Novel SQSTM1 mutations in patients with Paget's disease of bone in an unrelated multiethnic American population

More than 20 mutations of the Sequestosome 1 (SQSTM1) gene have been reported in patients of European descent affected by Paget's disease of bone (PDB). In this investigation, a systematic screening for SQSTM1 mutations was conducted in consecutively evaluated unrelated patients with phenotypical PDB living in the New York City area (NY, United States). Seventy unrelated PDB patients with a multiethnic background, mostly of Jewish, Italian American, and Western European ancestries, were recruited. Sequencing of exons 7 and 8 was performed on DNA samples isolated from peripheral blood. Seven patients (10%) had SQSTM1 mutations, of which three had a family history of PDB. Four patients carried the C1215T (P392L) mutation, and three patients carried novel SQSTM1 missense mutations: T1085A (S349T), C1209T (A390V), and T1290A (L417Q) mutations. All PDB patients with SQSTM1 mutations had polyostotic involvement, and the mean number of affected bones was significantly higher in pagetic patient carriers of a SQSTM1 mutation when compared to non-mutated PDB patients (4.0 vs. 2.0, respectively; P = 0.003). Haplotype analysis in patient carriers of the P392L mutation revealed that all P392L mutations were carried by haplotype 2. The SQSTM1 mutation rate in unrelated American patients described in the present study was similar to that reported in European populations.

Research Highlights
► Ten percent of American unrelated pagetic patients have SQSTM1 mutation.
► The P392L mutation is still the most frequent SQSTM1 mutation.
► Three novel SQSTM1 mutations were identified: S349T, A390V, L417Q.
► Pagetic patients carrier of SQSTM1 mutation have a higher number of affected bones.