The phenotypic spectrum ofCOL2A1mutations

Abstract

Heterozygous mutations of COL2A1 create several clinical entities collectively termed type II collagenopathies. These disorders not only impair skeletal growth but also cause ocular and otolaryngological abnormalities. The classical phenotypes include the spondyloepiphyseal dysplasia (SED) spectrum with variable severity, Stickler dysplasia type I (STD-I), and Kniest dysplasia (KND). Most COL2A1 mutations occur in the triple helical region of alpha 1(II) chains: the SED spectrum is mostly attributed to missense mutations that substitute bulky amino acids for glycine residues, STD-I to haploinsufficiency of truncation mutations, and KND to exon skipping due to splice-site mutations. To further elucidate the genotype-phenotype relationship of type II collagenopathies, we examined COL2A1 mutations in 56 families that were suspected of having type II collagenopathies, and found 38 mutations in 41 families. Phenotypes for all 22 missense mutations and one in-frame deletion in the triple helical region fell along the SED spectrum. Glycine to serine substitutions resulted in alternating zones that produce severer and milder skeletal phenotypes. Glycine to nonserine residue substitutions exclusively created more severe phenotypes. The gradient of the SED spectrum did not necessarily correlate with the occurrence of extraskeletal manifestations. All nine truncation or splice-site mutations in the triple helical or N-propeptide region caused STD-I or KND, and extraskeletal changes were inevitable in both phenotypes. All six C-propeptide mutations produced a range of atypical skeletal phenotypes and created ocular, but not otolaryngological, changes.

Patella Alta and Trochlea Dysplasia Is Associated with Abnormal Type II Collagen and Matrix Accumulation in Chondrocytes

“…In contrast, we suggest that the primary changes in chondrocytes and ECM leads to cartilage with subnormal strength and increased risk of premature patellofemoral arthritis. Our hypothesis may to some extent be confirmed by similar case reports, as our findings corresponds to certain human type II colla genopathies [14], such as Stickler syndrome and Kniest dysplasia. These similarities are; matrix accumulation in rER in chondrocytes, abnormal type II collagen heterofibrils, formation of collagen bundles in the ECM of the cartilage and cell death [14].…”

“…Our hypothesis may to some extent be confirmed by similar case reports, as our findings corresponds to certain human type II colla genopathies [14], such as Stickler syndrome and Kniest dysplasia. These similarities are; matrix accumulation in rER in chondrocytes, abnormal type II collagen heterofibrils, formation of collagen bundles in the ECM of the cartilage and cell death [14]. These features have recently been shown also to be present in cartilage from patients with OsteoChondritis Dissecans (OCD) [3].…”

The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype

“…The substitution of glycine with bulkier amino acids in a Gly-X-Y repeat were more often associated with severe phenotypes, such as achondrogenesis, type II or hypochondrogenesis, or with severe short stature phenotypes including Kniest, SEDC and SEMD Strudwick types. [4][5][6] Counter to previous reports, variants in the X or Y positions of the Gly-X-Y motif in the collagen chain did not seem to influence the phenotypes observed in our patients.…”

Czech dysplasia metatarsal type: another type II collagen disorder

“…In PLSD-T both truncating and missense mutations have been found, 23 -25 whereas in SPD only truncating mutations have been reported. 20,21,23,26 The two patients in this study, however, show that SPD can also result from missense mutations in the C-propeptide (Figure 4). The C-propeptide of the pro-a1(II) collagen chain contains eight cysteine residues.…”