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

We aimed to investigate the molecular basis underlying a novel phenotype including hypopituitarism associated with primary ovarian insufficiency. 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. 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. 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. Copyright © 2021 American College of Medical Genetics and Genomics. All rights reserved.

Citation

Leyla Akin, Karine Rizzoti, Louise C Gregory, Beatriz Corredor, Polona Le Quesne Stabej, Hywel Williams, Federica Buonocore, Stephane Mouilleron, Valeria Capra, Sinead M McGlacken-Byrne, Gabriel Á Martos-Moreno, Dimitar N Azmanov, Mustafa Kendirci, Selim Kurtoglu, Jenifer P Suntharalingham, Christophe Galichet, Stefano Gustincich, Velibor Tasic, John C Achermann, Andrea Accogli, Aleksandra Filipovska, Anatoly Tuilpakov, Mohamad Maghnie, Zoran Gucev, Zeynep Burcin Gonen, Luis A Pérez-Jurado, Iain Robinson, Robin Lovell-Badge, Jesús Argente, Mehul T Dattani. Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency. Genetics in medicine : official journal of the American College of Medical Genetics. 2022 Feb;24(2):384-397

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PMID: 34906446

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