Human Molecular Genetics, 2002, Vol. 11, No. 22 2735-2739
© 2002 Oxford University Press
Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease
1Department of Medicine and Therapeutics, University of Aberdeen, UK, 2Oxagen Ltd, Abingdon, UK, 3Department of Medicine, University of Auckland, New Zealand, 4Department of Clinical and Biomedical Sciences, Barwon Health, Geelong Hospital, University of Melbourne, Australia, 5Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Western Australia and 6Department of Medical Genetics, University of Antwerp, Belgium
Received June 12, 2002; Accepted August 8, 2002
Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of increased and disorganized bone turnover. Genetic factors are important in the pathogenesis of PDB, and in previous studies, we and others identified a locus for familial PDB by genome-wide search on 5q35-qter (PDB3). The gene encoding sequestosome 1 (SQSTM1/p62) maps to within the PDB3 critical region, and recent studies have identified a proline–leucine amino acid change at codon 392 of SQSTM1 (P392L) in French-Canadian patients with PDB. We conducted mutation screening of positional candidate genes in the PDB3 locus in patients with PDB, and also identified mutations in the gene encoding SQSTM1 as a common cause of familial and sporadic PDB. Three different mutations were found, all affecting the highly conserved ubiquitin-binding domain. The most common mutation was the P392L change in exon 8, which was found in 13 of 68 families (19.1%). Another mutation—a T insertion that introduces a stop codon at position 396 in exon 8—was found in four (5.8%) families. A third mutation affecting the splice donor site in intron 7 was found in one (1.5%) family. The P392L mutation was also found in 15 of 168 (8.9%) of patients with sporadic PDB and 0 of 160 of age- and sex-matched controls (P<0.0001). These studies confirm that mutations affecting the ubiquitin-binding domain of SQSTM1 are a common cause of familial and sporadic Paget's disease of bone.
* To whom correspondence should be addressed at: Department of Medicine and Therapeutics, University of Aberdeen Medical School, Foresterhill, Aberdeen AB25 2ZD, UK. Tel: +44 1224553025; Fax: +44 1224554761; Email: s.ralston{at}abdn.ac.uk
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