Intestinal Cobalamin Malabsorption (CUBN gene, Beagle)

Intestinal cobalamin malabsorption (ICM) is a metabolic disorder that hinders the proper absorption of vitamin B12 (cobalamin) in the intestine. This disorder can be caused by a defect in the CUBN protein, which is involved in the uptake of cobalamin from the intestinal lumen.

Symptoms

Signs of the disease usually appear in dogs between 6 and 12 weeks of age, including failure to thrive and chronic appetite. Dogs also experience diarrhea, lack of energy and drowsiness, altered mental status and lack of motivation to exercise or play.

Disease Management

Therapy to treat intestinal cobalamin malabsorption involves regular administration of cobalamin, either orally or parenterally, depending on the severity of the disease. In addition, it is essential to follow an adequate diet that is rich in high quality protein, low in fiber and with moderate levels of fat, to improve digestibility and nutrient absorption.

Genetic basis

This disease follows an autosomal recessive mode of inheritance. Autosomal recessive inheritance means that the dog, regardless of sex, must receive two copies of the mutation or pathogenic variant to be at risk of developing the disease. Both parents of an affected dog must carry at least one copy of the mutation. Animals with only one copy of the mutation are not at increased risk of developing the disease, but may pass the mutation on to future generations. Breeding between dogs carrying genetic variants that can cause disease, even if they do not show symptoms, is not recommended.

Technical report

The CUBN and AMN genes encode proteins that form a transmembrane protein complex essential for cobalamin uptake in the intestine. A mutation affecting the CUBN gene and the protein encoded by it has been identified. MIC in Beagles is caused by a deletion (c.786del) in the CUBN gene, resulting in a protein with less than 10% of the amino acids present in the wild-type protein. Consequently, it is likely to be a loss-of-function allele. In contrast, in Border Collies, a different causal variant is described that also consists of a single nucleotide deletion (c.8392delC). In the study by Sancho et al. (2020), a crossbred dog was identified that had compound heterozygosity, i.e. one copy of the variant discovered in Border Collies and another copy of the one discovered in Beagles. The effect of heterozygosity, at the clinical level, was very similar to that obtained in homozygosity for either variant.

Most affected breeds

  • Beagle
  • Border Collie
  • Komondor

Bibliography

Drögemüller M, Jagannathan V, Howard J,et al. A frameshift mutation in the cubilin gene (CUBN) in Beagles with Imerslund-Gräsbeck syndrome (selective cobalamin malabsorption). Anim Genet. 2014 Feb;45(1):148-50.

Erles K, Mugford A, Barfield D,et al. Systemic Scedosporium prolificans infection in an 11-month-old Border collie with cobalamin deficiency secondary to selective cobalamin malabsorption (canine Imerslund-Gräsbeck syndrome). J Small Anim Pract. 2018 Apr;59(4):253-256.

Owczarek-Lipska M, Jagannathan V, Drögemüller C,et al. A frameshift mutation in the cubilin gene (CUBN) in Border Collies with Imerslund-Gräsbeck syndrome (selective cobalamin malabsorption). PLoS One. 2013 Apr 16;8(4):e61144.

Sancho IM, Holmes A, Adamantos S. Imerslund-Grasbeck syndrome in a cross-breed dog. J Small Anim Pract. 2021 Aug;62(8):709-711.

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