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

Sci Rep. 2019 Jan 30;9(1):973. doi: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase / chemistry
  • Alkaline Phosphatase / genetics*
  • Amino Acid Sequence
  • Animals
  • Breeding
  • Calcification, Physiologic / genetics
  • Conserved Sequence
  • Dog Diseases / enzymology*
  • Dog Diseases / genetics*
  • Dog Diseases / urine
  • Dogs / genetics*
  • Ethanolamines / urine
  • Female
  • Homozygote
  • Hypophosphatasia / diagnostic imaging
  • Hypophosphatasia / genetics*
  • Hypophosphatasia / physiopathology
  • Hypophosphatasia / veterinary*
  • Male
  • Mutation, Missense / genetics*
  • Osteogenesis / genetics
  • Pedigree
  • Protein Domains
  • Whole Exome Sequencing


  • Ethanolamines
  • phosphorylethanolamine
  • Alkaline Phosphatase