Sequestosome 1 (SQSTM1) mutations in Paget's disease of bone from the United States.

Paget's disease of bone (PDB) is a localized bone disease characterized by excessive bone resorption due to overactive osteoclasts. Seven genetic loci (PDB1-PDB7) have been reported for late-onset PDB. PDB3 is the only locus where a gene, sequestosome 1 (SQSTM1), has been identified.

Clinical and cellular phenotypes associated with sequestosome 1 (SQSTM1) mutations.

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.

Three novel mutations in SQSTM1 identified in familial Paget's disease of bone.

Unlabelled: Mutations in Sequestosome 1 (SQSTM1) have been shown to segregate with familial Paget's disease of bone (PDB). We examined the coding sequence of SQSTM1 in five PDB pedigrees and found three novel mutations clustered around the C-terminal ubiquitin associated domain. Disruptions of the C-terminal domain of SQSTM1 seem to be a leading cause of familial PDB.