Small deletions in the type II collagen triple helix produce Kniest dysplasia

Kniest dysplasia is a moderately severe type II collagenopathy, characteriz ed by short trunk and limbs, kyphoscoliosis, midface hypoplasia, severe myo pia, and hearing loss. Mutations in the gene that encodes type II collagen (COL2A1), the predominant protein of cartilage, have been identified in a n umber of individuals with Kniest dysplasia, All but two of these previously described mutations cause in-frame deletions in type II collagen, either b y small deletions in the gene or splice site alterations, Furthermore, all but one of these mutations is located between exons 12 and 24 in the COL2A1 gene, We used heteroduplex analysis to identify sequence anomalies in five individuals with Kniest dysplasia, Sequencing of the index patients' genom ic DNA identified four new dominant mutations in COL2A1 that result in Knie st dysplasia: a 21-bp deletion in exon 16, an 18-bp deletion in exon 19, an d 4-bp deletions in the splice donor sites of introns 14 and 20, A previous ly described 28-bp deletion at the COL2A1 exon 12-intron 12 junction, delet ing the splice donor site, was identified in the fifth case. The latter thr ee mutations are predicted to result in exon skipping in the mRNA encoded f rom the mutant allele, These data suggest that Kniest dysplasia results fro m shorter type II collagen monomers, and support the hypothesis that altera tion of a specific COL2A1 domain, which may span from exons 12 to 24, leads to the Kniest dysplasia phenotype, Am. J Med, Genet, 85:105-112, 1999, Pub lished 1999 Wiley-Liss, Inc.dagger