Type II collagen defect in two sibs with the Goldblatt syndrome, a chondrodysplasia with dentinogenesis imperfecta, and joint laxity

Abstract

We report on a syndrome of spondylo-epimetaphyseal dysplasia, dentinogenesis imperfecta, and ligamentous hyperextensibility in two sibs born to nonconsanguineous parents. This chondrodysplasia was characterized by severe shortness of stature and an osteoporosis without fractures. Electron microscopic examination of the cartilage documented large vacuoles of dilated rough endoplasmic reticulum within the cytoplasm of chondrocytes. Gel electrophoresis of pepsin-soluble collagen extracted from cartilage demonstrated the presence of type II collagen chains with an abnormal mobility. Prolyl and lysyl hydroxylations were slightly increased. The abnormal molecules melted at a higher temperature than the normal ones. CNBr peptide mapping of type II collagen showed an altered electrophoretic migration of peptides CB 11, CB 8, and CB 10,5 whereas CB 9,7 looked normal. In addition, two small non-collagenous proteins isolated from cartilage were not found in an age-matched control individual but were detected in a normal newborn infant. The quantitation of proline-labelled collagen synthesized by dermal fibroblasts demonstrated a 50% reduction of total collagen. This decrease essentially affected the amount of extracellular type I collagen, which was secreted less efficiently than in control cells. Nevertheless, type I collagen chains behaved normally on 5% polyacrylamide gels. The reduced mRNA levels of alpha 1I and alpha 2I chains might reflect either a transcriptional defect or a decreased stability of mRNA transcripts. We suggest that the association of both pathological chondrocytes producing altered collagen type II and decreased synthesis of type I could be responsible for this peculiar phenotype. The overmodification of alpha 1II CNBr peptides is consistent with the presence of a single-base substitution in the COL2A1 gene. Whether there is a direct causal relationship between the type II collagen defect and the underexpression of type I collagen will require clarification.

Uncoupling of growth plate maturation and bone formation in mice lacking both Schnurri-2 and Schnurri-3

“…Skeletal elements formed through endochondral ossification are derived from cartilaginous templates that are replaced by osteoblast derived bone matrix. Decreases in bone mass are therefore frequently observed in mice with genetic mutations that impede the formation of the cartilaginous template through a disruption in chondrocyte biology (22)(23)(24). Accordingly, we anticipated that the osteosclerotic phenotype that we previously reported to be present in the Shn3 −/− strain would not be preserved in the chondrodysplastic Shn2/3-DKO mice (11).…”

Spondylometaphyseal dysplasia, east‐African Type: A new form of early, severe SMD with rounded vertebrae

“…Up to now, three types of SMD have been associated with molecular anomalies. Mutations of collagen type 2 have been shown in SEMD, Strudwick type [Tiller et al, 1995] and SMD with joint laxity and dentinogenesis imperfecta [Bonaventure et al, 1992;Maroteaux et al, 1996]. Mutations of the gene ATPSK2 encoding the PAPS synthase 2 are responsible for a SEMD, Pakistani type with autosomal recessive mode of inheritance [el Haque et al, 1981].…”

The type II collagenopathies: A spectrum of chondrodysplasias

“…It will be interesting to study type II collagen in these conditions. A possible type II collagen defect has been observed in a peculiar spondylometaphyseal dysplasia with joint laxity and dentinogenesis imperfecta [9]. The disorder has been described by Goldblatt et al [20] and bears distinct resemblance to earlier observations [26,48].…”