Genetics of Paget's disease of bone
Chapter 3 describes the results of mutation screening of a candidate gene, SQSTM1, from one of the linkage regions implicated in the pathogenesis of PDB in families of mainly British descent. Seven mutations that segregated with the disease were identified and all clustered in the ubiquitin-associated (UBA) domain of the protein. In Chapter 4, an association study and haplotype analysis was conducted in PDB families using SNPs in SQSTM1. This revealed that the most common SQSTM1 mutation was predominantly carried on one of two common haplotype backgrounds, suggesting that a strong founder effect exists in this population. The P392L mutations occurred on the same haplotype background in sporadic cases as in the PDB families, indicating that many ‘sporadic’ PDB cases may have occult familial PDB. A syndrome of PDB associated with inclusion body myopathy and dementia has recently been shown to be caused by mutations that cluster in the CDC48 domain of the VCP gene. In Chapter 5, the VCP gene was screened for mutations in familial PDB and an association study was conducted in patients with sporadic PDB. No mutations in this gene were found in the PDB families. Haplotype analysis of a region spanning this gene also failed to support the involvement of polymorphisms in this gene in determining risk of sporadic PDB. In Chapter 6, genome-wide linkage analysis was conducted in PDB families without SQSTM1 mutations. This revealed significant evidence of linkage at a locus on chromosome 10p13 (PDB6). All families involved in this analysis were found to have a high likelihood of linkage at this locus.