The molecular complexity of COL2A1 splicing variants and their significance in phenotype severity

Bone. 2024 Apr:181:117013. doi: 10.1016/j.bone.2024.117013. Epub 2024 Jan 19.

Abstract

Pathogenic single nucleotide variants (SNVs) found in the COL2A1 gene are associated with a broad range of skeletal dysplasias due to their impact on the structure and function of the Col2a1 protein. However, the molecular mechanisms of some nucleotide variants detected during diagnostic testing remain unclear. The interpretation of missense and splicing variants caused by SNVs poses a significant challenge for clinicians. In this work, we analyzed 22 splicing variants in the COL2A1 gene which have been found in patients with COL2A1-associated skeletal dysplasias. Using a minigene system, we investigated the impact of these SNVs on splicing and gained insights into their molecular mechanisms and genotype-phenotype correlations for each patient. The results of our study are very useful for improving the accuracy of diagnosis and the management of patients with skeletal dysplasias caused by SNVs in the COL2A1 gene.

Keywords: Collagen; Kniest dysplasia; Splicing; Stickler syndrome.

MeSH terms

  • Collagen Type II / genetics
  • Collagen Type II / metabolism
  • Humans
  • Mutation
  • Nucleotides*
  • Phenotype

Substances

  • Collagen Type II
  • Nucleotides
  • COL2A1 protein, human