Mutation analysis of hereditary multiple exostoses in the Chinese

Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bo ne disorder. It is genetically heterogeneous with at least three chromosoma l loci: EXT1 on 8q24.1, EXT2 on 11p11, and EXT3 on 19p. EXT1 and EXT2, the two genes responsible for EXT1 and EXT2, respectively, have been cloned. Re cently, three other members of the EXT gene family, named the EXT-like gene s (EXTL: EXTL1, EXTL2, and EXTL3), have been isolated. EXT1, EXT2, and the three EXTLs are homologous with one another. We have identified the intron- exon boundaries of EXTL;I and EXTL3 and analyzed EXT1, EXT2, EXTL1, and EXT L3, in 36 Chinese families with EXT to identify underlying disease-related mutations in the Chinese population. Of the 36 families, five and 12 family groups have mutations in EXT1 and EXT2, respectively. No disease-related m utation has been found in either EXTL1 or EXTL2, although one polymorphism has been detected in EXTL1. Of the 15 different mutations (three families s hare a common mutation in EXT2), 12 are novel. Most of the mutations are ei ther frameshift or nonsense mutations (12/15), These mutations lead directl y or indirectly to premature stop codons, and the mutations generate trunca ted proteins. This finding is consistent with the hypothesis that the devel opment of EXT is mainly attributable to loss of gene function. Missense mut ations are rare in our families, but these mutations may reflect some funct ionally crucial regions of these proteins. EXT1 is the most frequent single cause of EXT in the Caucasian population in Europe and North America. It a ccounts for about 40% of cases of EXT. Our study of 36 EXT Chinese families has found that EXT1 seems much less common in the Chinese population, alth ough the frequency of the EXT2 mutation is similar in the Caucasian and Chi nese populations. Our findings suggest a possibly different genetic spectru m of this disease in different populations.