TWNK gene

The TWNK gene provides instructions for proteins involved in the maintenance of mitochondrial DNA, and mutations in this gene are linked to various neurological and multisystem disorders.

Normal Function

The TWNK gene provides instructions for making two very similar proteins called Twinkle and Twinky. These proteins are found in the mitochondria, which are structures in which a process called oxidative phosphorylation occurs to convert the energy from food into a form that cells can use.

Mitochondria each contain a small amount of DNA, known as mitochondrial DNA (mtDNA), which is essential for the normal function of these structures. The Twinkle protein is involved in the production and maintenance of mtDNA. It functions as a mitochondrial DNA helicase, which means it binds to DNA and temporarily unwinds the two spiral strands (double helix) of the DNA molecule. This unwinding is necessary for copying (replicating) mtDNA. The function of the Twinky protein is unknown.

Health Conditions Related to Genetic Changes

Ataxia neuropathy spectrum

Mutations in the TWNK gene have been found in a small number of people with ataxia neuropathy spectrum. This condition is characterized by problems with coordination and balance (ataxia) and disturbances in nerve function (neuropathy). Mutations in the TWNK gene disrupt the function of Twinkle and lead to large deletions of mtDNA in the muscle tissue of affected individuals.

Infantile-onset spinocerebellar ataxia

At least six mutations in the TWNK gene have been found to cause infantile-onset spinocerebellar ataxia (IOSCA). The most common mutation replaces the amino acid tyrosine with the amino acid cysteine at position 508 in the Twinkle protein (Tyr508Cys or Y508C). These mutations interfere with the function of the Twinkle protein and result in reduced quantities of mtDNA (mtDNA depletion). Impaired mitochondrial function, especially in the nervous system, leads to neurological dysfunction.

Perrault syndrome

At least four TWNK gene mutations have been identified in families with Perrault syndrome, a condition characterized by hearing loss and abnormalities of the ovaries in affected females. Researchers predict that these mutations impair the helicase activity of the protein.

Progressive external ophthalmoplegia

At least 40 TWNK gene mutations have been identified in people with an eye condition called progressive external ophthalmoplegia. This disorder weakens the muscles that control eye movement and causes the eyelids to droop (ptosis). Researchers speculate that the mutated Twinkle protein has impaired helicase activity, which stalls the DNA replication process, resulting in large deletions of genetic material from mtDNA in muscle tissue.

Other disorders

In a few families, TWNK gene mutations lead to mtDNA depletion syndrome, hepatocerebral form. People with this condition experience weak muscle tone (hypotonia), a decrease in liver function, developmental delay, seizures, and loss of sensation and weakness in the limbs (peripheral neuropathy).

Other Names for This Gene

• C10orf2
• chromosome 10 open reading frame 2
• PEO1
• PEO1_HUMAN
• progressive external ophthalmoplegia 1 protein
• T7 gp4-like protein with intramitochondrial nucleoid localization
• T7-like mitochondrial DNA helicase
• twinkle