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.
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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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