The TWNK gene encodes a hexameric DNA helicase which unwinds short stretches of double-stranded DNA in the 5' to 3' direction and, along with mitochondrial single-stranded DNA binding protein and mtDNA polymerase gamma, is essential for mtDNA replication. The protein localizes to the mitochondrial matrix and mitochondrial nucleoids. Mutations in this gene cause infantile onset spinocerebellar ataxia (IOSCA) and progressive external ophthalmoplegia (PEO) and are also associated with several mitochondrial depletion syndromes. Alternative splicing results in multiple transcript variants encoding distinct isoforms.
The majority of the mutation described in the TWNKgene are associated with autosomal dominant PEO causing multiple mtDNA deletions, while a smaller subset of mutations are recessive and cause IOSCA in young children causing depletion of the mtDNA.
The pathophysiological mechanism underlying TWNK-related diseases is thought to involve defects in mtDNA replication and maintenance, leading to a depletion or accumulation of mtDNA mutations, oxidative stress, and mitochondrial dysfunction.
Diagnostic testing for TWNK-related diseases typically involves genetic testing, such as targeted sequencing or next-generation sequencing, to identify mutations in the TWNK gene. Additionally, biochemical assays may be used to measure mtDNA content and respiratory chain enzyme activities to support the diagnosis. Clinical features such as neurological symptoms, muscle weakness, and developmental delays can also help with diagnosis.
TWNK