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

• Published in: Journal of bone and mineral research Vol. 27; no. 2; pp. 342 - 351
• Main Authors: Pangrazio, Alessandra, Cassani, Barbara, Guerrini, Matteo M, Crockett, Julie C, Marrella, Veronica, Zammataro, Luca, Strina, Dario, Schulz, Ansgar, Schlack, Claire, Kornak, Uwe, Mellis, David J, Duthie, Angela, Helfrich, Miep H, Durandy, Anne, Moshous, Despina, Vellodi, Ashok, Chiesa, Robert, Veys, Paul, Lo Iacono, Nadia, Vezzoni, Paolo, Fischer, Alain, Villa, Anna, Sobacchi, Cristina
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-02-2012; Wiley; Wiley Subscription Services, Inc
• Subjects: Amino Acid Sequence; B-Lymphocytes - metabolism; Biological and medical sciences; Cell Compartmentation; Cell Differentiation; Female; Follow-Up Studies; Fundamental and applied biological sciences. Psychology; Hematopoietic Stem Cell Transplantation; Humans; HYPERCALCEMIA; IMMUNE SYSTEM; Infant; Infant, Newborn; Male; Molecular Sequence Data; Mutation - genetics; Original; Osteoclasts - pathology; OSTEOPETROSIS; Osteopetrosis - congenital; Osteopetrosis - genetics; RANK; Receptor Activator of Nuclear Factor-kappa B - chemistry; Receptor Activator of Nuclear Factor-kappa B - genetics; Skeleton and joints; TRANSPLANTATION; Vertebrates: osteoarticular system, musculoskeletal system; Hydroelectrolytic balance disorder; Calcium; Diseases of the osteoarticular system; Transplantation; RANK; Inorganic element; Genetic disease; Characterization; Hypercalcemia; Osteoarticular system; Metabolic disorder; Vertebrata; Mammalia; Osteopetrosis; Mutation; Osteochondrodysplasia; Immune system
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1002/jbmr.559

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 Here we present the characterization of five additional unpublished patients from four unrelated families in which we found five novel mutations in the TNFRSF11A gene, including two missense and two nonsense mutations and a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