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Sci Rep. 2019 Jan 30;9(1):973. doi: 10.1038/s41598-018-37801-2.

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

Author information

1
Department of Veterinary Biosciences, University of Helsinki, 00014, Helsinki, Finland.
2
Research Programs Unit, Molecular Neurology, University of Helsinki, 00014, Helsinki, Finland.
3
Department of Molecular Genetics, Folkhälsan Institute of Genetics, 00290, Helsinki, Finland.
4
Department of Equine and Small Animal Medicine, University of Helsinki, 00014, Helsinki, Finland.
5
Veterinary Bacteriology and Pathology Research Unit, Finnish Food Safety Authority Evira, 00790, Helsinki, Finland.
6
Department of Veterinary Biosciences, University of Helsinki, 00014, Helsinki, Finland. hannes.lohi@helsinki.fi.
7
Research Programs Unit, Molecular Neurology, University of Helsinki, 00014, Helsinki, Finland. hannes.lohi@helsinki.fi.
8
Department of Molecular Genetics, Folkhälsan Institute of Genetics, 00290, Helsinki, Finland. hannes.lohi@helsinki.fi.

Abstract

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.

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