Human Osteoclast-Poor Osteopetrosis with Hypogammaglobulinemia due to TNFRSF11A (RANK) Mutations

Matteo M. Guerrini, Cristina Sobacchi, Barbara Cassani, Mario Abinun, Sara S. Kilic, Alessandra Pangrazio, Daniele Moratto, Evelina Mazzolari, Jill Clayton-Smith, Paul Orchard, Fraser P. Coxon, Miep H. Helfrich, Julie C. Crockett, David Mellis, Ashok Vellodi, Ilhan Tezcan, Luigi D. Notarangelo, Michael J. Rogers, Paolo Vezzoni, Anna VillaAnnalisa Frattini

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248 Scopus citations


Autosomal-Recessive Osteopetrosis (ARO) comprises a heterogeneous group of bone diseases for which mutations in five genes are known as causative. Most ARO are classified as osteoclast-rich, but recently a subset of osteoclast-poor ARO has been recognized as due to a defect in TNFSF11 (also called RANKL or TRANCE, coding for the RANKL protein), a master gene driving osteoclast differentiation along the RANKL-RANK axis. RANKL and RANK (coded for by the TNFRSF11A gene) also play a role in the immune system, which raises the possibility that defects in this pathway might cause osteopetrosis with immunodeficiency. From a large series of ARO patients we selected a Turkish consanguineous family with two siblings affected by ARO and hypogammaglobulinemia with no defects in known osteopetrosis genes. Sequencing of genes involved in the RANKL downstream pathway identified a homozygous mutation in the TNFRSF11A gene in both siblings. Their monocytes failed to differentiate in vitro into osteoclasts upon exposure to M-CSF and RANKL, in keeping with an osteoclast-intrinsic defect. Immunological analysis showed that their hypogammaglobulinemia was associated with impairment in immunoglobulin-secreting B cells. Investigation of other patients revealed a defect in both TNFRSF11A alleles in six additional, unrelated families. Our results indicate that TNFRSF11A mutations can cause a clinical condition in which severe ARO is associated with an immunoglobulin-production defect.

Original languageEnglish (US)
Pages (from-to)64-76
Number of pages13
JournalAmerican Journal of Human Genetics
Issue number1
StatePublished - Jul 11 2008

Bibliographical note

Funding Information:
This work was supported by grants from Eurostells (STELLAR) and FIRB/MIUR to P.V. (RBIN04CHXT), from the Fondazione Telethon to C.S. (grant GGP08176), from the Fondazione Cariplo to A.F and from ISS Malattie Rare (New cell therapy approaches for infantile malignant Osteopetrosis) to P.V. and E-rare project to A.V.. The work reported in this paper has also been funded by the N.O.B.E.L. (Network Operativo per la Biomedicina di Eccellenza in Lombardia) Program from Fondazione Cariplo to P.V. and A.V. and by the European Calcified Tissue Society (M.H.H.) and the Chief Scientist's Office of the Scottish Executive, grant CZB/4/495 (M.H.H. and F.P.C.). The technical assistance of Maria Elena Caldana, Dario Strina, Lucia Susani and Kevin Mackenzie is acknowledged. We thank Jemni Ben Chibani and Ahmed-Noureddine Helal for providing DNA from normal individuals.


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