RANK-dependent autosomal recessive osteopetrosis: Characterization of five new cases with novel mutations

Alessandra Pangrazio, Barbara Cassani, Matteo M Guerrini, Julie C Crockett, Veronica Marrella, Luca Zammataro, Dario Strina, Ansgar Schulz, Claire Schlack, Uwe Kornak, David J Mellis, Angela Duthie, Miep H Helfrich, Anne Durandy, Despina Moshous, Ashok Vellodi, Robert Chiesa, Paul Veys, Nadia Lo Iacono, Paolo VezzoniAlain Fischer, Anna Villa, Cristina Sobacchi

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59 Citations (Scopus)


Autosomal recessive osteopetrosis (ARO) is a genetically heterogeneous disorder attributed to reduced bone resorption by osteoclasts. Most human AROs are classified as osteoclast rich, but recently two subsets of osteoclast-poor ARO have been recognized as caused by defects in either TNFSF11 or TNFRSF11A genes, coding the RANKL and RANK proteins, respectively. The RANKL/RANK axis drives osteoclast differentiation and also plays a role in the immune system. In fact, we have recently reported that mutations in the TNFRSF11A gene lead to osteoclast-poor osteopetrosis associated with hypogammaglobulinemia. Here we present the characterization of five additional unpublished patients from four unrelated families in which we found five novel mutations in the TNFRSF11A gene, including two missense and two nonsense mutations and a single-nucleotide insertion. Immunological investigation in three of them showed that the previously described defect in the B cell compartment was present only in some patients and that its severity seemed to increase with age and the progression of the disease. HSCT performed in all five patients almost completely cured the disease even when carried out in late infancy. Hypercalcemia was the most important posttransplant complication. Overall, our results further underline the heterogeneity of human ARO also deriving from the interplay between bone and the immune system, and highlight the prognostic and therapeutic implications of the molecular diagnosis. © 2012 American Society for Bone and Mineral Research.

Original languageEnglish
Pages (from-to)342-351
Number of pages10
JournalJournal of Bone and Mineral Research
Issue number2
Early online date9 Nov 2011
Publication statusPublished - Feb 2012

Bibliographical note

PMID: 22271396 [PubMed - indexed for MEDLINE] PMCID: PMC3306792 Free PMC Article


  • osteoperosis
  • rank
  • immune system
  • transplantaion
  • hypercalcaemia


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