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

Professor Hannes Lohi’s Research Group discovered three novel canine genes for Caffey, Raine and van den Ende-Gupta syndromes. Research revealed close similarities of the canine models of human rare disorders and highlighted the potential of comparative research approach for the development of rare disease diagnostics and treatments. Gene discoveries benefit also veterinary diagnostics and breeding programs.

Genetic research in dogs revealed the causes of hyperostosis in Terrier breeds, dental hypomineralization in Border Collie, and a skeletal syndrome in Wire Fox Terriers. The latter two syndromes were described first time in the study. Hyperostosis in Terriers have been described before but the genetic cause was found here. Gene discoveries helped to identify and name the conditions and link them to human rare disorders.

New candidate gene to human Caffey disease
Canine craniomandibular osteopathy (CMO) resembles clinically Caffey disease, also called infantile hyperostosis, in human and belongs to a group of self-limiting and difficult to diagnose swelling syndromes. In this study, a splicing variant in SLC37A2 was identified to be associated with CMO. SLC37A2 is a novel physiologically relevant candidate gene for human Caffey disease. It is a glucose-phosphate transporter, and its defect suggests an impaired glucose homeostasis in developing bone, leading to hyperostosis. The canine disease provides resources to better understand SLC37A2 functions in skeletal biology.

Gene discovery necessary for disease diagnostics
This study provides molecular identity for the canine conditions. Mutations in the SCARF2 and FAM20C genes have been associated with the human van den Ende-Gupta and Raine syndromes. Van den Ende-Gupta syndrome is characterized by a heterogeneous variety of craniofacial and skeletal abnormalities, and Raine syndrome by hypomineralization of bones and teeth. The clinical features in canine models closely resembled human syndromes both clinically and genetically. These two examples demonstrate again how similar human and canine rare disorders are. There is a growing interest in the development of better diagnostic and treatment options for rare disorders, and canine models can reveal genes and provide resources to better understand the conditions and even to try new treatments. Comparative studies between the two species should be increased in future.

Three new genetic tests for diagnostics and breeding
The study has also practical implications for veterinary diagnostics and breeding programs to improve canine welfare. Genetic tests developed in this study will help veterinarians to diagnose the conditions, which is often challenging in the developmental syndromes based on only clinical characteristics. Gene tests will also improve breeding programs since breeders have now new tools to identify carriers and to select proper mating partners to avoid affected puppies in future litters.

Original study:

Hytönen MK, Arumilli M, Lappalainen AK, Owczarek-Lipska M, Jagannathan V, Hundi S, Salmela E, Venta P, Sarkiala E, Jokinen T, Gorgas D, Kere J, Nieminen P, Drögemüller C, Lohi H.  Molecular Characterization of Three Canine Models of Human Rare Bone Diseases: Caffey, van den Ende-Gupta, and Raine Syndromes. PLoS Genet 12: e1006037, 2016