title: A Novel ANO5 Mutation Causing Gnathodiaphyseal Dysplasia With High Bone Turnover Osteosclerosis.
abstract: Gnathodiaphyseal dysplasia (GDD) is a rare skeletal syndrome that involves an osteopetrosis-like sclerosis of the long bones and fibrous dysplasia-like cemento-osseous lesions of the jawbone. Although the genetic analysis of the respective patients has revealed mutations in the ANO5 gene as an underlying cause, there is still no established consensus regarding the bone status of GDD patients. We report a new case of GDD in a 13-year-old boy with recurrent diaphyseal fractures of the femur, in whom we identified a novel de novo missense mutation in the ANO5 gene, causing a p.Ser500Phe substitution at the protein level. After confirming the presence of GDD-characteristic abnormalities within the jaw bones, we focused on a full osteologic assessment using dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and serum analyses. We thereby identified increased trabecular bone mass accompanied by elevated serum markers of bone formation and bone resorption. The high turnover bone pathology was further confirmed through the analysis of an iliac crest biopsy, where osteoblast and osteoclast indices were remarkably increased. Taken together, our findings provide evidence for a critical and generalized role of anoctamin-5 (the protein encoded by the ANO5 gene) in skeletal biology. As it is reasonable to speculate that modifying the function of anoctamin-5 might be useful for therapeutically activating bone remodeling, it is now required to analyze its function at a molecular level, for instance in mouse models. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Rolvien
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Department of Orthodontics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Koehne
authors.affiliation: Institute of Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lehmann
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Oheim
mesh_terms: D015502:Absorptiometry, Photon; D000293:Adolescent; D000595:Amino Acid Sequence; D000075368:Anoctamins / Q000737:chemistry / Q000235:genetics*; D015519:Bone Density; D016723:Bone Remodeling; D002113:Calcification, Physiologic; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010013:Osteogenesis Imperfecta / Q000150:complications* / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D010026:Osteosclerosis / Q000150:complications* / Q000000981:diagnostic imaging / Q000503:physiopathology; D010375:Pedigree; D014057:Tomography, X-Ray Computed
chemical_list: C547813:ANO5 protein, human; D000075368:Anoctamins
keywords: ANO5; BONE HISTOLOGY; BONE TURNOVER MARKERS; GDD; GNATHODIAPHYSEAL DYSPLASIA; HR-pQCT