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.
Subject(s)
Alkaline Phosphatase/genetics , Dog Diseases/enzymology , Dog Diseases/genetics , Dogs/genetics , Hypophosphatasia/genetics , Hypophosphatasia/veterinary , Mutation, Missense/genetics , Alkaline Phosphatase/chemistry , Amino Acid Sequence , Animals , Breeding , Calcification, Physiologic/genetics , Conserved Sequence , Dog Diseases/urine , Ethanolamines/urine , Female , Homozygote , Hypophosphatasia/diagnostic imaging , Hypophosphatasia/physiopathology , Male , Osteogenesis/genetics , Pedigree , Protein Domains , Exome SequencingABSTRACT
Ishibashi rats, a mutant strain with congenital spinal malformation discovered by Ishibashi in 1968, are generally regarded as an animal model for a human inborn error of spinal malformation. Biochemical values in serum or plasma of Ishibashi rats were compared with those of Wistar-Imamichi rats, and the following results were obtained: 1) In Ishibashi rat sera, alkaline phosphatase activity was significantly lower than that in sera of controls, and an intestinal type of isozyme was hardly detected. 2) All other serum biochemical parameters examined showed no significant difference between Ishibashi and Wistar-Imamichi rats. 3) The data suggest that Ishibashi rats may serve as an animal model of hypophosphatasia in man.
Subject(s)
Rats, Mutant Strains/metabolism , Rodent Diseases/congenital , Spine/abnormalities , Alkaline Phosphatase/blood , Animals , Disease Models, Animal , Female , Hypophosphatasia/veterinary , Male , RatsABSTRACT
In 8 elderly female dogs a syndrome of hypercalcaemia and hypophosphataemia was found in association with a perirectal adenocarcinoma. Following removal of the tumour the hypercalcaemia resolved within two days in four of the five operated animals.
