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dc.contributor.authorGuerrini, Matteo M.
dc.contributor.authorSobacchi, Cristina
dc.contributor.authorCassani, Barbara
dc.contributor.authorAbinun, Mario
dc.contributor.authorKilic, Sara S.
dc.contributor.authorPangrazio, Alessandra
dc.contributor.authorMoratto, Daniele
dc.contributor.authorMazzolari, Evelina
dc.contributor.authorClayton-Smith, Jill
dc.contributor.authorOrchard, Paul
dc.contributor.authorCoxon, Fraser P.
dc.contributor.authorHelfrich, Miep H.
dc.contributor.authorCrockett, Julie C.
dc.contributor.authorMellis, David
dc.contributor.authorVellodi, Ashok
dc.contributor.authorTezcan, Ilhan
dc.contributor.authorNotarangelo, Luigi D.
dc.contributor.authorRogers, Michael J.
dc.contributor.authorVezzoni, Paolo
dc.contributor.authorVilla, Anna
dc.contributor.authorFrattini, Annalisa
dc.date.accessioned2019-12-10T10:38:41Z
dc.date.available2019-12-10T10:38:41Z
dc.date.issued2008
dc.identifier.issn0002-9297
dc.identifier.urihttps://doi.org/10.1016/j.ajhg.2008.06.015
dc.identifier.urihttp://hdl.handle.net/11655/14072
dc.description.abstractAutosomal-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.
dc.language.isoen
dc.publisherCell Press
dc.relation.isversionof10.1016/j.ajhg.2008.06.015
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectGenetics & Heredity
dc.titleHuman Osteoclast-Poor Osteopetrosis With Hypogammaglobulinemia Due To Tnfrsf11A (Rank) Mutations
dc.typeinfo:eu-repo/semantics/article
dc.typeinfo:eu-repo/semantics/publishedVersion
dc.relation.journalAmerican Journal Of Human Genetics
dc.contributor.departmentÇocuk Sağlığı ve Hastalıkları
dc.identifier.volume83
dc.identifier.issue1
dc.identifier.startpage64
dc.identifier.endpage76
dc.description.indexWoS
dc.description.indexScopus


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