Mutation Update forCOL2A1Gene Variants Associated with Type II Collagenopathies

Abstract

Mutations in the COL2A1 gene cause a spectrum of rare autosomal-dominant conditions characterized by skeletal dysplasia, short stature, and sensorial defects. An early diagnosis is critical to providing relevant patient care and follow-up, and genetic counseling to affected families. There are no recent exhaustive descriptions of the causal mutations in the literature. Here, we provide a review of COL2A1 mutations extracted from the Leiden Open Variation Database (LOVD) that we updated with data from PubMed and our own patients. Over 700 patients were recorded, harboring 415 different mutations. One-third of the mutations are dominant-negative mutations that affect the glycine residue in the G-X-Y repeats of the alpha 1 chain. These mutations disrupt the collagen triple helix and are common in achondrogenesis type II and hypochondrogenesis. The mutations resulting in a premature stop codon are found in less severe phenotypes such as Stickler syndrome. The p.(Arg275Cys) substitution is found in all patients with COL2A1-associated Czech dysplasia. LOVD-COL2A1 provides support and potential collaborative material for scientific and clinical projects aimed at elucidating phenotype-genotype correlation and differential diagnosis in patients with type II collagenopathies.

Identification of an Autosomal Dominant Mutation in the COL2A1 Gene Leading to Spondyloepiphyseal Dysplasia Congenita in a Greek Family

“…Type II collagen is composed of 3 collagen α1 chains (COL2A1x3) and is a basic component of tissues such as the hyaline cartilage [Kusano et al, 2017]. Most COL2A1 mutations occur in the triple-helical region of α1 (II) chains [Barat-Houari et al, 2016].…”

New Genetic Diagnoses of Short Stature Provide Insights into Local Regulation of Childhood Growth

“…Premature osteoarthritis (OA) is a common feature of type II collagenopathies [57]. Mutations in glycine residues disrupt the collagen triple helix and cause disease in the heterozygous state, often with a severe phenotype, including achondrogenesis type II or hypochondrogenesis , spondyloepiphyseal dysplasia congenita , or spondyloepimetaphyseal dysplasia Strudwick type [57]. Nonsense and frameshift mutations result in haploinsufficiency and usually a less severe phenotype such as Stickler syndrome I, the most frequent type II collagenopathy.…”

“…Nonsense and frameshift mutations result in haploinsufficiency and usually a less severe phenotype such as Stickler syndrome I, the most frequent type II collagenopathy. Especially the p.Arg275Cys substitution is found in all patients with COL2A1 -associated Czech dysplasia [57]. …”

“…Mutations in type II collagen ( COL2A1 ) gene cause a spectrum of rare autosomal dominant conditions characterized by skeletal dysplasia, short stature, and ocular defects [54-56]. Premature osteoarthritis (OA) is a common feature of type II collagenopathies [57]. Mutations in glycine residues disrupt the collagen triple helix and cause disease in the heterozygous state, often with a severe phenotype, including achondrogenesis type II or hypochondrogenesis , spondyloepiphyseal dysplasia congenita , or spondyloepimetaphyseal dysplasia Strudwick type [57].…”

Estudo genético-clínico das displasias esqueléticas, com enfoque nas osteocondrodisplasias com acometimento do esqueleto axial, associado ao envolvimento epifisário e/ou metafisário

“…Um paciente (F7) com acondrogênese tipo 2, forma letal de colagenopatia tipo II, apresentou a mutação p.Gly1074Asp situada no domínio tripla-hélice da proteína. As mutações em resíduos de glicina na cadeia pró-alfa 1 de colágeno II, comprometem a montagem homotrimérica e a estabilidade da molécula, um efeito dominante negativo, frequentemente encontrado nos pacientes com fenótipos mais graves (Barat-Houari et al, 2016). Outra forma de fenótipo mais severo, a displasia de Kniest, foi diagnosticada em uma paciente (F11).…”