Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency.
Growth hormone deficiency
Hypopituitarism
Minor spliceosome
Primary ovarian insufficiency
U12-type spliceosome
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
10
04
2021
revised:
15
07
2021
accepted:
27
09
2021
pubmed:
16
12
2021
medline:
23
3
2022
entrez:
15
12
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34906446
pii: S1098-3600(21)05347-8
doi: 10.1016/j.gim.2021.09.019
pmc: PMC7612377
mid: EMS142040
pii:
doi:
Substances chimiques
Nuclear Proteins
0
RNA-Binding Proteins
0
RNPC3 protein, human
0
Prolactin
9002-62-4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
384-397Subventions
Organisme : Cancer Research UK
ID : FC001107
Pays : United Kingdom
Organisme : Medical Research Council
ID : FC001107
Pays : United Kingdom
Organisme : Arthritis Research UK
ID : FC001107
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 216362/Z/19/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : FC001107
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R006237/1
Pays : United Kingdom
Organisme : MRF
ID : MRF_MRF-099-0002-RG-UCLIC
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 209328/Z/17/Z
Pays : United Kingdom
Informations de copyright
Copyright © 2021 American College of Medical Genetics and Genomics. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of Interest All authors declare that they have no conflicts of interest.
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