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Bone. 2014 Feb;59:66-75. doi: 10.1016/j.bone.2013.10.021. Epub 2013 Nov 1.

Generation of the first autosomal dominant osteopetrosis type II (ADO2) disease models.

Author information

  • 1Department of Orthopedic Surgery, Indiana University, 541 North Clinical Drive, Indianapolis, IN 46202, USA.
  • 2Department of Medicine, Indiana University, 541 North Clinical Drive, Indianapolis, IN 46202, USA.
  • 3Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio - Coppito 2, 67100 L'Aquila, Italy.
  • 4Regenerative Medicine Unit, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Piazza Sant'Onofrio 4, 00165 Rome, Italy.
  • 5Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio - Coppito 2, 67100 L'Aquila, Italy. Electronic address: teti@univaq.it.
  • 6Department of Medicine, Indiana University, 541 North Clinical Drive, Indianapolis, IN 46202, USA; Department of Medical and Molecular Genetics, Indiana University, 541 North Clinical Drive, Indianapolis, IN 46202, USA.

Abstract

Autosomal dominant osteopetrosis type II (ADO2) is a heritable osteosclerotic disorder dependent on osteoclast impairment. In most patients it results from heterozygous missense mutations in the chloride channel 7 (CLCN7) gene, encoding for a 2Cl(-)/1H(+) antiporter. By a knock-in strategy inserting a missense mutation in the Clcn7 gene, our two research groups independently generated mouse models of ADO2 on different genetic backgrounds carrying the homolog of the most frequent heterozygous mutation (p.G213R) in the Clcn7 gene found in humans. Our results demonstrate that the heterozygous model holds true presenting with higher bone mass, increased numbers of poorly resorbing osteoclasts and a lethal phenotype in the homozygous state. Considerable variability is observed in the heterozygous mice according with the mouse background, suggesting that modifier genes could influence the penetrance of the disease gene.

© 2013.

KEYWORDS:

Autosomal dominant osteopetrosis; Chloride channel 7; Mouse model; Osteoclast; Osteopetrosis

PMID:
24185277
[PubMed - indexed for MEDLINE]
PMCID:
PMC3889206
Free PMC Article
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