CYP11B1 variants influence skeletal maturation via alternative splicing

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• Skeletal age (SA) deviation occurs in various growth disorders.
• Identifying genetic factors influencing SA is crucial for understanding growth.
• The adrenal gland's role in SA is not fully understood.

Purpose of the Study:

• To identify genetic determinants of skeletal age (SA) using genome-wide association study meta-analysis.
• To investigate the functional role of identified genetic variants in adrenal gland function.

Main Methods:

• Genome-wide association study meta-analysis of two multiethnic cohorts (N=4557).
• Prioritization of a synonymous variant (rs6410) in CYP11B1 for functional analysis.
• Analysis of adrenal RNA-sequencing data (GTEx) and RT-PCR validation.

Main Results:

• A significant association was found between the CYP11B1 locus and SA (rs6471570-A; P=6.2 × 10⁻¹²).
• The variant rs6410 in CYP11B1 was linked to altered alternative splicing events in adrenal tissue.
• These splicing changes were associated with intron retention and altered exon inclusion/exclusion.

Conclusions:

• CYP11B1, encoding 11-β-hydroxylase, plays a role in adrenal steroidogenesis and influences skeletal age in children.
• Alternative splicing of CYP11B1 is a potential mechanism affecting SA.
• Findings highlight the importance of adrenal steroidogenesis in regulating skeletal maturation.