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

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Akin L., Rizzoti K., Gregory L. C., Corredor B., Le Quesne Stabej P., Williams H., ...More

Genetics in Medicine, vol.24, no.2, pp.384-397, 2022 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 24 Issue: 2
  • Publication Date: 2022
  • Doi Number: 10.1016/j.gim.2021.09.019
  • Journal Name: Genetics in Medicine
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, EMBASE, MEDLINE
  • Page Numbers: pp.384-397
  • Keywords: Hypopituitarism, Minor spliceosome, Primary ovarian insuf fi ciency, U12-type spliceosome, popituitary phenotype, including severe growth hormone (GH) de fi ciency, hypoprolactinemia, U12-TYPE INTRONS, MUTATIONS, GENE, FAILURE, PROTEIN
  • Kayseri University Affiliated: No


© 2021 American College of Medical Genetics and GenomicsPurpose: 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.