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PLoS Genet. 2016 May 17;12(5):e1006037. doi: 10.1371/journal.pgen.1006037. eCollection 2016 May.

Molecular Characterization of Three Canine Models of Human Rare Bone Diseases: Caffey, van den Ende-Gupta, and Raine Syndromes.

Author information

1
Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.
2
Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
3
The Folkhälsan Institute of Genetics, Helsinki, Finland.
4
Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
5
Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
6
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, United States of America.
7
Division of Clinical Radiology, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
8
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
9
Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.

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.

PMID:
27187611
PMCID:
PMC4871343
DOI:
10.1371/journal.pgen.1006037
[Indexed for MEDLINE]
Free PMC Article

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