A homozygous missense variant in the alkaline phosphatase gene ALPL is associated with a severe form of canine hypophosphatasia

• Published in: Scientific Reports
• Main Authors: Kyöstilä, Kaisa, Syrjä, Pernilla, Lappalainen, Anu K., Arumilli, Meharji, Hundi, Sruthi, Karkamo, Veera, Viitmaa, Ranno, Hytönen, Marjo K., Lohi, Hannes
• Format: Text
• Language: English
• Published: Nature Publishing Group UK 2019
• Subjects: Article; karelian
• Online Access: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353930/; https://doi.org/10.1038/s41598-018-37801-2

Inherited skeletal disorders affect both humans and animals. In the current study, we have performed series of clinical, pathological and genetic examinations to characterize a previously unreported skeletal disease in the Karelian Bear Dog (KBD) breed. The disease was recognized in seven KBD puppies with a variable presentation of skeletal hypomineralization, growth retardation, seizures and movement difficulties. Exome sequencing of one affected dog revealed a homozygous missense variant (c.1301T > G; p.V434G) in the tissue non-specific alkaline phosphatase gene, ALPL. The identified recessive variant showed full segregation with the disease in a cohort of 509 KBDs with a carrier frequency of 0.17 and was absent from 303 dogs from control breeds. In humans, recessive and dominant ALPL mutations cause hypophosphatasia (HPP), a metabolic bone disease with highly heterogeneous clinical manifestations, ranging from lethal perinatal hypomineralization to a relatively mild dental disease. Our study reports the first naturally occurring HPP in animals, resembling the human infantile form. The canine HPP model may serve as a preclinical model while a genetic test will assist in breeding programs.