Identification of SQSTM1 mutations in familial Paget's disease in Australian pedigrees

• Published in: Bone (New York, N.Y.) N.Y.), 2004-07, Vol.35 (1), p.277-282
• Main Authors: Good, David A, Busfield, Frances, Fletcher, Barbara H, Lovelock, Paul K, Duffy, David L, Kesting, Janine B, Andersen, John, Shaw, Joanne T.E
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Australia; Biological and medical sciences; Chromosomes, Human, Pair 5; Diseases of the osteoarticular system; Exons; Fundamental and applied biological sciences. Psychology; Genetics; Humans; Linkage analysis; Lod Score; Medical sciences; Molecular Sequence Data; Mutation; Osteitis Deformans - genetics; Paget's disease of bone; Pedigree; Proteins - genetics; Sequestosome 1; Sequestosome-1 Protein; Traumas. Diseases due to physical agents; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2004.01.010

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.