Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiencyMore about Open Access at the Crick
Authors listLeyla 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
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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.
Journal Genetics in Medicine
Issue number 2