A single amino acid substitution (G103D) in the type II collagen triple helix produces Kniest dysplasia.

Kniest dysplasia is a moderately severe chondrodysplasia phenotype that results from mutations in the gene for type II collagen, COL2A1. Characteristics of the disorder include a short trunk and extremities, mid-face hypoplasia, cleft palate, myopia, retinal detachment, and hearing loss. Recently, deletions of all or part of exon 12 have been identified in individuals with Kniest dysplasia, suggesting that mutations within this region of the protein may primarily result in the Kniest dysplasia phenotype. We used SSCP to analyze an amplified genomic DNA fragment containing exon 12 from seven individuals with Kniest dysplasia. An abnormality was identified in one patient. DNA sequence analysis demonstrated that the patient was heterozygous for a G to A transition that implied substitution of glycine103 of the triple helical domain by aspartate. The mutation was not observed in DNA from either of the clinically unaffected parents of the proband. Protein microsequencing demonstrated expression of the abnormal allele in cartilage. These data demonstrate that point mutations which result in single amino acid substitutions can produce Kniest dysplasia and further support the hypothesis that alteration of a domain, which includes the region encoded by exon 12, in the type II collagen protein leads to this disorder.