Clinical and Cellular Phenotypes Associated With Sequestosome 1 (SQSTM1) Mutations

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Abstract
Familial Paget's disease of bone has been shown to be associated with mutations in the ubiquitin‐associated (UBA) domain of the sequestosome 1 (SQSTM1) gene. We have clinical findings on five families with diverse racial and ethnic backgrounds who all harbor SQSTM1 UBA domain mutations (P387L, P392L, D391fsX394, P392fsX394). Intrafamilial expressivity was highly variable. The probands in two of the families had early‐onset disease involving a large number of bones and highly elevated prediagnostic levels of serum alkaline phosphatase. Affected siblings in these same families had limited bone involvement and were only diagnosed by technetium‐99m methylene diphosphonate (MDP) bone scans. Furthermore, there was at least one subject in each family with no evidence of Paget's disease, although they carried one mutated copy of the SQSTM1 gene. A total of 18 such individuals were identified across the five kindreds. Thus, the gene seems to have highly variable expressivity, as well as incomplete penetrance, supporting the role of this gene as a predisposition gene for familial Paget's disease of the bone. Molecular studies of the SQSTM1 protein showed different cellular aggregation phenotypes depending on the nature of the mutation. In general, the point mutations formed larger cytoplasmic aggregates than the wildtype or truncation mutations. This aggregation phenotype was not altered on removal of the N‐terminal PB1 dimerization domain, implying that aggregate formation is not wholly mediated by interaction through the PB1 domain. Although there was a genotype/phenotype correlation on the cellular level, this was not apparent on the clinical level. This supports the argument that other nongenetic factors play an important role in the pathogenesis of the disease.