title: Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease.
abstract: 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.
authors.affiliation: Department of Medicine and Therapeutics, University of Aberdeen, UK.
authors.forename: Lynne J
authors.initials: LJ
authors.lastname: Hocking
authors.forename: Gavin J A
authors.initials: GJ
authors.lastname: Lucas
authors.forename: Anna
authors.initials: A
authors.lastname: Daroszewska
authors.forename: Jon
authors.initials: J
authors.lastname: Mangion
authors.forename: Mark
authors.initials: M
authors.lastname: Olavesen
authors.forename: Tim
authors.initials: T
authors.lastname: Cundy
authors.forename: Geoff C
authors.initials: GC
authors.lastname: Nicholson
authors.forename: Lynley
authors.initials: L
authors.lastname: Ward
authors.forename: Simon T
authors.initials: ST
authors.lastname: Bennett
authors.forename: Wim
authors.initials: W
authors.lastname: Wuyts
authors.forename: Wim
authors.initials: W
authors.lastname: Van Hul
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010001:Osteitis Deformans / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D011506:Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin; D004247:DNA