Human Osteoclast-Poor Osteopetrosis with Hypogammaglobulinemia due to TNFRSF11A (RANK) Mutations
Open accessAbstract
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.
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Active bone formation is lacking in osteoclast-poor osteopetrosis due to TNFRSF11A mutations or in dysosteosclerosis.
“In contrast to “osteoclast-rich” OPT, active bone formation is lacking in “osteoclast-poor” OPT (due to TNFRSF11A mutations226) or dysosteosclerosis (DSS) (an OPT of unknown etiology227).”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [226]
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High-Dose Diosgenin Reduces Bone Loss in Ovariectomized Rats via Attenuation of the RANKL/OPG Ratio
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Physiology and pathophysiology of the RANKL/RANK system
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Stem cell transplantation for osteopetrosis in patients beyond the age of 5 years
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Bone and bone marrow: The same organ
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- Authors
- Guerrini, M. M., Sobacchi, C., Cassani, B., Abinun, M., Kilic, S. S., Pangrazio, A., Moratto, D., Mazzolari, E., Clayton-Smith, J., Orchard, P., Coxon, F. P., Helfrich, M. H., Crockett, J. C., Mellis, D., Vellodi, A., Tezcan, I., Notarangelo, L. D., Rogers, M. J., Vezzoni, P., Villa, A., & Frattini, A.
- Affiliations
- Institute of Biomedical Technologies (IT)
- IRCCS Humanitas Research Hospital (IT)
- Newcastle University (GB)
- University of Brescia (IT)
- University of Minnesota (US)
- University of Aberdeen (GB)
- Great Ormond Street Hospital (GB)
- Harvard University (US)
- The San Raffaele Telethon Institute for Gene Therapy (IT)
- Corresponding author
- Villa, Anna
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 83
- Issue
- 1
- Pages
- 64-76
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2443850
- OpenAlex
- W2040034328
- Cited by
- 309
- References
- 23
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 8 · 2023: 2 · 2022: 17 · 2021: 12 · 2020: 24 · 2019: 19 · 2018: 11 · 2017: 21 · 2016: 17 · 2015: 17 · 2014: 24 · 2013: 18 · 2012: 24
- FWCI
- 9.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Bursa Uludag University - AVESIS (submittedVersion)
- Hacettepe University Institutional Repository (hacettepe.edu.tr) (submittedVersion, other-oa)
- Research Explorer (The University of Manchester) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- E-Rare
- Fondazione Telethon
- Fondazione Cariplo
- Ministero dell’Istruzione, dell’Università e della Ricerca (RBIN04CHXT)
- Army Research Office
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- osteopetrosis, RANK, RANKL, hypogammaglobulinemia, osteoclastogenesis, B cell defect, immunodeficiency, consanguinity, autosomal recessive osteopetrosis, macrophage colony-stimulating factor, monocytes
- MeSH terms
- Tartrate-Resistant Acid Phosphatase, Acid Phosphatase, Actins, Agammaglobulinemia, Amino Acid Sequence, Argentina, Arginine, Biopsy, Cell Line, Transformed, Cell Transformation, Viral, Cells, Cultured, Consanguinity, Cysteine, Dendrites, DNA Mutational Analysis, Herpesvirus 4, Human, Female, Genes, Recessive, Heterozygote, Homozygote, Humans, Ilium, Isoenzymes, Leukocytes, Mononuclear, Lipopolysaccharides, Male, Molecular Sequence Data, Osteoclasts, Osteopetrosis, Pakistan, Pedigree, Polymorphism, Genetic, Radiography, Thoracic, Turkey, Cohort Studies, Case-Control Studies, Macrophage Colony-Stimulating Factor, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Leukocyte Common Antigens, Models, Immunological, Receptors, Vitronectin, Amino Acid Substitution, Mutation, Missense, Cell Proliferation, Osteoprotegerin, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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