👤 George A Wells

Hereditary predisposition to multiple exostoses is a genetically heterogeneous disease. Recently, we have reported the identification of the EXT1 gene on human chromosome 8. We have now isolated a cDNA clone from a human adult lung cDNA library and have determined the genomic organization and promoter structure of the EXT1 gene. The gene is composed of 11 exons, ranging from 90 to 1735 bp, and spans approximately 350 kb of genomic DNA. Sequence analysis of the promoter region revealed the presence of a CpG island containing GC and CAAT boxes, but no TATA box. Such a promoter is characteristic for housekeeping genes. This finding is in good agreement with the ubiquitous expression of the EXT1 gene. Show less

We have cloned and sequenced the mouse cDNA homologous to the human Hereditary Multiple Exostoses (EXT1) gene. The mouse homolog shows 94% similarity at the nucleotide level and 99% similarity at the protein level compared to the human gene. The 5' UTRs are unusually conserved for non-coding sequences showing 94% similarity compared to 80% for the 3' UTRs. The high level of evolutionary conservation between the EXT1 proteins as well as the 5' UTR suggests that each plays an important and related role in both species. Show less

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the formation of cartilage-capped prominences that develop from the growth centers of the long bones. EXT is genetically heterogeneous, with three loci, currently identified on chromosomes 8q24.1, 11p13, and 19q. The EXT1 gene, located on chromosome 8q24.1, has been cloned and is encoded by a 3.4-kb cDNA. Five mutations in the EXT1 gene have been identified--four germ-line mutations, including two unrelated families with the same mutation, and one somatic mutation in a patient with chondrosarcoma. Four of the mutations identified resulted in frameshifts and premature termination codons, while the fifth mutation resulted in a substitution of leucine for arginine. Loss of heterozygosity (LOH) analysis of chondrosarcomas and chondroblastomas revealed multiple LOH events at loci on chromosomes 3q, 8q, 10q, and 19q. One sporadic chondrosarcoma demonstrated LOH for EXT1 and EXT3, while a second underwent LOH for EXT2 and chromosome 10. A third chondrosarcoma underwent LOH for EXT1 and chromosome 3q. These results agree with previous findings that mutations at EXT1 and multiple genetic events that include LOH at other loci may be required for the development of chondrosarcoma. Show less

Hereditary multiple exostoses is an autosomal dominant disorder that is characterized by short stature and multiple, benign bone tumours. In a majority of families, the genetic defect (EXT1) is linked to the Langer-Giedion syndrome chromosomal region in 8q24.1. From this region we have cloned and characterized a cDNA which spans chromosomal breakpoints previously identified in two multiple exostoses patients. Furthermore, the gene harbours frameshift mutations in affected members of two EXT1 families. The cDNA has a coding region of 2,238 bp with no apparent homology to other known gene sequences and thus its function remains elusive. However, recent studies in sporadic and exostosis-derived chondrosarcomas suggest that the 8q24.1-encoded EXT1 gene may have tumour suppressor function. Show less

Hereditary multiple exostoses (EXT) is an autosomal dominant skeletal disorder characterized by the formation of multiple exostoses on the long bones. EXT is genetically heterogeneous, with at least three loci involved: one (EXT1) in the Langer-Giedion region on 8q23-q24, a second (EXT2) in the pericentromeric region of chromosome 11, and a third (EXT3) on chromosome 19p. In this study, linkage analysis in seven extended EXT families, all linked to the EXT2 locus, refined the localization of the EXT2 gene to a 3-cM region flanked by D11S1355 and D11S1361/D11S554. This implies that the EXT2 gene is located at the short arm of chromosome 11, in band 11p11-p12. The refined localization of EXT2 excludes a number of putative candidate genes located in the pericentromeric region of chromosome 11 and facilitates the process of isolating the EXT2 gene. Show less

The Langer-Giedion syndrome (tricho-rhino-phalangeal syndrome type II, TRPS II) is characterized by craniofacial dysmorphism and skeletal abnormalities. It combines the clinical features of TRPS I and multiple cartilaginous exostoses (EXT). We have used YAC cloning, Southern blotting, PCR analysis, and fluorescence in situ hybridization to study chromosome 8 deletions, translocations, an inversion, and an insertion in patients with TRPS I, TRPS II or EXT. Our results indicate that the TRPS gene maps more than 1,000 kb proximal to the EXT1 gene and that both genes are affected in TRPS II. We conclude that TRPS II is not due to pleiotropic effects of mutations in a single gene, but that it is a true contiguous gene syndrome. Show less