neurology, Queen Square, London, UK; Department of Human Genetics and Hussman Institute for Human Genomics (M.A.G., S.Z.), Miller School of Medicine, University of Miami; The Genesis Project Foundation (M.A.G.), Miami, FL; The Dubowitz Neuromuscular Centre (F.M., A.Y.M.), UCL Institute of Child Health, London; and Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norwich, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (A.H., P.J.T., M.L., M.G.H., J.C.B., H.H., M.M.R.), UCL Institute of Neurology, Queen Square, London, UK; Department of Human Genetics and Hussman Institute for Human Genomics (M.A.G., S.Z.), Miller School of Medicine, University of Miami; The Genesis Project Foundation (M.A.G.), Miami, FL; The Dubowitz Neuromuscular Centre (F.M., A.Y.M.), UCL Institute of Child Health, London; and Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norwich, UK.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (A.H., P.J.T., M.L., M.G.H., J.C.B., H.H., M.M.R.), UCL Institute of Neurology, Queen Square, London, UK; Department of Human Genetics and Hussman Institute for Human Genomics (M.A.G., S.Z.), Miller School of Medicine, University of Miami; The Genesis Project Foundation (M.A.G.), Miami, FL; The Dubowitz Neuromuscular Centre (F.M., A.Y.M.), UCL Institute of Child Health, London; and Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norwich, UK. m.reilly@ucl.ac.uk.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
mesh_terms: D006801:Humans; D008297:Male; D009134:Muscular Atrophy, Spinal / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D020125:Mutation, Missense; D010641:Phenotype; D017480:Receptors, sigma / Q000235:genetics*; D013577:Syndrome; D055815:Young Adult; D000097605:Sigma-1 Receptor
chemical_list: D017480:Receptors, sigma; D000097605:Sigma-1 Receptor