title: Novel mutations in the EXT1 gene in two consanguineous families affected with multiple hereditary exostoses (familial osteochondromatosis).
abstract: Multiple hereditary exostoses (HME) is an autosomal dominant developmental disorder exhibiting multiple osteocartilaginous bone tumors that generally arise near the ends of growing long bones. Here, we report two large consanguineous families from Pakistan, who display the typical features of HME. Affected individuals also show a previously unreported feature--bilateral overriding of single toes. Analysis using microsatellite markers for each of the known EXT loci, EXT1, EXT2, and EXT3 showed linkage to EXT1. In the first family, mutation analysis of the EXT1 gene revealed that affected individuals were heterozygous for an in-frame G-to-C transversion at the conserved splice donor site in intron 1. This mutation is predicted to disrupt splicing of the first intron and produce a frameshift that leads to a premature termination codon. In the second family, an insertion of an A in exon 8 is predicted to produce a frameshift at codon 555 followed by a premature termination, a further 10 codons downstream. In both families, an increased number of affected male subjects were observed. In affected females in family 2, phenotypic variability and incomplete penetrance were noted.
authors.affiliation: Program in Genetics & Genomic Biology, Department of Genetics, Hospital for Sick Children, Toronto, Canada. muhammad@genet.sickkids.on.ca
authors.forename: M
authors.initials: M
authors.lastname: Faiyaz-Ul-Haque
authors.forename: W
authors.initials: W
authors.lastname: Ahmad
authors.forename: S H E
authors.initials: SH
authors.lastname: Zaidi
authors.forename: S
authors.initials: S
authors.lastname: Hussain
authors.forename: S
authors.initials: S
authors.lastname: Haque
authors.forename: M
authors.initials: M
authors.lastname: Ahmad
authors.forename: D H
authors.initials: DH
authors.lastname: Cohn
authors.forename: L-C
authors.initials: LC
authors.lastname: Tsui
mesh_terms: D001483:Base Sequence; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005097:Exostoses, Multiple Hereditary / Q000235:genetics* / Q000473:pathology; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D010154:Pakistan; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D000099058:Exostosin 1
chemical_list: D017351:N-Acetylglucosaminyltransferases; D000099058:Exostosin 1