Intestinal cobalamin (Vitamin B12) malabsorption, CUBN related
(Imerslund-Grasbeck Syndrome, megaloblastic anemia)
Gene: CUBN
Transmission: Autosomal recessive
For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease. Both parents of an affected animal must be carriers of at least one copy of the mutation. Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.
Mutations:
Border Collie mutation: Deletion, CUBN gene; c.8392 del.C, p.(Q2798R fs STOP 3), exon53
Beagle mutation: Deletion, CUBN gene; c.786 del., p.(D262E fs STOP 47), exon8
Komondor mutation: Substitution (splicing error), CUBN gene; c.8746+1 G>A
Medical systems: Metabolism, blood, digestive
Breeds: American Staffordshire Terrier/Amstaff, Australian Cattle Dog, Australian Shepherd, Beagle, Border Collie, German Shepherd, Komondor, Koolie, Miniature American Shepherd
Age of onset of symptoms: From 6 to 12 weeks.
Cobalamin malabsorption (also known as Imerslund-Grasbeck syndrome) is a genetic disorder caused by a defect in a cell membrane receptor in the intestines involved in vitamin B12 absorption. The receptor is made up of two subunits, one coded for by the Cubilin (CUBN) gene, the other coded for by the Amnionless (AMN) gene. Vitamin B12 plays an important role in metabolism, ensuring many normal functions of the brain and nervous system as well as the formation of red blood cells. However, vitamin B12 cannot be synthesized by the animal and must be absorbed from the diet. Early symptoms are difficult to diagnose, but include increased protein levels in the urine, anemia, weakness, poor growth and anorexia. More severe symptoms can include seizures, coma and death. Dogs receiving cobalamin supplementation can live normal lives for the most part.
Cobalamin malabsorption in the dog can be cause by genetic defects in either of the Cubilin (CUBN) or the AMN genes, and for both genes, by more than one mutation. The CUBN gene mutation tends to have a wider breed distribution than the AMN gene mutation.
References:
OMIA link: [1786-9615]
Donner J, Freyer J, Davison S, et al. (2023) Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs. PLoS Genet. 19(2):e1010651. [pubmed/36848397]
Kather S, Grützner N, Kook PH, et al. (2020) Review of cobalamin status and disorders of cobalamin metabolism in dogs. J Vet Intern Med. 34(1):13-28. [pubmed/31758868]
Kook PH, Hersberger M. (2019) Daily oral cyanocobalamin supplementation in Beagles with hereditary cobalamin malabsorption (Imerslund-Gräsbeck syndrome) maintains normal clinical and cellular cobalamin status. J Vet Intern Med. 33(2):751-757. [pubmed/30554416]
Stanley E, Appleman E, Schlag A, Siegel A. (2019) Relationship between cobalamin and folate deficiencies and anemia in dogs. J Vet Intern Med. 2019 Jan;33(1):106-113. [pubmed/30499147]
Fyfe JC, Hemker SL, Frampton A, et al. (2018) Inherited selective cobalamin malabsorption in Komondor dogs associated with a CUBN splice site variant. BMC Vet Res 14:41. [pubmed/30591068]
Mizukami K, Yabuki A, Kohyama M, et al. (2016) Molecular prevalence of multiple genetic disorders in Border collies in Japan and recommendations for genetic counselling. Vet J. 214:21-23. [pubmed/27387721]
Gold AJ, Scott MA, Fyfe JC. (2015) Failure to thrive and life-threatening complications due to inherited selective cobalamin malabsorption effectively managed in a juvenile Australian shepherd dog. Can Vet J. 56(10):1029-34. [pubmed/26483576]
Fyfe JC, Hemker SL, Venta PJ, et al. (2013) An exon 53 frameshift mutation in SUBN abrogates cubam function and causes Imerslaund-Grasbeck syndrome in dogs. Molecular Genetics and Metabolism 109:390-396. [pubmed/23746554]
Owczarek-Lipska M, Jagannathan V, Drögemüller C, et al. (2013) A frameshift mutation in the cubilin gene (CUBN) in Border Collies with Imerslund-Gräsbeck syndrome (selective cobalamin malabsorption). PloS One 8(4):e61144. [pubmed/23613799]
Contributed by: Laurence Danvoye and Janessa Savaria, class of 2027, Veterinary Medicine Faculty, University of Montreal. (Translation: DWS).