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

Hereditary multiple exostoses (EXT) is an autosomal dominant bone disease c haracterized by the formation of cartilage-capped prominences. EXT is genet ically heterogeneous with at least four chromosomal loci. Among the four lo ci, the exostosis type 1 gene (EXT1) and type 2 gene (EXT2) have been clone d. Previous studies have shown that disease-type-specific frequency of muta tions is different among various ethnic populations. To determine those fre quencies in the Japanese, we conducted a large-scale mutation screening on both genes. In 23 of 43 Japanese families examined, we found 21 different m utations, of which 18 are novel. Seventeen (40%) of the 23 families had a m utation in EXT1 and six (14%) had a mutation in EXT2, suggesting that the f ormer mutations are more frequent than the latter in Japanese EXT families. Of the 17 families T-Vith EXT1 mutations, 13 had those causing premature t ermination of the EXT1 protein and four showed missense mutations, whereas five of the six families with EXT2 mutations had those causing premature te rmination and one showed missense mutation. Interestingly, all four EXT1 mi ssense mutations occurred in an arginine residue at codon 340 (R340) that i s known as a critical site for expression of heparan sulfate glycosaminogly cans, suggesting that the region encompassing the arginine residue may play an important role in the function of the EXT1 protein. These results expan d our knowledge of the ethnic difference of EXT and the structure-function relationship of the EXT genes. (C) 2001 Wiley-Liss, Inc.