Pathogenic Variants in RNPC3 are Associated with Hypopituitarism and Primary Ovarian Insufficiency

PURPOSE: We aimed to investigate the molecular basis underlying a novel phenotype including hypopituitarism associated with POI. METHODS: We used NGS to identify variants in all pedigrees. Expression of Rnpc3/RNPC3 was analysed by in situ hybridization on murine/human embryonic sections. Crispr/Cas9 was used to generate mice carrying the p.L483F pathogenic variant in the conserved murine Rnpc3 RRM2 domain. RESULTS: We described 15 patients from nine pedigrees with biallelic mutations in RNPC3, encoding a specific protein component of the minor spliceosome, associated with a hypopituitary phenotype including severe GHD, hypoprolactinaemia, variable TSH deficiency and anterior pituitary hypoplasia. POI was diagnosed in eight of nine affected females whilst males had normal gonadal function. Additionally, two affected males displayed normal growth off GH treatment, despite severe biochemical GHD. In both mouse and human embryos, Rnpc3/RNPC3 was expressed in the developing forebrain including the hypothalamus and Rathke’s pouch. Female rnpc3 mutant mice displayed a reduction in pituitary GH content, but with no reproductive impairment in young mice. Male mice exhibited no obvious phenotype. CONCLUSION: Our findings suggest novel insights into the role of RNPC3 in female-specific gonadal function and emphasize a critical role of the minor spliceosome in pituitary and ovarian development and function.