A homozygous mutation of TWNK identified in premature ovarian insufficiency warns of late-onset perrault syndrome.

BACKGROUND: Primary ovarian insufficiency (POI) is defined as cessation of ovarian function before the age of 40 years, which is characterized by amenorrhoea, infertility, elevated gonadotrophin level and sex-steroid deficiency. The phenotypes of POI are heterogeneous, including isolated and syndromic forms. Perrault syndrome (PS), characterized by sensorineural hearing loss (SNHL) and ovarian dysfunction before 40 years in females, is one type of syndromic POI. Genetic defects play a vital role in the pathogenesis of POI.

METHODS AND RESULTS: To illustrate the genetic causation of Perrault syndrome, we performed whole exome sequencing (WES) in one pedigree with the disease, and identified a novel homozygous mutation in TWNK (c.1388G > A, p.R463Q). TWNK encodes a hexameric DNA helicase in mitochondria and plays a critical role in mtDNA replication. In order to determine the effect of the novel mutation on the mitochondrial function, we generated immortalized cell lines by infecting lymphocytes from the family members with EB virus in vitro. Functional studies found that TWNK p.R463Q impaired mtDNA replication and the respiration potential of mitochondria, while the ROS level remains unaffected.

CONCLUSION: Our study provided evidence that TWNK mutation impaired the ovarian function by dysfunctional mitochondria. Moreover, considering the patients here presented POI onset earlier than SNHL, specific variants localizing in different locus of TWNK might induce heterogeneous phenotypes, indicating that the genetic screening of patients with POI would be useful for early recognition of other disease or other phenotypes of syndromic POI.