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Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL


Autosomal recessive osteopetrosis is usually associated with normal or elevated numbers of nonfunctional osteoclasts. Here we report mutations in the gene encoding RANKL (receptor activator of nuclear factor–KB ligand) in six individuals with autosomal recessive osteopetrosis whose bone biopsy specimens lacked osteoclasts. These individuals did not show any obvious defects in immunological parameters and could not be cured by hematopoietic stem cell transplantation; however, exogenous RANKL induced formation of functional osteoclasts from their monocytes, suggesting that they could, theoretically, benefit from exogenous RANKL administration.

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Figure 1: Family pedigrees of the individuals with ARO examined in this study.
Figure 2: Osteoclast generation and bone resorption in vitro from an individual with osteoclast-poor ARO.


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We are grateful to the affected individuals and their families for their cooperation. We thank R. Dulbecco for encouragement. The work reported in this paper has also been funded by the NOBEL (Network Operativo per la Biomedicina di Eccellenza in Lombardia) Program from Fondazione Cariplo (to P.V. and A.V.) and from a career establishment award of the European Calcified Tissue Society to M.H. and from Telethon grants #GGP06119 to A.T. and #GGP07059 to C.S. This work was supported by grants from Eurostells (STELLAR) and FIRB/MIUR (Fondo per Investimenti Ricerca di Base/Ministero dell'Università e della Ricerca) to P.V. (RBIN04CHXT), grants from Progetto Italia-USA “Malattie Rare” Convenzione n. 526D/61 to P.V. and A.T. and grants from Fondazione Cariplo to A.F. We acknowledge the technical assistance of M.E. Caldana (Segrate), J. Greenhorn and K. Mackenzie (Aberdeen).

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C.S., A.F., L.S. and A.P. performed molecular analysis; M.M.G. and A.V. studied the immunological phenotype; M.A., A.C., R.B., A.T., A.d.F., G.M., N.B., P.G., C.M. and G.E. provided clinical data and bone biopsies; F.P.C. and D.I.S. performed osteoclast studies and immunocytochemical analysis; M.J.R. performed the protein structure-function analysis and P.V., A.V., A.F., M.J.R. and M.H.H. designed the experiments and wrote the manuscript.

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Correspondence to Annalisa Frattini.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Tables 1–3 and Supplementary Figures 1–4 (PDF 2234 kb)

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Sobacchi, C., Frattini, A., Guerrini, M. et al. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet 39, 960–962 (2007).

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