A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis

Ann Neurol. 2011 Dec;70(6):913-9. doi: 10.1002/ana.22534. Epub 2011 Aug 12.


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.

Interpretation: 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.

MeSH terms

  • Amyotrophic Lateral Sclerosis / etiology
  • Amyotrophic Lateral Sclerosis / genetics*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Line
  • Child
  • Child, Preschool
  • Chromosome Mapping
  • Chromosomes, Human, Pair 9
  • Cloning, Molecular
  • Enzyme Inhibitors / pharmacology
  • Family Health
  • Female
  • Genetic Predisposition to Disease*
  • Glutamic Acid / genetics
  • Glutamine / genetics
  • Humans
  • In Situ Nick-End Labeling
  • Infant
  • Male
  • Mice
  • Motor Neurons / drug effects
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Mutagenesis, Site-Directed / methods
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics*
  • Receptors, sigma / genetics*
  • Saudi Arabia
  • Thapsigargin / pharmacology
  • Transfection


  • Enzyme Inhibitors
  • Receptors, sigma
  • sigma-1 receptor
  • Glutamine
  • Glutamic Acid
  • Thapsigargin