title: Identification of SQSTM1 mutations in familial Paget's disease in Australian pedigrees.
abstract: We have conducted a genome-wide scan on a pedigree containing 372 adult members, of whom 49 have PDB. In the present study, we report linkage of a large pedigree to the PDB3 region on chromosome 5q35-qter with a peak multipoint LOD score of 6.77. Sequestosome 1 (SQSTM/p62) has been identified as the causative PDB gene in this region. Six sequestosome 1 mutations have been described to date. Four mutations have been identified in exon 8, 1210delT and 1215delC both resulting in premature stop codon at amino acid 394, 1215C to T (P392L), 1224insT (E396X), one mutation in exon 7, 1200C to T (P387L) and a G to A splice junction mutation at IVS7+1. These mutations cluster in the C terminus of the protein and are predicted to disrupt the ubiquitin binding properties of sequestosome 1. Sequence analysis of the gene encoding sequestosome 1 revealed a single base pair deletion (1215delC) segregating with the majority of affected members in the pedigree. This deletion introduces a stop codon at position 394, resulting in premature termination of the protein (L394X) and loss of the ubiquitin-associated binding domain. Screening of affected members from 10 further PDB families identified the previously reported P392L mutation in one family. No SQSTM1/p62 coding mutations were found in the remaining 9 families or in 113 age-matched controls.
authors.affiliation: Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane, Australia. d.good@qut.edu.au
authors.forename: David A
authors.initials: DA
authors.lastname: Good
authors.forename: Frances
authors.initials: F
authors.lastname: Busfield
authors.forename: Barbara H
authors.initials: BH
authors.lastname: Fletcher
authors.forename: Paul K
authors.initials: PK
authors.lastname: Lovelock
authors.forename: David L
authors.initials: DL
authors.lastname: Duffy
authors.forename: Janine B
authors.initials: JB
authors.lastname: Kesting
authors.forename: John
authors.initials: J
authors.lastname: Andersen
authors.forename: Joanne T E
authors.initials: JT
authors.lastname: Shaw
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D001315:Australia; D002895:Chromosomes, Human, Pair 5; D005091:Exons; D006801:Humans; D008126:Lod Score; D008969:Molecular Sequence Data; D009154:Mutation; D010001:Osteitis Deformans / Q000235:genetics*; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D011506:Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein