Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations.
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.
Guerrini
Matteo M
MM
Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, Segrate 20090, Italy.
Sobacchi
Cristina
C
Cassani
Barbara
B
Abinun
Mario
M
Kilic
Sara S
SS
Pangrazio
Alessandra
A
Moratto
Daniele
D
Mazzolari
Evelina
E
Clayton-Smith
Jill
J
Orchard
Paul
P
Coxon
Fraser P
FP
Helfrich
Miep H
MH
Crockett
Julie C
JC
Mellis
David
D
Vellodi
Ashok
A
Tezcan
Ilhan
I
Notarangelo
Luigi D
LD
Rogers
Michael J
MJ
Vezzoni
Paolo
P
Villa
Anna
A
Frattini
Annalisa
A
D000135:Acid Phosphatase / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000361:Agammaglobulinemia / Q000097:blood*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001118:Argentina; D001120:Arginine / Q000378:metabolism; D001706:Biopsy; D016022:Case-Control Studies; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D015331:Cohort Studies; D003241:Consanguinity; D003545:Cysteine / Q000378:metabolism; D004252:DNA Mutational Analysis; D003712:Dendrites / Q000502:physiology; D005260:Female; D005808:Genes, Recessive; D004854:Herpesvirus 4, Human / Q000502:physiology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007085:Ilium / Q000601:surgery; D007527:Isoenzymes / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D018448:Models, Immunological; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D010022:Osteopetrosis / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D053244:Osteoprotegerin / Q000378:metabolism; D010154:Pakistan; D010375:Pedigree; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D053245:RANK Ligand / Q000378:metabolism; D013902:Radiography, Thoracic / Q000379:methods; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D019030:Receptors, Vitronectin / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D000071681:Tartrate-Resistant Acid Phosphatase; D014421:Turkey
D000199:Actins; D007527:Isoenzymes; D008070:Lipopolysaccharides; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D019030:Receptors, Vitronectin; C505686:TNFRSF11A protein, human; D016173:Macrophage Colony-Stimulating Factor; D001120:Arginine; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D017493:Leukocyte Common Antigens; D003545:Cysteine