Guerrini, Matteo M.Sobacchi, CristinaCassani, BarbaraAbinun, MarioPangrazio, AlessandraMoratto, DanieleMazzolari, EvelinaClayton-Smith, JillOrchard, PaulCoxon, Fraser P.Helfrich, Miep H.Crocket, Julie C.Mellis, DavidVellod, AshokTezcan, İlhanNotarangelo, Luigi D.Rogers, Michael J.Vezzoni, PaoloVilla, AnnaFrattini, Annalisa2021-10-192021-10-192008-07Guerrini, M. M. vd. (2008). "Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations". American Journal of Human Genetics, 83(1), 64-76.0002-92971537-6605https://doi.org/10.1016/j.ajhg.2008.06.015http://hdl.handle.net/11452/22406Autosomal-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 TNESF11 (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 TNERSF11A 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.eninfo:eu-repo/semantics/openAccessGenetics & HeredityAutosomal recessive osteopetrosisReceptor activator differentiationDuplicationDiseaseTCIRG1CellsAcid phosphataseActinsAgammaglobulinemiaAmino acid sequenceAmino acid substitutionAntigens, CD45ArgentinaArginineBiopsyCase-control studiesCell line, transformedCell proliferationCell transformation, viralCells, culturedCohort studiesConsanguinityCysteineHomozygoteHumansIliumIsoenzymesLeukocytes, mononuclearLipopolysaccharidesMacrophage colony-stimulating factorMaleModels, immunologicalMolecular sequence dataMutation, missenseOsteoclastsOsteopetrosisOsteoprotegerinPakistanPedigreePolymorphismGeneticProtein structure, tertiaryRadiography, thoracicRANK ligandReceptor activator of nuclear factor-kappa BReceptors, vitronectinSequence homology, amino AcidTurkeyArticle0002577840000082-s2.0-46349084493647683118606301Genetics & HeredityOsteopetrosis; Osteopetrosis with Renal Tubular Acidosis; Chloride ChannelsColony stimulating factor 1Osteoclast differentiation factorReceptor activator of nuclear factor kappa BAlbers Schoenberg diseaseAleleArticleB lymphocyteConsanguinityGene mutationGene sequenceHumanHuman tissueİmmune deficiencyİmmune systemİmmunoglobulin deficiencyİmmunological parametersIn vitro studyMonocyteNucleotide sequenceOsteoclastPriorityJournalSibling