CYP11B1 variants influence skeletal maturation via alternative splicing.

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State: Public
Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_46540000AB04
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
CYP11B1 variants influence skeletal maturation via alternative splicing.
Journal
Communications biology
Author(s)
Grgic O., Gazzara M.R., Chesi A., Medina-Gomez C., Cousminer D.L., Mitchell J.A., Prijatelj V., de Vries J., Shevroja E., McCormack S.E., Kalkwarf H.J., Lappe J.M., Gilsanz V., Oberfield S.E., Shepherd J.A., Kelly A., Mahboubi S., Faucz F.R., Feelders R.A., de Jong F.H., Uitterlinden A.G., Visser J.A., Ghanem L.R., Wolvius E.B., Hofland L.J., Stratakis C.A., Zemel B.S., Barash Y., Grant SFA, Rivadeneira F.
ISSN
2399-3642 (Electronic)
ISSN-L
2399-3642
Publication state
Published
Issued date
09/11/2021
Peer-reviewed
Oui
Volume
4
Number
1
Pages
1274
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
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.
Keywords
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
Yes
Create date
15/11/2021 14:42
Last modification date
08/08/2024 6:32
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