Cartilage expression of a type II collagen mutation in an inherited form of osteoarthritis associated with a mild chondrodysplasia.

Abstract

In a family who expressed severe dominantly inherited osteoarthritis, the underlying mutation was traced by genomic sequencing to a single base change which predicts an amino acid substitution of cysteine for arginine at residue 519 of the triple-helical domain of the type II collagen molecule (AlaKokko, L., C. T. Baldwin, R. W. Moskowitz, and D. J. . Proc. NatL Acad. Sci. USA. 87:6565-6568). In the present study we examined whether this predicted protein phenotype was evident in articular cartilage obtained from an affected family member who underwent hip surgery. The cartilage collagen was solubilized by CNBr digestion. Cysteine residues were labeled by reduction and alkylation with 14C-iodoacetate. Collagen CNBr-peptides were fractionated by ion exchange and reverse phase column chromatography. One peptide from the al(II) chain, al(II) CB8, was found to be radiolabeled. Tryptic peptides were prepared from it and identified by microsequence analysis. The results show that approximately one-quarter of the al(II) chains present in the polymeric extracellular collagen of the patient's cartilage contained the Ar&g19-to-Cys substitution. The protein exhibited other abnormal properties including disulfide-bonded al(II)-dimers and signs of posttranslational overmodification. The premature cartilage failure and osteoarthritis are presumably a result of the abnormal type II collagen being expressed in the cartilage matrix. (J. Clin. Invest. 1991. 87:357-361.)

Molecular genetics of rhegmatogenous retinal detachment

“…Cysteine does not usually occur in the mature fibrillar collagen molecule. Similar mutations both in type II and type I collagens 14,15 showed that cysteinecontaining collagen is poorly secreted. Thus, both the PTC and arginine to cysteine substitutions, lead us to believe that the membraneous anomaly is due to a lack of critical mass of type II collagen, during development of the eye, resulting in the clinical observation of a vestigial vitreous gel in the retrolental space.…”

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

“…p.(Arg550Cys), c.1648C4T was novel, but p.(Arg719Cys), c.2155C4T has already been reported once in a patient with osteoarthritis and mild chondrodysplasia. 10 Eyre et al 11 have demonstrated that p.(Arg719Cys), c.2155C4T is responsible for a reduction in protein secretion and a limited collagen assembly. The fourth arginine to cystein variant, p.(Arg904Cys), c.2710C4T, was found once in a Stickler case and once in a Kniest case, from our series.…”

Cartilage Extracellular Matrix Integrity and OA

“…Similarly in the 1990s, particular families were discovered to have missense mutation (R519C) causing the production of abnormal type II collagen pro-alphachains. These alpha chains formed protein dimers leading to mild chondrodysplasia followed by a unique form of familial OA (Byers, 2001;Eyre et al, 1991;Pun et al, 1994;Bleasel et al, 1998).…”