The type II collagenopathies: A spectrum of chondrodysplasias

Abstract

With the application of molecular techniques the aetiopathogenesis of skeletal dysplasias is gradually elucidated. Recent advances show that some bone dysplasias result from defects in the biosynthesis of type II (cartilage) collagen. Clinical entities caused by mutations in the COL2A1 gene coding for type II collagen comprise achondrogenesis II, hypochondrogenesis, spondyloepiphyseal dysplasia congenita, Kniest dysplasia, Stickler arthroophthalmopathy and mild dominant spondyloarthropathy. The mutations are expressed in the heterozygous state, and inheritance of type II collagenopathies is autosomal dominant. The wide range of clinical manifestations is not well understood but characterization of the basic defect may provide clues to establish specific genotype-phenotype correlations.

Stickler syndrome caused by COL2A1 mutations: genotype–phenotype correlation in a series of 100 patients

“…15 The probe set for COL2A1 (SALSA MLPA kit P214) covering exons 1,4,6,8,10,16,17,19,20,24,27,29,31,35,39,43,46, 49, 51 and 54 was used.…”

“…On the other hand, missense mutations (usually glycine substitutions) in COL2A1 usually result in short-stature disorders, such as achondrogenesis type II/hypochondrogenesis, SEDC, Kniest dysplasia, spondyloperipheral dysplasia and Torrance dysplasia (MIM nos 200610, 183900, 156550, 271700, 151210, respectively). 5,10,11 The aim of this study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of Stickler syndrome patients with a heterozygous mutation in the COL2A1 gene.…”

Occurrence of deletion of a COL2A1 allele as the mutation in Stickler syndrome shows that a collagen type II dosage effect underlies this syndrome

“…Small in-frame deletions, mostly between exons 12 and 24, result in the more severe Kniest dysplasia. Glycine substitutions at different locations along the helix result in other type II collagen disorders (Spranger et al, 1994). A relationship exists between the amount of type II collagen in the extracellular matrix and the phenotypic severity, with less type II collagen in cartilage in the more severe disorders (Mortier et al, 1995).…”

Molecular genetics of rhegmatogenous retinal detachment

“…2 Thus Stickler syndrome was related to other chondrodysplasias such as achondrogenesis, hypochondrogenesis, splondyloepiphyseal dysplasia and Kniest dysplasia, which result from dominant negative mutations in the COL2A1 gene. 3 The first mutations characterised in Stickler syndrome all lead to premature termination codons (PTC), and so resulted in haploinsufficiency of type II collagen. [4][5][6] This was also the case for the original family described by Stickler, where missplicing of intron/exon 17/18 resulted in a frameshift of the mRNA sequence.…”