Endocrine Abstracts (2002) 3 P124

Hereditary multiple exostosis due to an acceptor splice site mutation in the EXT1 gene

MC Lemos1,2, PT Christie1, B Harding1, P Kotanko3, T Javor3 & RV Thakker1


1Nuffield Department of Medicine, University of Oxford, Oxford, UK; 2Department of Endocrinology, University Hospital of Coimbra, Coimbra, Portugal; 3Department of Internal Medicine, Krankenhaus der Barmherzigen, Bruder, Graz, Austria.


Hereditary multiple exostosis (HME) is an autosomal dominant disorder characterised by the development of benign cartilage-capped tumours, located at the juxtaepiphyseal regions of long bones. Patients suffer from short stature and skeletal deformities and may occasionally develop chondrosarcomas or osteosarcomas.

HME is a genetically heterogeneous disorder and three loci referred to as EXT1, EXT2 and EXT3 have been mapped to chromosomes 8q24.1, 11p11-12 and 19p, respectively. The genes causing EXT1 and EXT2 have been identified and we have performed studies to identify the genetic abnormality in 27 members (14 affected and 13 unaffected ) of an Austrian kindred. An analysis of two intragenic polymorphisms of the EXT1 gene revealed cosegregation with HME. DNA sequence analysis of the EXT1 gene using 17 pairs of PCR primers to amplify the 11 exons and 20 exon-intron boundaries revealed a g to c transversion at the acceptor splice site of intron 8 (base 1723 -1). This was associated with the loss of a Pst1 restriction enzyme site, that facilitated the confirmation of the mutation and its cosegregation with HME in the kindred. In addition, analysis of 110 alleles from 55 unrelated individuals revealed an absence of this abnormality, thereby demonstrating that it was not a common polymorphism. In order to investigate the functional consequences of this acceptor splice site mutation, EBV-transformed lymphoblastoid RNA was utilised with appropriate primers in RT-PCR reactions. This revealed skipping of exon 9 with the resultant loss of 161 bp that caused a frameshift and a premature termination at codon 653. Thus, our studies which have identified a novel splice site mutation are the first to demonstrate exon skipping of the EXT1 gene, and this may help to further elucidate the role of this gene in the development of the bone tumours associated with hereditary multiple exostosis.

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