RANK-dependent autosomal recessive osteopetrosis: Characterization of five new cases with novel mutations
Year: 2011
Type: article
Study design: Case Report
Abstract: 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 Here we present the characterization of five additional unpublished patients from four unrelated families in which we found five novel mutations in the TNFRSF11A gene, including two missense and two nonsense mutations and a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.
DOI: 10.1002/jbmr.559
Authors: 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 Vezzoni, Alain Fischer, Anna Villa, Cristina Sobacchi
Institutions: Institute of Genetic and Biomedical Research, National Research Council, IRCCS Humanitas Research Hospital, Fondazione Humanitas per la Ricerca, University of Aberdeen, University Hospital Ulm, Max Planck Institute for Molecular Genetics, Hôpital Necker-Enfants Malades, Inserm, Université Paris Descartes, Great Ormond Street Hospital
Language: English
Topic: Bone Metabolism and Diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2052704689