HNF1A gene mutations and premature ovarian failure (POF): evidence from a clinical paradigm combining MODY 3 and POF

Abstract Premature ovarian failure (POF) defines the occurrence of ovarian failure prior to the age of 40. It occurs in one out of 100 women but is very rare before age 20 (1:10,000). Maturity-onset diabetes of the young (MODY), caused by mutations in the HNF1A gene, is also a rare disorder; all types of MODY account for 1–2% of adult diabetic cases. These two rare nosologic entities coexisted in an adolescent girl evaluated for delayed puberty. Although this combination could represent a chance association, an interrelation might exist. We examined HNF1A expression in human fetal and adult ovaries by immunohistochemistry using a polyclonal HNF1A antibody. HNF1A protein was expressed in both the fetal and adult human ovaries. Based on these findings, we hypothesize that HNF1A participates in ovarian organogenesis and/or function and that mutations in the HNF1A gene might represent another molecular defect causing POF, possibly in combination with other genetic factors. The study underlines the importance of rare clinical paradigms in leading the way to elucidation of the pathogenetic mechanisms of rare diseases.