Inherited selective cobalamin malabsorption in Komondor dogs associated with a CUBN splice site variant

Abstract Background Three Komondor dogs in a small family and 3 sporadic cases exhibited a constellation of signs that included juvenile-onset of failure-to-thrive, inappetence, vomiting and/or diarrhea, and weakness. In each we documented dyshematopoiesis, increased anion gap, methylmalonic acidemia/-uria, and serum cobalamin deficiency. Urine protein electrophoresis demonstrated excretion of cubam ligands. All clinical signs and metabolic abnormalities, except proteinuria, were reversed by regular parenteral cobalamin administration. The pattern of occurrence and findings in the disorder suggested an autosomal recessive inheritance of cobalamin malabsorption with proteinuria, a condition in humans called Imerslund-Gräsbeck syndrome. The purpose of this study was to determine the molecular cause of this disorder in Komondors. Results Whole genome sequencing of two affected Komondor dogs of unknown relatedness and one parent and a clinically-normal littermate of an affected dog revealed a pathogenic single-base change in the CUBN intron 55 splice donor consensus sequence (NM_001003148.1: c.8746 + 1G > A) that was homozygous in affected dogs and heterozygous in the unaffected parents. Alleles of the variant co-segregated with alleles of the disease locus in the entire family and all more distantly-related sporadic cases. A population study using a simple allele-specific DNA test indicated mutant allele frequencies of 8.3 and 4.5% among North American and Hungarian Komondors, respectively. Conclusions DNA testing can be used diagnostically in Komondors when clinical signs are suggestive of cobalamin deficiency or to inform Komondor breeders prospectively and prevent occurrence of future affected dogs. This represents the third cubilin variant causing inherited selective cobalamin malabsorption in a large animal ortholog of human Imerslund-Gräsbeck syndrome.