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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-2520 Copyright © 2005 by The Endocrine Society A Novel EXT1 Splice Site Mutation in a Kindred with Hereditary Multiple Exostosis and OsteoporosisManuel C. Lemos, Peter Kotanko, Paul T. Christie, Brian Harding, Theodora Javor, Christine Smith, Richard Eastell and Rajesh V. ThakkerAcademic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford Center for Diabetes, Endocrinology, and Metabolism, Churchill Hospital (M.C.L., P.T.C., B.H., R.V.T.), Headington, Oxford OX3 7LJ, United Kingdom; Krankenhaus der Barmherzigen Brüder, Department of Internal Medicine, Teaching Hospital Medical University Graz (P.K., T.J.), A-8020 Graz, Austria; and Bone Metabolism Group, Division of Clinical Sciences, University of Sheffield, Northern General Hospital (C.S., R.E.), Sheffield S5 7AU, United Kingdom Address all correspondence and requests for reprints to: Dr. Rajesh V. Thakker, Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford Center for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom. E-mail: rajesh.thakker{at}ndm.ox.ac.uk. Context: Hereditary multiple exostosis (HME) is an autosomal dominant disorder characterized by the development of benign cartilage-capped tumors at the juxta-epiphyseal regions of long bones. HME is usually caused by mutations of EXT1 or EXT2. Objective: The objective of this study was to investigate a three-generation Austrian kindred with HME for EXT1 and EXT2 mutations and for abnormalities of bone mineral density (BMD). Methods: DNA sequence and mRNA analyses were used to identify the mutation and its associated consequences. Serum biochemical and radiological investigations assessed bone metabolism and BMD.
Results: HME-affected members had a lower femoral neck BMD compared with nonaffected members (z-scores, –2.98 vs. –1.30; P = 0.011), and in those less than 30 yr of age, the lumbar spine BMD was also low (z-scores, –2.68 vs. –1.42; P = 0.005). However, they had normal mobility and normal serum concentrations of calcium, phosphate, alkaline phosphatase activity, creatinine, PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, osteocalcin, and ß-crosslaps. DNA sequence analysis of EXT1 revealed a heterozygous g Conclusions: A novel heterozygous acceptor splice site mutation of EXT1 results in HME that is associated with a low peak bone mass, indicating a possible additional role for EXT1 in bone biology and in regulating BMD. This article has been cited by other articles:
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c transversion that altered the invariant ag dinucleotide of the intron 8 acceptor splice site. RT-PCR analysis using lymphoblastoid RNA showed that the mutation resulted in skipping of exon 9 with a premature termination at codon 599. DNA sequence abnormalities of the osteoprotegerin gene, which is in close proximity to the EXT1 gene, were not detected. 
