Primary ovarian insufficiency is caused by recessive partial loss-of-function mutations in genes for mitochondrial protein homeostasis. S. B. Pierce1, T. Walsh1, S. Gulsuner1, M. K. Lee1, M.-C. King1,2 1) Medicine (Medical Genetics), University of Washington, Seattle, WA; 2) Genome Sciences, University of Washington, Seattle, WA.
Primary ovarian insufficiency (POI), a form of hypergonadotropic hypogonadism, causes infertility in approximately 1% of women of normal 46,XX karyotype by 40 years of age. Both genetic and non-genetic causes of POI have been identified, but the mechanism of ovarian dysfunction in most cases is unknown. Heretofore, mutations in 14 genes have been reported to account for about 15% of cases. In a search for additional genes responsible for POI, we identified families with both POI in young women and sensorineural hearing loss (SNHL) in both females and males, described clinically as Perrault syndrome. Our participants are 15 families with between one and six affected relatives. In 5 of the 15 families, the POI and SNHL phenotypes are explained by recessive mutations in HARS2, LARS2, or HSD17B4. HARS2 and LARS2 encode mitochondrial aminoacyl-tRNA synthetases, which are required for mitochondrial protein translation. Together with CLPP, which encodes a mitochondrial ATP-dependent protease and also causes POI and SNHL, mutations in HARS2 and LARS2 reveal a role for mitochondria in the maintenance of ovarian function. Although mutations in genes encoding mitochondrial proteins have not previously been implicated in POI, our findings are consistent with increasing evidence that mitochondrial integrity is critical for oocyte competence and subsequent embryonic development. Thus, our focus on POI in association with another highly vulnerable phenotype, in this case hearing loss, reveals a specific functional class of genes as critical for fertility. Among individuals in our series carrying mutations in HARS2, LARS2, and HSD17B4, none carry two completely null alleles. This is consistent with the essential activities of these genes, for which complete loss of function is likely to be incompatible with life. Indeed, more severe recessive mutations in HSD17B4 are known to cause DBP deficiency, a disorder of peroxisomal fatty acid -oxidation that is usually fatal in early childhood. Similarly, mutations in CHD7 have been implicated in POI, whereas more severe alleles cause CHARGE syndrome. Our approach of evaluating families affected by both POI and SNHL has resulted in the identification of new genes harboring mutations for POI and has revealed mitochondrial protein homeostasis as critical for maintenance of fertility. Gene discovery for the remaining families is in progress.
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