Abstract for presentation at 11th International Congress of Human Genetics

Frequency of Sequestosome 1 (SQSTM1) Mutations in Hereditary and Sporadic Paget’s Disease of Bone in the United States

  • Emily Rhodes, Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, United States
  • Dr Teresa Johnson-Pais, Department of Pediatrics, University of Texas Health Science Center, San Antonio, TX, United States
  • Dr Fred Singer, John Wayne Cancer Institute, St. John’s Health Center, Santa Monica, California, United States
  • Julie Wisdom, Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, United States
  • Dr Henry Bone, Michigan Bone and Mineral Clinic, Detroit, MI, United States
  • Dr Jan Bruder, Department of Medicine -Endocrinology, University of Texas Health Science Center, San Antonio, TX, United States
  • Dr Kenneth Simcic, Department of Medicine -Endocrinology, University of Texas Health Science Center, San Antonio, TX, United States
  • Dr Robin Leach, Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, United States

    • Paget’s disease of bone (PDB) is a metabolic bone disease characterized by excessive bone resorption and formation due to overactive osteoclasts. This disease is distinguished by focal areas of increased and disorganized bone turnover, resulting in bone pain and fractures. One to 3 million Americans have PDB, making it the second most common metabolic bone disease. Classic familial PDB is characterized by late onset, autosomal dominant segregation, genetic heterogeneity and incomplete penetrance. Seven genetic loci (PDB1-PDB7) have been reported for late onset PDB. However, PDB3 is the only locus where a gene, SQSTM1, has been identified. Sequestosome 1 (SQSTM1/p62) plays a role in osteoclast differentiation through its involvement in the RANK signal transduction pathway and has been implicated in both sporadic and hereditary PDB. A total of 13 mutations have been reported in SQSTM1 and all are in or near the ubiquitin binding domain. Studies suggest that the SQSTM1 mutation, P392L, is responsible for 46% of familial and 16% sporadic PDB in French-Canadians and 19% of familial and 9% of sporadic PDB in patients of British origin.
    The purpose of this study was to determine the mutation frequency of SQSTM1 amongst PDB patients in the United States. Blood samples were obtained from a total of 100 PDB patients (64 sporadic and 36 hereditary). DNA was extracted from samples and PCR and sequencing was performed on all 8 exons. Mutations were found in 8/36 (22.2%) of hereditary patients and 0/64 (0%) of sporadic patients. P392L mutations were found in four hereditary PDB patients, representing both Caucasians and African Americans.
    These findings suggest a role of SQSTM1 in hereditary PDB. Interestingly, our study finds no evidence that SQSTM1 is implicated in sporadic PDB in the United States. We are in the process of analyzing more blood US samples. The information we obtain will help determine the role of SQSTM1 in PDB in the United States population.

    Conference Organiser - ICMS Pty Ltd