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PMID:18606301

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Citation

Guerrini, MM, Sobacchi, C, Cassani, B, Abinun, M, Kilic, SS, Pangrazio, A, Moratto, D, Mazzolari, E, Clayton-Smith, J, Orchard, P, Coxon, FP, Helfrich, MH, Crockett, JC, Mellis, D, Vellodi, A, Tezcan, I, Notarangelo, LD, Rogers, MJ, Vezzoni, P, Villa, A and Frattini, A (2008) Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am. J. Hum. Genet. 83:64-76

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.

Links

PubMed PMC2443850 Online version:10.1016/j.ajhg.2008.06.015

Keywords

Acid Phosphatase/metabolism; Actins/metabolism; Agammaglobulinemia/blood; Amino Acid Sequence; Amino Acid Substitution; Antigens, CD45/metabolism; Argentina; Arginine/metabolism; Biopsy; Case-Control Studies; Cell Line, Transformed; Cell Proliferation; Cell Transformation, Viral; Cells, Cultured; Cohort Studies; Consanguinity; Cysteine/metabolism; DNA Mutational Analysis; Dendrites/physiology; Female; Genes, Recessive; Herpesvirus 4, Human/physiology; Heterozygote; Homozygote; Humans; Ilium/surgery; Isoenzymes/metabolism; Leukocytes, Mononuclear/drug effects; Leukocytes, Mononuclear/pathology; Lipopolysaccharides/pharmacology; Macrophage Colony-Stimulating Factor/pharmacology; Male; Models, Immunological; Molecular Sequence Data; Mutation, Missense; Osteoclasts/metabolism; Osteoclasts/pathology; Osteoclasts/ultrastructure; Osteopetrosis/diagnosis; Osteopetrosis/genetics; Osteopetrosis/pathology; Osteopetrosis/physiopathology; Osteopetrosis/radiography; Osteoprotegerin/metabolism; Pakistan; Pedigree; Polymorphism, Genetic; Protein Structure, Tertiary; RANK Ligand/metabolism; Radiography, Thoracic/methods; Receptor Activator of Nuclear Factor-kappa B/chemistry; Receptor Activator of Nuclear Factor-kappa B/genetics; Receptor Activator of Nuclear Factor-kappa B/immunology; Receptors, Vitronectin/metabolism; Sequence Homology, Amino Acid; Turkey

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TNFA

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNR11

involved_in

GO:0002250: adaptive immune response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNR11

involved_in

GO:0030316: osteoclast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNR11

involved_in

GO:0034097: response to cytokine

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNR11

involved_in

GO:0071847: TNFSF11-mediated signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNR11

involved_in

GO:0071848: positive regulation of ERK1 and ERK2 cascade via TNFSF11-mediated signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNF11

involved_in

GO:0030316: osteoclast differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNF11

involved_in

GO:0071847: TNFSF11-mediated signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNF11

involved_in

GO:0071848: positive regulation of ERK1 and ERK2 cascade via TNFSF11-mediated signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CSF1

involved_in

GO:0030316: osteoclast differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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