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

Kaisa Kyöstilä,Anu K Lappalainen,Ranno Viitmaa,Meharji Arumilli,Sruthi Hundi,Marjo K Hytönen,Veera Karkamo,Pernilla Syrjä,Hannes Lohi

doi:10.1038/s41598-018-37801-2

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.

Highlights

The genetic skeletal diseases are a group of inherited conditions that affect the bone and cartilage tissues
The allelic heterogeneity of human HPP is reflected on the clinical spectrum, which ranges from stillbirth to a mild disease of the adulthood[12]
We aimed to elucidate the clinical, pathological and genetic aspects of an inherited skeletal disease found in the Karelian Bear Dog (KBD) breed

Summary

Introduction

The genetic skeletal diseases are a group of inherited conditions that affect the bone and cartilage tissues. The most recent update on genetic skeletal disorders encompasses more than 400 distinct conditions, resulting from defects in over 350 different genes[1]. One such condition is hypophosphatasia (HPP), a metabolic bone disease characterized by defective skeletal mineralization[2,3]. Purebred dogs (Canis lupus familiaris) are affected with a high number of naturally occurring genetic disorders that are often breed-specific or found only in a few related breeds. We were able to define the second skeletal phenotype in the breed as HPP, which represents the first report of naturally occurring HPP in animals

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