Motor neuron disease: genes and variants

Genes linked to Motor neuron disease

• SOD1: Superoxide dismutase [Cu-Zn]

  It detoxifies superoxide radicals in the cytosol and mitochondrial intermembrane space, limiting oxidative injury. Pathogenic variants cause amyotrophic lateral sclerosis mainly through toxic properties of mutant protein rather than simple loss of antioxidant activity.

  5 disease-causing and 0 uncertain variants in SOD1 are linked to Motor neuron disease.

• TARDBP: TAR DNA-binding protein 43

  TDP-43 is an RNA-binding protein that regulates RNA processing, splicing, stability, and transport. Its normal activity supports neuronal and muscle cells, while abnormal TDP-43 accumulation is closely associated with amyotrophic lateral sclerosis and frontotemporal degeneration.

  2 disease-causing and 0 uncertain variants in TARDBP are linked to Motor neuron disease.

• TBK1: Serine/threonine-protein kinase TBK1

  It activates IRF3 and related antiviral pathways after innate immune sensing and also participates in autophagy and cellular homeostasis. Loss-of-function variants can cause amyotrophic lateral sclerosis or frontotemporal dementia, while increased pathway activity can support inflammatory disease and some cancers.

  0 disease-causing and 5 uncertain variants in TBK1 are linked to Motor neuron disease.

Weakly linked (only a few uncertain records): OPTN and PARK7.

Known disease-causing variants in Motor neuron disease

Same protein, different disease

• Amyotrophic lateral sclerosis is also caused by SOD1 variants; they fall mostly in different places as the Motor neuron disease variants (104 disease-causing).
• Spastic tetraplegia and axial hypotonia, progressive is also caused by SOD1 variants; they fall mostly in different places as the Motor neuron disease variants (5 disease-causing).
• Amyotrophic lateral sclerosis is also caused by TARDBP variants; they fall mostly in different places as the Motor neuron disease variants (12 disease-causing).
• FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, TARDBP-RELATED is also caused by TARDBP variants; they fall mostly in different places as the Motor neuron disease variants (8 disease-causing).

Diseases related to Motor neuron disease

• Amyotrophic lateral sclerosis, also linked to SOD1, TARDBP and TBK1
• Frontotemporal dementia and/or amyotrophic lateral sclerosis, also linked to TBK1
• FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, TARDBP-RELATED, also linked to TARDBP
• Spastic tetraplegia and axial hypotonia, progressive, also linked to SOD1

Frequently asked questions

Which genes are linked to Motor neuron disease?

In CATVariant, Motor neuron disease is linked to 3 analyzed proteins: SOD1 (Superoxide dismutase [Cu-Zn]), TARDBP (TAR DNA-binding protein 43) and TBK1 (Serine/threonine-protein kinase TBK1).

How many genetic variants are linked to Motor neuron disease?

16 variants: 7 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 9 are of uncertain significance or have conflicting reports.

Which uncertain variants in Motor neuron disease look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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