title: RANK-dependent autosomal recessive osteopetrosis: characterization of five new cases with novel mutations.
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 Here we present the characterization of five additional unpublished patients from four unrelated families in which we found five novel mutations in the TNFRSF11A gene, including two missense and two nonsense mutations and a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.
authors.affiliation: Institute of Genetic and Biomedical Research, Milan Unit, National Research Council, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pangrazio
authors.forename: Barbara
authors.initials: B
authors.lastname: Cassani
authors.forename: Matteo M
authors.initials: MM
authors.lastname: Guerrini
authors.forename: Julie C
authors.initials: JC
authors.lastname: Crockett
authors.forename: Veronica
authors.initials: V
authors.lastname: Marrella
authors.forename: Luca
authors.initials: L
authors.lastname: Zammataro
authors.forename: Dario
authors.initials: D
authors.lastname: Strina
authors.forename: Ansgar
authors.initials: A
authors.lastname: Schulz
authors.forename: Claire
authors.initials: C
authors.lastname: Schlack
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
authors.forename: David J
authors.initials: DJ
authors.lastname: Mellis
authors.forename: Angela
authors.initials: A
authors.lastname: Duthie
authors.forename: Miep H
authors.initials: MH
authors.lastname: Helfrich
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Despina
authors.initials: D
authors.lastname: Moshous
authors.forename: Ashok
authors.initials: A
authors.lastname: Vellodi
authors.forename: Robert
authors.initials: R
authors.lastname: Chiesa
authors.forename: Paul
authors.initials: P
authors.lastname: Veys
authors.forename: Nadia
authors.initials: N
authors.lastname: Lo Iacono
authors.forename: Paolo
authors.initials: P
authors.lastname: Vezzoni
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.forename: Cristina
authors.initials: C
authors.lastname: Sobacchi
mesh_terms: D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000378:metabolism; D002451:Cell Compartmentation; D002454:Cell Differentiation; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010010:Osteoclasts / Q000473:pathology; D010022:Osteopetrosis / Q000151:congenital* / Q000235:genetics; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000737:chemistry / Q000235:genetics*
chemical_list: D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human