Abstract
Aim:
A previous study showed that individuals of Japanese descent affected by early onset familial Paget's disease of bone (PDB) carried a 27-bp duplication at position 75 (75dup27) in the TNFRSF11A gene encoding RANK. Here we report the identification of a novel mutation (78dup27) in exon 1 of TNFRSF11A in a Chinese family with early onset PDB.
Methods:
We conducted clinical and genetic studies in a non-consanguineous Chinese family with early onset PDB. The entire coding region of TNFRSF11A was amplified and directly sequenced directly.
Results:
A novel 27-bp duplication in exon 1 (78dup27) in TNFRSF11A was found in four affected individuals and one asymptomatic individual. Although this duplication was the same length as the previously identified mutation (27 bp, from bases 78 to 104), in our patients the nine duplicated amino acids in the RANK signal peptide were LLLLCALLA. The phenotypes of affected individuals in this family overlapped with both early onset PDB and classic PDB, but several distinguishing features were found in our patients. The key difference between our familial PDB and the Japanese early onset PDB was the age of onset, which in most of our patients was during their late 20s (except for the propositus' niece). Another notable difference was that the propositus' son (24 years old), who carried the 78dup27 mutation, had no clinical symptoms or bone abnormalities, except for increased serum ALP, OC and CTX.
Conclusion:
Our findings may provide a better understanding of the clinical features of early onset PDB and support the notion of a hot spot for mutations in exon 1 of the TNFRSF11A gene.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Ralston SH, Langston AL, Reid IR . Pathogenesis and management of Paget's disease of bone. Lancet 2008; 372: 155–63.
Zhang ZL, Meng XW, Xing XP, Wang O, Xia WB, Li M, et al. Prospective study of pamidronate disodium in treatment of Paget's disease of bone. Zhonghua Yi Xue Za Zhi 2003; 83: 1653–6.
Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H, Wallace RG, et al. Mutations in TNFRSF11A, affecting the signal peptide RANK, cause familial expansile osteolysis. Nat Genet 2000; 24: 45–8.
Nakatsuka K, Nishizawa Y, Ralston SH . Phenotypic characterization of early onset Paget's disease of bone caused by a 27-bp duplication in the TNFRSF11A gene. J Bone Miner Res 2003; 18: 1381–5.
Good DA, Busfield F, Fletcher BH, Lovelock PK, Duffy DL, Kesting JB, et al. Identification of SQSTM1 mutations in familial Paget's disease in Australian pedigrees. Bone 2004; 35: 277–8.
Leach RJ, Singer FR, Ench Y, Wisdom JH, Pina DS, Johnson-Pais TL . Clinical and cellular phenotypes associated with sequestosome 1 (SQSTM1) mutations. J Bone Miner Res 2006; 21 (Suppl2): P45–50.
Laurin N, Brown JP, Morissette J, Raymond V . Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet 2002; 70: 1582–8.
Palenzuela L, Vives-Bauza C, Fernández-Cadenas I, Meseguer A, Sarret E, Schwartz S, et al. Familial expansile osteolysis in a large Spanish kindred resulting from an insertion mutation in the TNFRSF11A gene. J Med Genet 2002; 39: E67.
Johnson-Pais TL, Singer FR, Bone HG, McMurray CT, Hansen MF, Leach RJ . Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis. J Bone Miner Res 2003; 18: 376–80.
Whyte MP, Hughes AE . Expansile skeletal hyperphosphatasia is caused by a 15-base pair tandem duplication in TNFRSF11A encoding RNA and is allelic to familial expansile osteolysis. J Bone Miner Res 2002; 17: 26–9.
Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL, et al. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci U S A 2000; 97: 1566–71.
Morissette J, Laurin N, Brown JP . Sequestosome 1: mutation frequencies, haplotypes, and phenotypes in familial Paget's disease of bone. J Bone Miner Res 2006; 21(Suppl2):P38–44.
Martini G, Gennari L, Merlotti D, Salvadori S, Franci MB, Campagna S, et al. Serum OPG and RANKL levels before and after intravenous bisphosphonate treatment in Paget's disease of bone. Bone 2007; 40: 457–63.
Alvarez L, Peris P, Guañabens N, Vidal S, Ros I, Pons F, et al. Serum osteoprotegerin and its ligand in Paget's disease of bone: relationship to disease activity and effect of treatment with bisphosphonates. Arthrit Rheumatism 2003; 48: 824–8.
Ralston SH . Pathogenesis of Paget's disease of bone. Bone 2008; 43: 819–25.
Sparks AB, Peterson SN, Bell C, Loftus BJ, Hocking L, Cahill DP, et al. Mutation screening of the TNFRSF11A gene encoding receptor activator of NF kappa B (RANK) in familial and sporadic Paget's disease of bone and osteosarcoma. Calcif Tissue Int 2001; 68: 151–5.
Riches PL, Imanishi Y, Nakatsuka K, Ralston SH . Clinical and biochemical response of TNFRSF11A-mediated early-onset familial Paget disease to bisphosphonate therapy. Calcif Tissue Int 2008; 83: 272–5.
Acknowledgements
This project was supported by the National Natural Science Foundation of China (No 30570891, 30771019, and 30800387) and the Program of Shanghai Subject Chief Scientist (No 08XD1403000).
We thank the patients for their participation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ke, Yh., Yue, H., He, Jw. et al. Early onset Paget's disease of bone caused by a novel mutation (78dup27) of the TNFRSF11A gene in a Chinese family. Acta Pharmacol Sin 30, 1204–1210 (2009). https://doi.org/10.1038/aps.2009.90
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2009.90
Keywords
This article is cited by
-
Familial Paget’s disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27)
Journal of Bone and Mineral Metabolism (2023)
-
Genetic disorders associated with the RANKL/OPG/RANK pathway
Journal of Bone and Mineral Metabolism (2021)
-
Rare Inherited forms of Paget’s Disease and Related Syndromes
Calcified Tissue International (2019)
-
Paget's disease of bone—genetic and environmental factors
Nature Reviews Endocrinology (2015)
-
Exclusion of TNFRSF11B as Candidate Gene for Otosclerosis in Campania Population
Indian Journal of Otolaryngology and Head & Neck Surgery (2014)
