Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations

Matteo M. Guerrini, Cristina Sobacchi, Barbara Cassani, Mario Abinun, Sara S. Kilic, Alessandra Pangrazio, Daniele Moratto, Evelina Mazzolari, Jill Clayton-Smith, Paul Orchard, Fraser Coxon, Miep H. Helfrich, Julie C. Crockett, David Mellis, Ashok Vellodi, Ilhan Tezcan, Luigi D. Notarangelo, Michael J. Rogers, Paolo Vezzoni, Anna VillaAnnalisa Frattini

Research output: Contribution to journalArticlepeer-review

250 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)64-76
Number of pages13
JournalAmerican Journal of Human Genetics
Issue number1
Publication statusPublished - 11 Jul 2008


  • acid phosphatase
  • actins
  • agammaglobulinemia
  • amino acid sequence
  • amino acid substitution
  • antigens, CD45
  • Argentina
  • arginine
  • biopsy
  • case-control studies
  • cell line, transformed
  • cell proliferation
  • cell transformation, viral
  • cells, cultured
  • cohort studies
  • consanguinity
  • cysteine
  • DNA mutational analysis
  • dendrites
  • female
  • genes, recessive
  • herpesvirus 4, human
  • heterozygote
  • homozygote
  • humans
  • ilium
  • isoenzymes
  • 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
  • RANK Ligand
  • radiography, thoracic
  • receptor activator of nuclear factor-kappa B
  • receptors, vitronectin
  • sequence homology, amino acid
  • Turkey


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