TY - JOUR
T1 - Sequestosome 1 (SQSTM1) mutations in Paget's disease of bone from the United States
AU - Rhodes, Emily C.
AU - Johnson-Pais, Teresa L.
AU - Singer, Frederick R.
AU - Ankerst, Donna P.
AU - Bruder, Jan M.
AU - Wisdom, Julie
AU - Hoon, Dave S.B.
AU - Lin, Emerald
AU - Bone, Henry G.
AU - Simcic, Kenneth J.
AU - Leach, Robin J.
N1 - Funding Information:
This work was supported by NIDCR, grant DE14318 for the CO STAR Program, NIAMS grant RO1 AR44919-01, and funding from the Eli and Edythe L. Broad Foundation and Lois Rosen. We thank Yasmin Ench and Sharon Huang for technical assistance. We also thank all of the patients who participated in this study.
PY - 2008/4
Y1 - 2008/4
N2 - 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. Mutations in SQSTM1 have been associated with both sporadic and hereditary PDB in different populations. However, the SQSTM1 mutation frequency in PDB patients from a more heterogeneous population has never been reported. To investigate this, we determined the frequency of mutations in patients from the United States. Blood was collected from sporadic and hereditary PDB patients in the United States. DNA was isolated from whole blood or from serum. The SQSTM1 sequence was determined for exons and intron/exon junctions from whole blood and serum. A total of 112 (39 hereditary, 73 sporadic) samples were collected. Eight mutations were found in hereditary PDB patients, for a mutation frequency of 20.5% (95% confidence interval [CI] 10.8-35.5%) and did not differ significantly from mutation rates observed in studies in Canada, Great Britain, and The Netherlands. No mutations were found in sporadic patients, for a frequency of 0% (95% CI 0.0-5.0%), which was statistically significantly lower than the mutation rates previously observed in populations from Australia (P = 0.009), Canada (P = 0.008), Great Britain (P = 0.02), and France (P = 0.04) but not compared to rates from Belgium, The Netherlands, and Italy. Four out of five families with the P392L mutation carried it on the H2 haplotype. Mutations in SQSTM1 seem to contribute to the pathogenesis of PDB in hereditary, but not sporadic, patients in the United States.
AB - 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. Mutations in SQSTM1 have been associated with both sporadic and hereditary PDB in different populations. However, the SQSTM1 mutation frequency in PDB patients from a more heterogeneous population has never been reported. To investigate this, we determined the frequency of mutations in patients from the United States. Blood was collected from sporadic and hereditary PDB patients in the United States. DNA was isolated from whole blood or from serum. The SQSTM1 sequence was determined for exons and intron/exon junctions from whole blood and serum. A total of 112 (39 hereditary, 73 sporadic) samples were collected. Eight mutations were found in hereditary PDB patients, for a mutation frequency of 20.5% (95% confidence interval [CI] 10.8-35.5%) and did not differ significantly from mutation rates observed in studies in Canada, Great Britain, and The Netherlands. No mutations were found in sporadic patients, for a frequency of 0% (95% CI 0.0-5.0%), which was statistically significantly lower than the mutation rates previously observed in populations from Australia (P = 0.009), Canada (P = 0.008), Great Britain (P = 0.02), and France (P = 0.04) but not compared to rates from Belgium, The Netherlands, and Italy. Four out of five families with the P392L mutation carried it on the H2 haplotype. Mutations in SQSTM1 seem to contribute to the pathogenesis of PDB in hereditary, but not sporadic, patients in the United States.
KW - Bone
KW - Genetic
KW - Osteoclast
KW - Paget's disease
KW - Sequestosome 1
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U2 - 10.1007/s00223-008-9114-9
DO - 10.1007/s00223-008-9114-9
M3 - Article
C2 - 18379713
AN - SCOPUS:43049108052
SN - 0171-967X
VL - 82
SP - 271
EP - 277
JO - Calcified tissue international
JF - Calcified tissue international
IS - 4
ER -