osteoprotegerin and Agammaglobulinemia

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.

Topics: Acid Phosphatase; Actins; Agammaglobulinemia; Amino Acid Sequence; Amino Acid Substitution; Argentina; Arginine; Biopsy; Case-Control Studies; Cell Line, Transformed; Cell Proliferation; Cell Transformation, Viral; Cells, Cultured; Cohort Studies; Consanguinity; Cysteine; Dendrites; DNA Mutational Analysis; Female; Genes, Recessive; Herpesvirus 4, Human; Heterozygote; Homozygote; Humans; Ilium; Isoenzymes; Leukocyte Common Antigens; Leukocytes, Mononuclear; Lipopolysaccharides; Macrophage Colony-Stimulating Factor; Male; Models, Immunological; Molecular Sequence Data; Mutation, Missense; Osteoclasts; Osteopetrosis; Osteoprotegerin; Pakistan; Pedigree; Polymorphism, Genetic; Protein Structure, Tertiary; Radiography, Thoracic; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Vitronectin; Sequence Homology, Amino Acid; Tartrate-Resistant Acid Phosphatase; Turkey

A new entity manifested by severe congenital neutropenia associated with osteoporosis and recurrent bone fracture is described in a family. A possible role for a new recognized cytokine system involved in bone remodeling, the osteoprotegerin/receptor activator of nuclear factor-kappa B ligand, is suggested.

Topics: Agammaglobulinemia; Bone Remodeling; Carrier Proteins; Cells, Cultured; Child, Preschool; Consanguinity; Failure to Thrive; Fibroblasts; Filgrastim; Fractures, Spontaneous; Genes, Recessive; Glycoproteins; Granulocyte Colony-Stimulating Factor; Humans; Immunoglobulins, Intravenous; Male; Membrane Glycoproteins; Neutropenia; Osteoporosis; Osteoprotegerin; Pancytopenia; Pedigree; Peripheral Blood Stem Cell Transplantation; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Recombinant Proteins; Recurrence