A Frameshift Mutation in the Cubilin Gene (CUBN) in Border Collies with Imerslund-Gräsbeck Syndrome (Selective Cobalamin Malabsorption)

Abstract

Imerslund-Gräsbeck syndrome (IGS) or selective cobalamin malabsorption has been described in humans and dogs. IGS occurs in Border Collies and is inherited as a monogenic autosomal recessive trait in this breed. Using 7 IGS cases and 7 non-affected controls we mapped the causative mutation by genome-wide association and homozygosity mapping to a 3.53 Mb interval on chromosome 2. We re-sequenced the genome of one affected dog at ∼10× coverage and detected 17 non-synonymous variants in the critical interval. Two of these non-synonymous variants were in the cubilin gene (CUBN), which is known to play an essential role in cobalamin uptake from the ileum. We tested these two CUBN variants for association with IGS in larger cohorts of dogs and found that only one of them was perfectly associated with the phenotype. This variant, a single base pair deletion (c.8392delC), is predicted to cause a frameshift and premature stop codon in the CUBN gene. The resulting mutant open reading frame is 821 codons shorter than the wildtype open reading frame (p.Q2798Rfs*3). Interestingly, we observed an additional nonsense mutation in the MRC1 gene encoding the mannose receptor, C type 1, which was in perfect linkage disequilibrium with the CUBN frameshift mutation. Based on our genetic data and the known role of CUBN for cobalamin uptake we conclude that the identified CUBN frameshift mutation is most likely causative for IGS in Border Collies.

Insights into Morphology and Disease from the Dog Genome Project

“…However, it works against fine-mapping efforts, as many marker alleles cosegregate with the causal variant. Fortunately, as the costs of conducting whole-genome sequencing (WGS) decrease, platform performance improves, and the tools needed to reliably call variants are refined, fine mapping to identify the causal genetic underpinnings of traits and diseases is becoming less laborious (Frischknecht et al 2013, Karlsson et al 2013, Owczarek-Lipska et al 2013a, Schoenebeck et al 2012). …”

Degenerative Liver Disease in Young Beagles with Hereditary Cobalamin Malabsorption Because of a Mutation in the Cubilin Gene

“…Analogous to the recent identification of the causative mutation in cobalamin‐deficient border collies,9 a whole genome resequencing approach was used in the described beagles. Stored blood samples (EDTA) from case 1 and a paraffin‐embedded formalin‐fixed liver sample from case 2 were used to isolate genomic DNA.…”

“…In dogs, primary cobalamin malabsorption, which is analogous to IGS in humans, has been reported in young Australian Shepherds,3 a Beagle,4 Border Collies,5, 6, 7 and Giant Schnauzers 8. The genetic defects in affected Border Collies and Beagles recently have been identified as 2 independent mutations in the CUBN gene 9, 10. Similar to human patients, dogs typically present at a young age with inappetence, weakness, and failure to thrive 4, 5, 6, 8, 11.…”

Hepatic fungal infection in a young beagle with unrecognised hereditary cobalamin deficiency (Imerslund‐Gräsbeck syndrome)

“…Genotyping performed on this sample using a previously described method (Owczarek‐Lipska et al . ) revealed that the dog carried the CUBN:c.786delC mutation in a homozygous state, confirming hereditary cobalamin deficiency (Drögemüller et al . ).…”

“…, Owczarek‐Lipska et al . ). Similar to humans, dogs typically present at a young age with inappetence, weakness and failure to thrive.…”