SETX

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 the structure of senataxin, researchers believe that it is one of a class of proteins called helicases that are involved in DNA repair and the production of RNA, a chemical cousin of DNA. Helicases attach to particular regions of DNA and temporarily unwind the two spiral strands of a DNA molecule. By unwinding the strands near sites of DNA damage, helicases allow other proteins to reach damaged areas and fix them. Senataxin is thought to aid in DNA repair through this helicase mechanism. This mechanism may also be involved in RNA production.

amyotrophic lateral sclerosis - caused by mutations in the SETX gene

Researchers have identified three SETX mutations that cause type 4 amyotrophic lateral sclerosis, a slowly progressive form of the disease that typically affects people under age 25. These mutations replace one of the protein building blocks (amino acids) used to make senataxin with an incorrect amino acid. This type of mutation may alter the 3-dimensional shape of senataxin and disrupt its normal function. It is unclear how mutations in the SETX gene cause type 4 amyotrophic lateral sclerosis.

ataxia with oculomotor apraxia - caused by mutations in the SETX gene

At least 17 mutations in the SETX gene have been found to cause ataxia with oculomotor apraxia type 2. Most of the mutations replace one of the amino acids used to make senataxin. A few mutations in the SETX gene lead to an abnormally short, nonfunctional version of the protein. Mutations in the SETX gene are thought to disrupt the helicase function of senataxin. A lack of functional senataxin can lead to an accumulation of DNA damage in cells, particularly affecting brain cells in the part of the brain involved in coordinating movements (the cerebellum). This accumulation can lead to cell death in the cerebellum, causing the characteristic movement problems of ataxia with oculomotor apraxia type 2.