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

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• dc.contributor.author Akin, Leyla
• dc.contributor.author Pérez Jurado, Luis Alberto
• dc.contributor.author Dattani, Mehul T.
• dc.date.accessioned 2023-03-23T07:04:24Z
• dc.date.available 2023-03-23T07:04:24Z
• dc.date.issued 2022
• dc.description.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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Akin L, Rizzoti K, Gregory LC, Corredor B, Le Quesne Stabej P, Williams H et al. Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency. Genet Med. 2022;24(2):384-97. DOI: 10.1016/j.gim.2021.09.019
• dc.identifier.doi http://dx.doi.org/10.1016/j.gim.2021.09.019
• dc.identifier.issn 1098-3600
• dc.identifier.uri http://hdl.handle.net/10230/56328
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Genet Med. 2022;24(2):384-97
• dc.rights © Elsevier http://dx.doi.org/10.1016/j.gim.2021.09.019
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Growth hormone deficiency
• dc.subject.keyword Hypopituitarism
• dc.subject.keyword Minor spliceosome
• dc.subject.keyword Primary ovarian insufficiency
• dc.subject.keyword U12-type spliceosome
• dc.title Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion