Abstract
PurposeWe aimed to investigate the molecular basis underlying a novel phenotype including hypopituitarism associated with primary ovarian insufficiency. MethodsWe used next-generation sequencing to identify variants in all pedigrees. Expression of Rnpc3/RNPC3 was analyzed by in situ hybridization on murine/human embryonic sections. CRISPR/Cas9 was used to generate mice carrying the p.Leu483Phe pathogenic variant in the conserved murine Rnpc3 RRM2 domain. ResultsWe described 15 patients from 9 pedigrees with biallelic pathogenic variants in RNPC3, encoding a specific protein component of the minor spliceosome, which is associated with a hypopituitary phenotype, including severe growth hormone (GH) deficiency, hypoprolactinemia, variable thyrotropin (also known as thyroid-stimulating hormone) deficiency, and anterior pituitary hypoplasia. Primary ovarian insufficiency was diagnosed in 8 of 9 affected females, whereas males had normal gonadal function. In addition, 2 affected males displayed normal growth when off GH treatment despite severe biochemical GH deficiency. 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. ConclusionOur findings suggest novel insights into the role of RNPC3 in female-specific gonadal function and emphasize a critical role for the minor spliceosome in pituitary and ovarian development and function.
Highlights
Primary ovarian insufficiency (POI), characterized by amenorrhea with elevated gonadotropin concentrations, includes a spectrum ranging from 46,XX gonadal dysgenesis to premature menopause
IGF-1 and peak growth hormone (GH) during provocation tests were undetectable at age 9.7 years, patient T6 showed growth without GH until age 15 years when the growth velocity decreased to 4 cm/y and recombinant human GH therapy was started
Using Next-generation sequencing (NGS), we identified a series of biallelic pathogenic variants in RNPC3 in 15 patients from 9 families with severe GHD
Summary
Primary ovarian insufficiency (POI), characterized by amenorrhea with elevated gonadotropin concentrations, includes a spectrum ranging from 46,XX gonadal dysgenesis to premature menopause. Nonsyndromic POI occurs in 1% of women; early-onset forms manifesting as primary amenorrhea with the absence of pubertal development affect approximately 1 in 100,000 females.[1] To date, more than 50 genes have been associated with POI.[2] Overall, known genetic causes, including X chromosomal abnormalities, account for 20% to 25% of cases.[3,4,5,6,7,8,9,10,11]. Pre–messenger RNA splicing is an essential step in gene expression in all eukaryotes. RNPC3 encodes the U11/U12-65K protein, a component of the U12dependent spliceosome.[13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
