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SETX gene

Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

SETX gene

The SETX gene encodes the helicase senataxin, a protein involved in transcription, RNA processing, and DNA repair; mutations in this gene are associated with neurodegenerative conditions such as amyotrophic lateral sclerosis and ataxia with oculomotor apraxia type 2.

Overview

Normal Function

The SETX gene provides instructions for making a protein called senataxin. Senataxin is produced in a wide range of tissues, including the brain, spinal cord, and muscles. Based on its structure, researchers believe it belongs to a class of proteins called helicases, which attach to particular regions of DNA or RNA and temporarily unwind the strands. By unwinding the strands, helicases allow other proteins to reach the nucleic acids to perform their functions. Although senataxin’s role in cells is not completely understood, it appears to be involved in the production of proteins from genes (transcription), the processing of RNA molecules, and the repair of damaged DNA.

Health Conditions Related to Genetic Changes

Amyotrophic lateral sclerosis

MedlinePlus Genetics provides information about Amyotrophic lateral sclerosis.

Ataxia with oculomotor apraxia

At least 125 mutations in the SETX gene have been found to cause ataxia with oculomotor apraxia type 2. This condition is characterized by difficulty coordinating movements (ataxia) and problems with side‑to‑side movements of the eyes (oculomotor apraxia). Most mutations replace single protein building blocks (amino acids) in senataxin. The mutations associated with ataxia with oculomotor apraxia type 2 are thought to disrupt the helicase function of senataxin. Although it is unclear how impaired senataxin function leads to the signs and symptoms of this disorder, some researchers suggest that it disrupts DNA repair and can lead to an accumulation of DNA damage in cells. This accumulation can lead to cell death and seems particularly harmful to cells in the cerebellum, causing the characteristic movement problems.

Charcot‑Marie‑Tooth disease

MedlinePlus Genetics provides information about Charcot‑Marie‑Tooth disease.

Other Names for This Gene

  • ALS4
  • AOA2
  • KIAA0625
  • SCAR1
  • Sen1
  • SETX_HUMAN

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

  • Tests of SETX

Scientific Articles on PubMed

  • PubMed

Catalog of Genes and Diseases from OMIM

  • SENATAXIN; SETX

Gene and Variant Databases

  • NCBI Gene
  • ClinVar

References

  • Becherel OJ, Yeo AJ, Stellati A, Heng EY, Luff J, Suraweera AM, Woods R, Fleming J, Carrie D, McKinney K, Xu X, Deng C, Lavin MF. Senataxin plays an essential role with DNA damage response proteins in meiotic recombination and gene silencing. PLoS Genet. 2013 Apr;9(4):e1003435. doi:10.1371/journal.pgen.1003435.
  • Bennett CL, La Spada AR. Unwinding the role of senataxin in neurodegeneration. Discov Med. 2015 Feb;19(103):127-36.
  • Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA, Nicholson GA, Auer‑Grumbach M, Wagner K, De Jonghe P, Griffin JW, Fischbeck KH, Timmerman V, Cornblath DR, Chance PF. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004 Jun;74(6):1128-35. doi:10.1086/421054.
  • Ferraiuolo L, Kirby J, Grierson AJ, Sendtner M, Shaw PJ. Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat Rev Neurol. 2011 Nov;7(11):616-30. doi:10.1038/nrneurol.2011.152.
  • Fogel BL, Perlman S. Novel mutations in the senataxin DNA/RNA helicase domain in ataxia with oculomotor apraxia 2. Neurology. 2006 Dec 12;67(11):2083-4. doi:10.1212/01.wnl.0000247661.19601.28.
  • Groh M, Albulescu LO, Cristini A, Gromak N. Senataxin: Genome Guardian at the Interface of Transcription and Neurodegeneration. J Mol Biol. 2017 Oct 27;429(21):3181-3195. doi:10.1016/j.jmb.2016.10.021.
  • Le Ber I, Bouslam N, Rivaud‑Pechoux S, et al. Frequency and phenotypic spectrum of ataxia with oculomotor apraxia 2: a clinical and genetic study in 18 patients. Brain. 2004 Apr;127(Pt 4):759-67. doi:10.1093/brain/awh080.
  • Moreira MC, Klur S, Watanabe M, et al. Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia‑ocular apraxia 2. Nat Genet. 2004 Mar;36(3):225-7. doi:10.1038/ng1303.
  • Nanetti L, Cavalieri S, Pensato V, et al. SETX mutations are a frequent genetic cause of juvenile and adult onset cerebellar ataxia with neuropathy and elevated serum alpha‑fetoprotein. Orphanet J Rare Dis. 2013 Aug 14;8:123. doi:10.1186/1750-1172-8-123.
  • Suraweera A, Becherel OJ, Chen P, et al. Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage. J Cell Biol. 2007 Jun 18;177(6):969-79. doi:10.1083/jcb.200701042.

Genomic Location

The SETX gene is found on chromosome 9.

Medical Encyclopedia

  • Genes
  • Genetics

Understanding Genetics

  • What is DNA?
  • What is a gene?
  • What is a gene variant and how do variants occur?

Frequently Asked Questions

taxia with oculomotor apraxia type 2 (AOA2) is a progressive neurodegenerative disorder that typically begins in childhood or adolescence with balance issues and eye movement problems, slowly worsening over decades. In contrast, amyotrophic lateral sclerosis (ALS) is generally a more rapidly progressive motor neuron disease that leads to significant muscle weakness and paralysis within years. While both involve the SETX gene, AOA2 is characterized by cerebellar ataxia and elevated alpha-fetoprotein levels, whereas ALS primarily affects motor neurons without the specific eye movement apraxia seen in AOA2.
The SETX gene encodes senataxin, a helicase protein essential for RNA processing and DNA repair. Mutations in this gene disrupt the protein's ability to unwind RNA or DNA strands, leading to the accumulation of toxic RNA aggregates and impaired DNA repair mechanisms. This cellular stress causes progressive damage to neurons, particularly in the cerebellum and brainstem, resulting in the loss of coordination and motor control characteristic of the associated disorders.
Early signs often include difficulty walking or frequent stumbling, which may be mistaken for clumsiness or a lack of coordination. A hallmark early symptom is oculomotor apraxia, where individuals have difficulty initiating voluntary eye movements, often compensating by turning their head to look at objects. Other early indicators may include slurred speech (dysarthria) and elevated levels of alpha-fetoprotein (AFP) in the blood, which can be detected through routine blood tests before severe neurological decline occurs.
Currently, there is no cure for ataxia with oculomotor apraxia type 2 or SETX-related ALS. Treatment is supportive and focuses on managing symptoms to improve quality of life. This includes physical and occupational therapy to maintain mobility and prevent falls, speech therapy for communication difficulties, and nutritional support. Research into gene therapy and RNA-targeted therapies is ongoing, but no approved disease-modifying treatments are available at this time.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.