Mutation frequencies of EXT1 and EXT2 in 43 Japanese families with hereditary multiple exostoses

Hereditary multiple exostoses (EXT) is an autosomal dominant bone disease characterized by the formation of cartilage-capped prominences. EXT is genetically heterogeneous with at least four chromosomal loci. Among the four loci, the exostosis type 1 gene (EXT1) and type 2 gene (EXT2) have been cloned. Previous studies have shown that disease-type-specific frequency of mutations is different among various ethnic populations. To determine those frequencies in the Japanese, we conducted a large-scale mutation screening on both genes. In 23 of 43 Japanese families examined, we found 21 different mutations, of which 18 are novel. Seventeen (40%) of the 23 families had a mutation in EXT1 and six (14%) had a mutation in EXT2, suggesting that the former mutations are more frequent than the latter in Japanese EXT families. Of the 17 families with EXT1 mutations, 13 had those causing premature termination of the EXT1 protein and four showed missense mutations, whereas five of the six families with EXT2 mutations had those causing premature termination and one showed missense mutation. Interestingly, all four EXT1 missense mutations occurred in an arginine residue at codon 340 (R340) that is known as a critical site for expression of heparan sulfate glycosaminoglycans, suggesting that the region encompassing the arginine residue may play an important role in the function of the EXT1 protein. These results expand our knowledge of the ethnic difference of EXT and the structure-function relationship of the EXT genes.