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. Author Summary Rare developmental disorders make a major contribution to pediatric hospital admissions and mortality. There is a growing interest in the development of therapeutics for these conditions, but that requires understanding of the genetic cause and pathology. Research can be facilitated by physiologically relevant models, such as dogs with corresponding disorders. We have characterized the clinical 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 mutations in the canine SLC37A2 , SCARF2 and FAM20C 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 glucose-phosphate transporter in osteoclasts, and its defect suggests an impaired glucose homeostasis in developing bone, leading to hyperostosis. Mutations in the SCARF2 and FAM20C genes have been associated with the human van den Ende-Gupta and Raine syndromes. Our study provides molecular identity for the canine conditions and presents three novel physiologically relevant models of human rare diseases.
【초록키워드】 Treatment, Macrophage, pathology, therapy, Mutation, Pathogenesis, Mortality, Therapeutics, pediatric, children, Sequencing, variant, rare diseases, molecular mechanism, Clinical features, therapeutic, Research, Lineage, next generation sequencing, canine, Hospital admission, molecular, disease, rare disease, trials, clinical feature, mechanism, homeostasis, Glucose, candidate gene, Hospital admissions, complementary, developmental disorders, phosphate, developmental disorder, craniomandibular osteopathy, infantile cortical hyperostosis, therapeutic trials, skeletal, identity, disorders, tissues, approaches, molecular mechanisms, syndrome, genome-wide association, FAM20C, genetic cause, hyperostosis, SCARF2, SLC37A2, missense variant, pathogenic variant, enhancer, Genes, feature, Cell, performed, affected, include, characterized, provide, condition, facilitated, expressed, conditions, experiments, developmental, associations, cortical, 【제목키워드】 Human, Model, bone, characterization,