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Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency

Akin, L; Rizzoti, K; Gregory, LC; Corredor, B; Le Quesne Stabej, P; Williams, H; Buonocore, F; ... Dattani, MT; + view all (2022) Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency. Genetics in Medicine , 24 (2) pp. 384-397. 10.1016/j.gim.2021.09.019. Green open access

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Abstract

PURPOSE: We aimed to investigate the molecular basis underlying a novel phenotype including hypopituitarism associated with primary ovarian insufficiency. METHODS: We 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. RESULTS: We 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. CONCLUSION: Our 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.

Type: Article
Title: Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.gim.2021.09.019
Publisher version: https://doi.org/10.1016/j.gim.2021.09.019
Language: English
Additional information: This research was funded in part, by the Wellcome Trust [FC001107, MR/R006237/1, 209328/Z/17/Z, 216362/Z/19/Z]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Keywords: Growth hormone deficiency, Hypopituitarism, Minor spliceosome, Primary ovarian insufficiency, U12-type spliceosome
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10141644
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