A type X collagen mutation causes Schmid metaphyseal chondrodysplasia

Abstract

The expression of type X collagen is restricted to hypertrophic chondrocytes in regions undergoing endochondral ossification, such as growth plates. The precise function of type X collagen is unknown but the tissue-specific expression prompted us to examine the gene in hereditary disorders of cartilage and bone growth (osteochondrodysplasias). We have identified a 13 base pair deletion in one type X collagen allele segregating with autosomal dominant Schmid metaphyseal chondrodysplasia in a large Mormon kindred (lod score = 18.2 at theta = 0). The mutation produces a frameshift which alters the highly conserved C-terminal domain of the alpha 1(X) chain and reduces the length of the polypeptide by nine residues. This mutation may prevent association of the mutant polypeptide during trimer formation, resulting in a decreased amount of normal protein.

Use of conformation sensitive gel electrophoresis to detect single-base changes in the gene for COL10A1

“…Of the previousy reported mutations in the COLf OAf gene causing SMCD, five were single base substitutions that altered amino acid codons and eight were either single base substitutions or deletions that introduced premature termination codons (Warman et al, 1993;Dharmavaram et al, 1994;McIntosh et al, 1994McIntosh et al, , 1995Wallis et al, 1994;Bonaventure et al, 1995;Chan et al, 1995). Surprisingly, all patients with SMCD were found to have mutations in the COLJOAf gene and all the mutations were within the last 160 codons for the NC1 domain.…”

“…Mutations in the COLf OAf gene were shown to cause Schmid metaphyseal chondrodysplasia (SMCD) , an autosomal dominant disorder characterized by slighly short stature, short limbs, coxa vara, and a waddling gait (Lachman et al, 1988). More than 12 mutations in theCOLf OAf gene in patients with SMCD have been previously reported (Warman et al, 1993;Dharmavaram et al, 1994;McIntosh et al, 1994McIntosh et al, ,1995Wallis et al, 1994;Bonaventure et al, 1995;Chan et al, 1995). All mutations to date have been located in the C-terminal noncollagenous domain of type X collagen and within less than 50 base pairs (bp) of coding sequence.…”

Novel missense mutation resulting in the substitution of tyrosine by cysteine at codon 597 of the type X collagen gene associated with Schmid metaphyseal chondrodysplasia

“…A 13-bp deletion in the region of the noncollagenous carboxy (C)-terminal (NC1) domain of type X collagen was identified in one allele segregating with autosomal dominant SMCD (Warman et al 1993). Subsequently, additional mutations, i.e., frameshift and missense mutations, were reported (McIntosh et al 1994, Wallis et al 1994).…”

A recurrent 1992delCT mutation of the type X collagen gene in a Japanese patient with Schmid metaphyseal chondrodysplasia

“…All of the known SMCD mutations are different (Warman et al, 1993;Wallis et aZ, 1994;McIntosh et aZ, 1994McIntosh et aZ, , 1995Dharmavaram et aL, 1994;Chan et aL, 1995;Bonaventure et aL, 1995). However, three of the reported deletions were initiated at nucleotide 1856 of C O L I O A 1 .…”

“…Seventeen different SMCD mutations reported to date have all been located within the carboxyl (C)-terminal noncollagenous domain coding region of the type X collagen gene (COLIOA1) (Warman et al, 1993;Wallis et al, 1994;McIntosh et al, 1994McIntosh et al, , 1995DharmavarReceived March 21, 1996;Revised version accepted June 17, 1996. * To whom correspondence should be addressed.…”