Absence of Somatic SQSTM1 Mutations in Paget's Disease of Bone

Background: Paget's disease is a common focal bone disorder that appears to be caused by a combination of genetic and environmental factors. Mutations in the SQSTM1 gene are found in about one third of families with Paget's disease and 8% of sporadic cases. Other potential loci linked to the disease have also been identified, and a number of environmental factors have been suggested to be involved in the disease. However, the focal nature of Paget's is still unexplained. Therefore, we examined the possibility that somatic mutations in the SQSTM1 gene are present in the local lesions, using RNA collected from primary osteoblast and bone marrow cell cultures of patients with this condition. Methods: SQSTM1 was sequenced, and allelic discrimination for the common P392L mutation was performed in cDNA samples from 14 osteoblast cultures and from 14 cultures of bone marrow cells. Results: In these 28 samples drawn from 23 patients, the wild-type sequence of SQSTM1 was found in all but one marrow sample, which was heterozygous for the P392L mutation. DNA from peripheral blood in this subject had an identical sequence of SQSTM1, indicating that this was a germline mutation. Conclusion: We conclude that somatic mutations for SQSTM1 are not commonly present in Paget's disease. (J Clin Endocrinol Metab 94: 691-694, 2009)