Mutation frequencies ofEXT1 andEXT2 in 43 Japanese families with hereditary multiple exostoses

Abstract

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.

Live births after simultaneous avoidance of monogenic diseases and chromosome abnormality by next-generation sequencing with linkage analyses

“…2A). Genetic diagnosis of the husband showed a frame-shift point mutation c.233delC at the exostosin glycosyltransferase 2 (EXT2) gene, already known to cause this disease (29).…”

Hereditary Multiple Exostoses: Clinical, Molecular and Radiologic Survey in 9 Families

“…All except two mutations identified in our study are novel. EXT1 mutation p.Leu490Profs*31 in proband 5 and ETX2 mutation p.Val187Profs*115 found in family 9 have been already described (Song et al, 1999;Seki et al, 2001). In our families with HME, the molecular basis of the disease was not recognized in 22% of probands.…”

The relation of Hereditery Multiple Exostoses and trace elements

“…However in Caucasian and Japanese patients, mutations were detected in EXT1 genes more than in EXT2 genes. Premature terminations of the EXT proteins were caused by most of the mutations in the two genes [12,18].…”

“…173 HME is genetically heterogeneous, and three loci have been identified so far: EXT1, on chromosome 8q23-q24; EXT2, on 11p11-p12; and EXT3, on the short arm of chromosome 19 [8,9,10,11]. Loss of heterozygosity at the EXT1, EXT2 and EXT3 loci has been observed among patients with EXT-related and unrelated chondrosarcomas, suggesting that EXT genes are tumour suppressors in chondrosarcomas [12,13,14].…”