title: A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis.
abstract: OBJECTIVE
  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of motor neurons in the brain and spinal cord, leading to muscle weakness and eventually death from respiratory failure. ALS is familial in about 10% of cases, with SOD1 mutations accounting for 20% of familial cases. Here we describe a consanguineous family segregating juvenile ALS in an autosomal recessive pattern and describe the genetic variant responsible for the disorder.
  
  
  METHODS
  We performed homozygosity mapping and direct sequencing to detect the genetic variant and tested the effect of this variant on a motor neuron-like cell line model (NSC34) expressing the wild-type or mutant gene.
  
  
  RESULTS
  We identified a shared homozygosity region in affected individuals that spans ~120 kbp on chromosome 9p13.3 containing 9 RefSeq genes. Sequencing the SIGMAR1 gene revealed a mutation affecting a highly conserved amino acid located in the transmembrane domain of the encoded protein, sigma-1 receptor. The mutated protein showed an aberrant subcellular distribution in NSC34 cells. Furthermore, cells expressing the mutant protein were less resistant to apoptosis induced by endoplasmic reticulum stress.
  
  
  CONCLUSIONS
  Sigma-1 receptors are known to have neuroprotective properties, and recently Sigmar1 knockout mice have been described to have motor deficiency. Our findings emphasize the role of sigma-1 receptors in motor neuron function and disease.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. amr@kfshrc.edu.sa
authors.forename: Amr
authors.initials: A
authors.lastname: Al-Saif
authors.forename: Futwan
authors.initials: F
authors.lastname: Al-Mohanna
authors.forename: Saeed
authors.initials: S
authors.lastname: Bohlega
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000235:genetics; D005973:Glutamine / Q000235:genetics; D006801:Humans; D020287:In Situ Nick-End Labeling; D007223:Infant; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016297:Mutagenesis, Site-Directed / Q000379:methods; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017480:Receptors, sigma / Q000235:genetics*; D012529:Saudi Arabia; D019284:Thapsigargin / Q000494:pharmacology; D014162:Transfection; D000097605:Sigma-1 Receptor
chemical_list: D004791:Enzyme Inhibitors; D018698:Glutamic Acid; D005973:Glutamine; D017480:Receptors, sigma; D019284:Thapsigargin; D000097605:Sigma-1 Receptor