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

• Published in: Scientific reports Vol. 9; no. 1; p. 973
• Main Authors: Kyöstilä, Kaisa, Syrjä, Pernilla, Lappalainen, Anu K., Arumilli, Meharji, Hundi, Sruthi, Karkamo, Veera, Viitmaa, Ranno, Hytönen, Marjo K., Lohi, Hannes
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-01-2019; Nature Publishing Group
• Subjects: 13/1; 13/51; 45/22; 45/23; 45/77; 631/136/818; 631/208/2489/144; 692/308/2056; 692/699/317; Alkaline phosphatase; Bone diseases; Canine teeth; Dental disorders; Dental enamel; Genetic screening; Growth rate; Humanities and Social Sciences; Hypophosphatasia; Mineralization; multidisciplinary; Phosphatase; Science; Science (multidisciplinary); Seizures
• ISSN: 2045-2322; 2045-2322
• 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.