title: Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone.
abstract: Paget disease of bone (PDB) is a common disorder characterized by focal and disorganized increases of bone turnover. Genetic factors are important in the pathogenesis of PDB. We and others recently mapped the third locus associated with the disorder, PDB3, at 5q35-qter. In the present study, by use of 24 French Canadian families and 112 unrelated subjects with PDB, the PDB3 locus was confined to approximately 300 kb. Within this interval, two disease-related haplotype signatures were observed in 11 families and 18 unrelated patients. This region encoded the ubiquitin-binding protein sequestosome 1 (SQSTM1/p62), which is a candidate gene for PDB because of its association with the NF-kappaB pathway. Screening SQSTM1/p62 for mutations led to the identification of a recurrent nonconservative change (P392L) flanking the ubiquitin-associated domain (UBA) (position 394-440) of the protein that was not present in 291 control individuals. Our data demonstrate that two independent mutational events at the same position in SQSTM1/p62 caused PDB in a high proportion of French Canadian patients.
authors: Centre de Recherche en Endocrinologie Moléculaire et Oncologique, Centre de Recherche du Centre Hospitalier de l'Université Laval, 2705 Laurier Boulevard, Québec, PQ, Canada G1V 4G2.
authors: Nancy
authors: N
authors: Laurin
authors: Jacques P
authors: JP
authors: Brown
authors: Jean
authors: J
authors: Morissette
authors: Vincent
authors: V
authors: Raymond
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001483:Base Sequence; D002170:Canada; D002352:Carrier Proteins / Q000235:genetics*; D005602:France / Q000208:ethnology; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010001:Osteitis Deformans / Q000235:genetics*; D011506:Proteins; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D011506:Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein