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Am J Hum Genet ; 83(1): 64-76, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18606301

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.


Subject(s)
Agammaglobulinemia/blood , Osteoclasts/pathology , Osteopetrosis/genetics , Receptor Activator of Nuclear Factor-kappa B/genetics , Acid Phosphatase/metabolism , Actins/metabolism , Amino Acid Sequence , Amino Acid Substitution , 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 , Leukocyte Common Antigens/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/ultrastructure , Osteopetrosis/diagnosis , Osteopetrosis/diagnostic imaging , Osteopetrosis/pathology , Osteopetrosis/physiopathology , 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/immunology , Receptors, Vitronectin/metabolism
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