Functional analysis of a novel pathogenic variant in CREBBP associated with bone development

Area of Science:

• Genetics and Molecular Biology
• Developmental Biology
• Orthopedics

Background:

• CREBBP is implicated in syndromic skeletal dysplasias, but its role in non-syndromic bone development is less understood.
• A novel pathogenic CREBBP variant (c.C3862T/p.R1288W) was identified in a patient with non-syndromic polydactyly.
• This study investigates the skeletal impact of this specific CREBBP variant.

Purpose of the Study:

• To create and characterize a mouse model for a novel pathogenic CREBBP variant (p.R1289W).
• To elucidate the molecular mechanisms by which this CREBBP variant affects bone development.
• To determine if this variant can cause non-syndromic skeletal dysplasia.

Main Methods:

• Generated a homozygous Crebbp p.R1289W mouse model.
• Compared skeletal phenotypes of mutant and wild-type (WT) mice.
• Isolated and analyzed bone marrow stem cells (BMSCs) for proliferation, apoptosis, and differentiation potential.

Main Results:

• Crebbp p.R1289W mice exhibited significantly reduced body length and increased digit cartilage length.
• BMSCs from mutant mice showed decreased proliferation and increased apoptosis.
• Analysis of the distal femoral growth plate revealed reduced proliferation and elevated apoptosis in Crebbp p.R1289W mice.
• Evidence suggests Crebbp p.R1289W promotes chondrocyte differentiation.

Conclusions:

• The Crebbp p.R1289W variant plays a pathogenic role in mouse skeletal development.
• This variant can independently cause non-syndromic skeletal dysplasia.
• The study provides the first animal model for this novel CREBBP variant, advancing understanding of its skeletal disease mechanisms.