title: Generation of the first autosomal dominant osteopetrosis type II (ADO2) disease models.
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.
authors.affiliation: Department of Orthopedic Surgery, Indiana University, 541 North Clinical Drive, Indianapolis, IN 46202, USA.
authors.forename: Imranul
authors.initials: I
authors.lastname: Alam
authors.affiliation: Department of Medicine, Indiana University, 541 North Clinical Drive, Indianapolis, IN 46202, USA.
authors.forename: Amie K
authors.initials: AK
authors.lastname: Gray
authors.affiliation: Department of Medicine, Indiana University, 541 North Clinical Drive, Indianapolis, IN 46202, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Chu
authors.affiliation: Department of Medicine, Indiana University, 541 North Clinical Drive, Indianapolis, IN 46202, USA.
authors.forename: Shoji
authors.initials: S
authors.lastname: Ichikawa
authors.affiliation: Department of Medicine, Indiana University, 541 North Clinical Drive, Indianapolis, IN 46202, USA.
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio - Coppito 2, 67100 L'Aquila, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Capannolo
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio - Coppito 2, 67100 L'Aquila, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Capulli
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio - Coppito 2, 67100 L'Aquila, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Maurizi
authors.affiliation: Regenerative Medicine Unit, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Piazza Sant'Onofrio 4, 00165 Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Muraca
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio - Coppito 2, 67100 L'Aquila, Italy. Electronic address: teti@univaq.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Teti
authors.affiliation: Department 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.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Econs
authors.affiliation: Regenerative Medicine Unit, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Piazza Sant'Onofrio 4, 00165 Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Del Fattore
mesh_terms: D000818:Animals; D001483:Base Sequence; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000235:genetics; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D005799:Genes, Dominant; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010022:Osteopetrosis / Q000235:genetics*; D010641:Phenotype; D055114:X-Ray Microtomography
chemical_list: D015415:Biomarkers; D018118:Chloride Channels; C490803:Clcn7 protein, mouse
keywords: Autosomal dominant osteopetrosis; Chloride channel 7; Mouse model; Osteoclast; Osteopetrosis