Abstract
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 language | English |
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Pages (from-to) | 64-76 |
Number of pages | 13 |
Journal | American Journal of Human Genetics |
Volume | 83 |
Issue number | 1 |
DOIs | |
Publication status | Published - 11 Jul 2008 |
Keywords
- 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