Positional cloning of a gene involved in hereditary multiple exostoses

Abstract

Hereditary multiple exostosis (EXT) is an autosomal dominant condition mainly characterized by the presence of multiple exostoses on the long bones. These exostoses are benign cartilaginous tumors (enchondromata). Three different EXT loci on chromosomes 8q (EXT1), 11p (EXT2) and 19p (EXT3) have been reported, and recently the EXT1 gene was identified by positional cloning. To isolate the EXT2 gene, we constructed a contig of yeast artificial chromosomes (YAC) and P1 clones covering the complete EXT2 candidate region on chromosome 11p11-p12. One of the transcribed sequences isolated from this region corresponds to a novel gene with homology to the EXT1 gene, and harbours inactivating mutations in different patients with hereditary multiple exostoses. This indicates that this gene is the EXT2 gene. EXT2 has an open reading frame encoding 718 amino acids with an overall homology of 30.9% with EXT1, suggesting that a family of related genes might be responsible for the development of EXT.

Molecular and clinical examination of an Italian DEFECT 11 family

“…The position of these markers was obtained from the Généthon linkage map 24 and a detailed map of the EXT2 region published by Wuyts et al 14 …”

“…8 In addition to the DEFECT 11 syndrome, these benign bone tumours can also be found in another contiguous gene syndrome, the Langer-Giedion syndrome (LGS) 9 or they can be present as an isolated autosomal dominant condition. In approximately 2-5% of the patients, malignant transformation of an exostosis occurs, resulting in the development of a chondrosarcoma 10,11 So far two EXT genes have already been identified, EXT1 on chromosome 8q24 12 and EXT2 on chromosome 11p11-p12, 13,14 while a third locus, EXT3, has been mapped on chromosome 19p. 15 The EXT genes are members of a larger family of homologous genes which also currently includes three EXT-like genes -EXTL1, 16 EXTL2 17 and EXTL3.…”

Multiple Osteochondromas

“…Both EXT1 and EXT2 mRNA is ubiquitously expressed [17][18][19]. A high level of expression of Ext1 and Ext2 mRNA has been found in developing limb buds of mouse embryos [44,45] and expression was demonstrated to be confined to the proliferating and prehypertrophic chondrocytes of the growth plate [46].…”

“…Two genes, EXT1 and EXT2 located respectively at 8q24 and 11p11-p12, have been isolated to cause MO [16][17][18][19]. Additional linkage to chromosome 19p has been found, suggesting the existence of an EXT3-gene [20].…”

“…The EXT1 gene is composed of 11 exons and has a coding region of 2238 bp [17][18][19][20][21][22][23][24]. The EXT2-gene contains 16 exons [18,19] and its cDNA defines a single open reading frame of 2154 bp.…”