SOD1 – Amyotrophic lateral sclerosis type 1

Autosomal dominant mutations in SOD1 cause amyotrophic lateral sclerosis type 1 (ALS1), characterized by adult-onset motor neuron degeneration, variable penetrance and progression. The hallmark is distal limb weakness progressing to fatal paralysis over 2–5 years. Age at onset ranges widely, with incomplete penetrance observed in obligate carriers of several missense variants (e.g., c.1485A>C (p.Asn139His)) (PMID:15050430).

Multiple unrelated families (n>50 probands) across diverse ethnicities harbor heterozygous SOD1 variants, confirming autosomal dominant inheritance with reduced penetrance (PMID:8179602; PMID:20472325). Segregation analysis in familial cohorts, including Spanish, Japanese, Chinese and Mediterranean pedigrees, demonstrates co-segregation with disease and obligate carriers lacking clinical signs. Founder effects (e.g., R115G in Germany) further support recurrent alleles.

Variant spectrum encompasses over 150 heterozygous changes: primarily missense substitutions distributed in all five exons, plus rare small insertions (c.272_274dup (p.Asp91_Lys92insAsn)), nonsense (p.Leu127Ter), splice and frameshift mutations. A representative example is c.1485A>C (p.Asn139His) identified in three affected members of a Spanish kindred with incomplete penetrance (PMID:15050430).

Mechanistic studies reveal a toxic gain-of-function: H46R mutants are structurally stable but lack copper binding and enzymatic activity in vivo (PMID:7805862). Transgenic mice expressing G93A SOD1 develop motor neuron disease with mitochondrial vacuolation mimicking human ALS1 (PMID:7605627). The H48Q variant exhibits novel superoxide-dependent peroxidase activity, generating reactive oxidants at the active site (PMID:9343373).

Rescue and modifier experiments further confirm pathogenicity: administration of putrescine-modified catalase delays disease onset and weakness in G93A transgenic mice without altering survival, supporting oxidative damage as a therapeutic target (PMID:10486188). The copper chaperone CCS directly interacts with both wild-type and mutant SOD1, suggesting modulation of copper delivery may mitigate toxicity (PMID:9726962).

No association has been found between ALS and LOX gene variants, underscoring the specificity of SOD1 in ALS1 (PMID:11675877). Polymorphisms in SOD1 introns and nonpathogenic variants in sporadic ALS cases further delineate pathogenic alleles.

Collectively, definitive genetic and functional evidence establishes SOD1 as the causative gene for autosomal dominant ALS1. Genetic testing for SOD1 mutations is clinically actionable for diagnostic confirmation, familial risk assessment, and stratification in therapeutic trials.

References

• Journal of the neurological sciences • 2004 • A novel exon 5 mutation (N139H) in the SOD1 gene in a Spanish family associated with incomplete penetrance. PMID:15050430
• Biochemical and biophysical research communications • 1994 • A novel mutation in Cu/Zn superoxide dismutase gene in Japanese familial amyotrophic lateral sclerosis. PMID:8179602
• Neurobiology of aging • 2011 • FUS, TARDBP, and SOD1 mutations in a Taiwanese cohort with familial ALS. PMID:20472325
• FEBS letters • 1994 • Impaired copper binding by the H46R mutant of human Cu,Zn superoxide dismutase, involved in amyotrophic lateral sclerosis. PMID:7805862
• Neuron • 1995 • An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. PMID:7605627
• Archives of biochemistry and biophysics • 1997 • Superoxide-dependent peroxidase activity of H48Q: a superoxide dismutase variant associated with familial amyotrophic lateral sclerosis. PMID:9343373
• Experimental neurology • 1999 • Therapeutic benefits of putrescine-modified catalase in a transgenic mouse model of familial amyotrophic lateral sclerosis. PMID:10486188
• Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases • 2001 • Mutations in the lysyl oxidase gene are not associated with amyotrophic lateral sclerosis. PMID:11675877
• The Journal of biological chemistry • 1998 • The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase. PMID:9726962

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