title: Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations.
abstract: 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.
authors.affiliation: Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, Segrate 20090, Italy.
authors.forename: Matteo M
authors.initials: MM
authors.lastname: Guerrini
authors.forename: Cristina
authors.initials: C
authors.lastname: Sobacchi
authors.forename: Barbara
authors.initials: B
authors.lastname: Cassani
authors.forename: Mario
authors.initials: M
authors.lastname: Abinun
authors.forename: Sara S
authors.initials: SS
authors.lastname: Kilic
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pangrazio
authors.forename: Daniele
authors.initials: D
authors.lastname: Moratto
authors.forename: Evelina
authors.initials: E
authors.lastname: Mazzolari
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.forename: Paul
authors.initials: P
authors.lastname: Orchard
authors.forename: Fraser P
authors.initials: FP
authors.lastname: Coxon
authors.forename: Miep H
authors.initials: MH
authors.lastname: Helfrich
authors.forename: Julie C
authors.initials: JC
authors.lastname: Crockett
authors.forename: David
authors.initials: D
authors.lastname: Mellis
authors.forename: Ashok
authors.initials: A
authors.lastname: Vellodi
authors.forename: Ilhan
authors.initials: I
authors.lastname: Tezcan
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rogers
authors.forename: Paolo
authors.initials: P
authors.lastname: Vezzoni
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.forename: Annalisa
authors.initials: A
authors.lastname: Frattini
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000361:Agammaglobulinemia / Q000097:blood*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001118:Argentina; D001120:Arginine / Q000378:metabolism; D001706:Biopsy; D016022:Case-Control Studies; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D015331:Cohort Studies; D003241:Consanguinity; D003545:Cysteine / Q000378:metabolism; D004252:DNA Mutational Analysis; D003712:Dendrites / Q000502:physiology; D005260:Female; D005808:Genes, Recessive; D004854:Herpesvirus 4, Human / Q000502:physiology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007085:Ilium / Q000601:surgery; D007527:Isoenzymes / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D018448:Models, Immunological; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D010022:Osteopetrosis / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D053244:Osteoprotegerin / Q000378:metabolism; D010154:Pakistan; D010375:Pedigree; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D053245:RANK Ligand / Q000378:metabolism; D013902:Radiography, Thoracic / Q000379:methods; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D019030:Receptors, Vitronectin / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D000071681:Tartrate-Resistant Acid Phosphatase; D014421:Turkey
chemical_list: D000199:Actins; D007527:Isoenzymes; D008070:Lipopolysaccharides; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D019030:Receptors, Vitronectin; C505686:TNFRSF11A protein, human; D016173:Macrophage Colony-Stimulating Factor; D001120:Arginine; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D017493:Leukocyte Common Antigens; D003545:Cysteine