Novel EXT1 and EXT2 mutations in hereditary multiple exostoses families of Indian origin

Hereditary multiple exostosis (HME) is an autosomal dominant bone disorder, characterized by short stature and the presence of multiple benign tumors mainly at the ends of long bones. HME is genetically heterogeneous with two known genes on 8q24 (EXT1) and 11p11 (EXT2), and a third minor locus mapped to 19p (EXT3). The majority of EXT1 and EXT2 mutations result in premature protein truncation and loss of function.

We analyzed two autosomal dominant HME families of Indian origin. Linkage analysis using fluorescently labeled microsatellite markers at the candidate gene regions was performed. Mutation analysis was carried out by bidirectional sequencing of purified PCR products.

We found linkage in one family to EXT1 and in the other family to EXT2. Mutation screening in the EXT1 gene revealed a novel frameshift mutation, a single base deletion in exon 1 (c.142delC). This mutation segregated in all affected members and was absent in the unaffected family members and 60 unrelated controls. In the second family, a previously unreported stop mutation, the substitution c.817C>T, was observed in the EXT2 gene in all affected members and in none of the unaffected family members and 90 unrelated controls.

Our findings expand the mutation spectrum of EXT1 and EXT2 and highlight the genetic and phenotypic heterogeneity of HME.