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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acid Phosphatase / metabolism
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Actins / metabolism
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Agammaglobulinemia / blood*
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Amino Acid Sequence
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Amino Acid Substitution
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Argentina
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Arginine / metabolism
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Biopsy
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Case-Control Studies
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Cell Line, Transformed
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Cell Proliferation
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Cell Transformation, Viral
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Cells, Cultured
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Cohort Studies
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Consanguinity
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Cysteine / metabolism
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DNA Mutational Analysis
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Dendrites / physiology
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Female
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Genes, Recessive
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Herpesvirus 4, Human / physiology
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Heterozygote
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Homozygote
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Humans
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Ilium / surgery
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Isoenzymes / metabolism
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Leukocyte Common Antigens / metabolism
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / pathology
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Lipopolysaccharides / pharmacology
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Macrophage Colony-Stimulating Factor / pharmacology
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Male
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Models, Immunological
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Molecular Sequence Data
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Mutation, Missense
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Osteoclasts / metabolism
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Osteoclasts / pathology*
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Osteoclasts / ultrastructure
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Osteopetrosis / diagnosis
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Osteopetrosis / diagnostic imaging
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Osteopetrosis / genetics*
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Osteopetrosis / pathology
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Osteopetrosis / physiopathology
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Osteoprotegerin / metabolism
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Pakistan
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Pedigree
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Polymorphism, Genetic
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Protein Structure, Tertiary
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RANK Ligand / metabolism
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Radiography, Thoracic / methods
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Receptor Activator of Nuclear Factor-kappa B / chemistry
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Receptor Activator of Nuclear Factor-kappa B / genetics*
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Receptor Activator of Nuclear Factor-kappa B / immunology
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Receptors, Vitronectin / metabolism
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Sequence Homology, Amino Acid
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Tartrate-Resistant Acid Phosphatase
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Turkey
Substances
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Actins
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Isoenzymes
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Lipopolysaccharides
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Osteoprotegerin
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Vitronectin
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TNFRSF11A protein, human
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Macrophage Colony-Stimulating Factor
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Arginine
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Acid Phosphatase
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Tartrate-Resistant Acid Phosphatase
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Leukocyte Common Antigens
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Cysteine