Endocrine Abstracts

Mutations in the genes of PROK2/R2 cause isolated hypogonadotropic hypogonadism (IHH) in humans, and defects in the PROK2/R2 pathway metabolic disturbances in mice. The role of naturally occuring mutations in the reproductive and metabolic health of the general population remains unknown. We hypothesized that individuals with naturally occurring rare PROK/R2 variants will display dysregulation of their reproductive and metabolic fitness. We examined whole exome sequencing data of participants of the large dataset of the Massachusetts General Brigham Biobank (MGBB) (N=53,408). Using a recall-by-genotype approach, we recruited and examined the reproductive and overall health of 25 individuals with rare PROK2/R2 deleterious variants (cases) compared to 24 non-carrier controls. Evaluation of medical histories, physical exams, laboratory test results and dedicated questionnaires were used for assessment of the reproductive and overall health of the participants. A frequently sampled intravenous glucose tolerance test was performed in a subset of individuals to assess the β-cell function and insulin sensitivity of the participants. While no differences were observed in the overall health of individuals with PROK2/R2 variants compared to health controls, PROK2/R2-positive male participants were at higher risk for being evaluated for infertility compared to healthy controls [41% of PROK2/R2 positive participants were evaluated for infertility compared to 6% of non-carrier controls, OR 12.5 (1.19-130), P value 0.04]. In addition, they demonstrated a lower adult size testicular volume at exam compared to non-carrier controls [19 (2.7) mls vs 21 (2.9) mls, P value 0.02]. No differences in glucose regulation was noted between the two groups. In conclusion, impaired PROK2/R2 signaling may contribute to subtle deficits in reproductive fitness of male carriers in the general population. This study highlights the importance of recall by genotype studies in assessing the phenotypic expressivity, the full phenotypic spectrum, and the penetrance of disease associated human genetic variants.