A novel EXT1 splice site mutation in a kindred with hereditary multiple exostosis and osteoporosis.

Journal article

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 beta-crosslaps. DNA sequence analysis of EXT1 revealed a heterozygous g-->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. 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.

Authors: Lemos, M; Kotanko, P; Christie, P; Harding, B; Javor, T

• Publication status: Published
• Journal: Journal of clinical endocrinology and metabolism
• Volume: 90
• Issue: 9
• Pages: 5386-5392
• Publication date: 2005-09-01
• DOI: 10.1210/jc.2004-2520
• EISSN: 1945-7197
• ISSN: 0021-972X
• Language: English
• Keywords: Female; Humans; Adolescent; Bone Density; Mutation; DNA, Recombinant; Introns; Reverse Transcriptase Polymerase Chain Reaction; Case-Control Studies; Heterozygote; Femur Neck; Lumbar Vertebrae; N-Acetylglucosaminyltransferases; Cytosine; Guanine; Middle Aged; Adult; Osteoporosis; Male; Pedigree; Exostoses, Multiple Hereditary