CYP11B1 variants influence skeletal maturation via alternative splicing.
Détails
Télécharger: 34754074_BIB_46540000AB04.pdf (1325.68 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY 4.0
Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_46540000AB04
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
CYP11B1 variants influence skeletal maturation via alternative splicing.
Périodique
Communications biology
ISSN
2399-3642 (Electronic)
ISSN-L
2399-3642
Statut éditorial
Publié
Date de publication
09/11/2021
Peer-reviewed
Oui
Volume
4
Numéro
1
Pages
1274
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Publication Status: epublish
Résumé
We performed genome-wide association study meta-analysis to identify genetic determinants of skeletal age (SA) deviating in multiple growth disorders. The joint meta-analysis (N = 4557) in two multiethnic cohorts of school-aged children identified one locus, CYP11B1 (expression confined to the adrenal gland), robustly associated with SA (rs6471570-A; β = 0.14; P = 6.2 × 10 <sup>-12</sup> ). rs6410 (a synonymous variant in the first exon of CYP11B1 in high LD with rs6471570), was prioritized for functional follow-up being second most significant and the one closest to the first intron-exon boundary. In 208 adrenal RNA-seq samples from GTEx, C-allele of rs6410 was associated with intron 3 retention (P = 8.11 × 10 <sup>-40</sup> ), exon 4 inclusion (P = 4.29 × 10 <sup>-34</sup> ), and decreased exon 3 and 5 splicing (P = 7.85 × 10 <sup>-43</sup> ), replicated using RT-PCR in 15 adrenal samples. As CYP11B1 encodes 11-β-hydroxylase, involved in adrenal glucocorticoid and mineralocorticoid biosynthesis, our findings highlight the role of adrenal steroidogenesis in SA in healthy children, suggesting alternative splicing as a likely underlying mechanism.
Mots-clé
Age Determination by Skeleton, Alternative Splicing, Bone Development/genetics, Child, Female, Humans, Male, Steroid 11-beta-Hydroxylase/genetics, Steroid 11-beta-Hydroxylase/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
15/11/2021 14:42
Dernière modification de la notice
08/08/2024 6:32