title: Molecular Characterization of Three Canine Models of Human Rare Bone Diseases: Caffey, van den Ende-Gupta, and Raine Syndromes.
abstract: One to two percent of all children are born with a developmental disorder requiring pediatric hospital admissions. For many such syndromes, the molecular pathogenesis remains poorly characterized. Parallel developmental disorders in other species could provide complementary models for human rare diseases by uncovering new candidate genes, improving the understanding of the molecular mechanisms and opening possibilities for therapeutic trials. We performed various experiments, e.g. combined genome-wide association and next generation sequencing, to investigate the clinico-pathological features and genetic causes of three developmental syndromes in dogs, including craniomandibular osteopathy (CMO), a previously undescribed skeletal syndrome, and dental hypomineralization, for which we identified pathogenic variants in the canine SLC37A2 (truncating splicing enhancer variant), SCARF2 (truncating 2-bp deletion) and FAM20C (missense variant) genes, respectively. CMO is a clinical equivalent to an infantile cortical hyperostosis (Caffey disease), for which SLC37A2 is a new candidate gene. SLC37A2 is a poorly characterized member of a glucose-phosphate transporter family without previous disease associations. It is expressed in many tissues, including cells of the macrophage lineage, e.g. osteoclasts, and suggests a disease mechanism, in which an impaired glucose homeostasis in osteoclasts compromises their function in the developing bone, leading to hyperostosis. Mutations in SCARF2 and FAM20C have been associated with the human van den Ende-Gupta and Raine syndromes that include numerous features similar to the affected dogs. Given the growing interest in the molecular characterization and treatment of human rare diseases, our study presents three novel physiologically relevant models for further research and therapy approaches, while providing the molecular identity for the canine conditions.
authors.affiliation: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|The Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Marjo K
authors.initials: MK
authors.lastname: Hytönen
authors.affiliation: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|The Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Meharji
authors.initials: M
authors.lastname: Arumilli
authors.affiliation: Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Anu K
authors.initials: AK
authors.lastname: Lappalainen
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Marta
authors.initials: M
authors.lastname: Owczarek-Lipska
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Jagannathan
authors.affiliation: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|The Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Sruthi
authors.initials: S
authors.lastname: Hundi
authors.affiliation: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|The Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Salmela
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Patrick
authors.initials: P
authors.lastname: Venta
authors.affiliation: Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Eva
authors.initials: E
authors.lastname: Sarkiala
authors.affiliation: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.|Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Jokinen
authors.affiliation: Division of Clinical Radiology, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gorgas
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|The Folkhälsan Institute of Genetics, Helsinki, Finland.|Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.
authors.forename: Pekka
authors.initials: P
authors.lastname: Nieminen
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Cord
authors.initials: C
authors.lastname: Drögemüller
authors.affiliation: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.|Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|The Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Hannes
authors.initials: H
authors.lastname: Lohi
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000818:Animals; D017920:Antiporters / Q000235:genetics; D054119:Arachnodactyly / Q000235:genetics* / Q000473:pathology; D016569:Blepharophimosis / Q000235:genetics* / Q000473:pathology; D001847:Bone Diseases / Q000235:genetics / Q000473:pathology; D047389:Casein Kinase I / Q000235:genetics; D002972:Cleft Palate / Q000235:genetics* / Q000473:pathology; D003286:Contracture / Q000235:genetics* / Q000473:pathology; D017271:Craniomandibular Disorders / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D004285:Dogs; D005094:Exophthalmos / Q000235:genetics* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D006958:Hyperostosis, Cortical, Congenital / Q000235:genetics* / Q000473:pathology; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D010026:Osteosclerosis / Q000235:genetics* / Q000473:pathology; D051128:Scavenger Receptors, Class F / Q000235:genetics
chemical_list: D017920:Antiporters; D016326:Extracellular Matrix Proteins; C469357:SCARF2 protein, human; D051128:Scavenger Receptors, Class F; C569995:Slc37a2 protein, human; D047389:Casein Kinase I; C524449:FAM20C protein, human