Abstract
BackgroundThree 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.ResultsWhole 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.ConclusionsDNA 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.
Highlights
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
We describe here autosomal recessive selective intestinal cobalamin malabsorption with proteinuria in Komondor dogs characterized by failure to thrive, dyshematopoiesis, and metabolic disturbances during the juvenile period, as occur in Imerslund-Gräsbeck syndrome (I-GS) of other dog breeds and human patients
Clinical signs of I-GS in Komondors Owners of affected Komondors first noted signs of failure-to-thrive between 2.5 and 5 months of age that were progressive until institution of parenteral cobalamin administration
Summary
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. Cobalamin is synthesized only by certain microorganisms, and monogastric species obtain this vitamin from animal-derived foods via a complex receptor-mediated mechanism of the GI tract initially delineated in William Castle’s investigations of pernicious anemia [3]. Hereditary selective cobalamin malabsorption is caused mainly by defects that interrupt secretion or function of intrinsic factor (IF), a protein product of gastric parietal cells in humans and pancreatic duct cells in dogs, or of cubam, the highly specific, IF-cobalamin receptor on the apical, brush-border membrane of epithelial cells in the distal small intestine [5]. Cubam selectively mediates absorption of the IF-cobalamin complex from food, and absorbed cobalamin binds transcobalamin, a plasma transport protein for delivery of the vitamin to cells [4]
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