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GENATLAS PHENOTYPE
last update : 10-01-2023
Symbol ALS1
Location 21q22.11
HGNC id 442
Name amyotrophic lateral sclerosis 1
Other name(s) familial amyotrophic lateral sclerosis
Corresponding gene SOD1
Other symbol(s) FALS
Main clinical features
  • neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis
  • familial or sporadic, slow or fast progression with loss of neurofilament expression, an exceptionnal recessive form D90A, probably due to a linked protective factor
  • deficits in axonal transport observed before disease onset, may represent one of the first pathological signs of motor neurons dysfunction; impairment of fast retrograde transport in a particular neuron may therefore be a predictor of neurodegeneration (PMID: 21059924))
    • Genetic determination autosomal dominant
    autosomal recessive
    Prevalence . 25 p100 of familial ALS (Kabuta 2009) . 3 percent of all ALS (PMID: 20460269)
    Function/system disorder neurology
    Type disease
    Gene product
    Name superoxide dismutase (SOD1)
    Mechanism(s)
    Gene mutationChromosome rearrangementEffectComments
    unknown   abnormal protein/gain of function alters the folding patterns of the protein
    Remark(s)
  • altered zinc binding site leading to gain of function by an unknown mechanism, modified by CNTF (early onset of the disease)
  • toxic mechanism by which this pathogenic protein could affect motor neuron survival and contribute to the selective motor neuronal degeneration
  • SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content
  • SOD1 mutants generate vascular changes prior to motor neuron degeneration
  • mutations destabilize the native structure of SOD1, leading to aberrant protein interactions for aggregation
  • scrambling of the conserved disulfide bond will be a key event to cause the pathological changes in disease-associated mutant SOD1 proteins (PMID: 23264618))
  • mutant SOD1 can directly increase microtubule dynamics through its destabilizing effect on microtubules in neurons(Kabuta 2009)
  • havin less likely significant cognitive changes compared to non-SOD1 FALS patients (Wicks 2009)
  • in mutant SOD1-linked amyotrophic lateral sclerosis (ALS), accumulation of misfolded mutant SOD1 in spinal cord mitochondria is thought to cause mitochondrial dysfunction (PMID: 20460269))
  • inhibition of mitochondrial protein import is demonstrated to be a direct result of mutant SOD1 (PMID: 21078990))
  • mutant SOD1 might accumulate inside the intermembrane space (IMS), overriding the physiological retention regulated by the copper chaperone for superoxide dismutase (CCS) (PMID: 26379505))
  • mislocalization and accumulation of structurally disordered, immature SOD1 protein conformers in spinal cord motor neurons of SOD1-linked familial amyotrophic lateral sclerosis cases, and sporadic amyotrophic lateral sclerosis cases, compared with control motor neurons (PMID: 35512359))
    • Genotype/Phenotype correlations H46R, dramatically reduce the ability of these enzymes to stably bind copper, which affects subsequent post-translational folding to achieve dimeric structure and the H46R mutation is associated with a very slowly progressing form of the disease