OMIA 000565-9615 : Intestinal cobalamin malabsorption, AMN-related in Canis lupus familiaris
Entry edited by John C. Fyfe, D.V.M., Ph. D.
Intestinal cobalamin malabsorption can be caused by mutations in the AMN gene (this entry) or by mutations in the CUBN gene [OMIA 001786-9615].Inheritance: Autosomal recessive Mapping: Using a whole-genome scan with microsatellite markers in a pedigree of 88 dogs of known disorder phenotype, He et al. (2003) mapped this disorder to a 4Mb interval on chromosome CFA8. The authors noted that this region of CFA8 has conserved synteny with the region of chromosome HSA14q that harbours a very strong comparative candidate gene, namely AMN (amnionless), mutations in which cause the same clinical disorder in humans. Molecular basis: By adopting a comparative positional cloning approach, having established AMN as a very strong comparative positional candidate gene (see Mapping section above), He et al. (2005) showed that the causative mutation in Giant Schnauzers is an "in-frame deletion of 33 nucleotides in exon 10 of AMN . . . [namely] c.1113_1145del"; the causative mutation in Australian shepherds is "a G>A transition at position 3 of the cDNA sequence [of AMN] (c.3G>A), thereby disrupting the Kozak consensus sequence for translation initiation". Clinical features: Signs begin around 6 to 12 weeks of age, and include failure to thrive and chronic inappetance. Affected animals also demonstrate neutropenia with hypersegmentation, nonregenerative anemia with anisocytosis and poikilocytosis, megaloblastic changes of the bone marrow, decreased serum Cbl concentrations, methylmalonic aciduria, and homocysteinemia. These animals have normal renal function, but low-molecular weight urinary protein excretion (Fyfe et al., 1991). Pathology: In normal dogs, Cbl is ingested in the diet and binds to intrinsic factor, a glycoprotein made by the gastric mucosa and the pancreatic duct epithelium. The complex of intrinsic factor (IF) and Cbl is absorbed through binding receptors on enterocytes in the distal jejunum and ileum. Signs of intestinal cobalamin malabsorption are due to absence of receptors for the IF-Cbl complex at the brush border (Fyfe et al., 1991).
Affected dogs have one of two demonstrated mutations in the gene coding for amnionless, a protein that complexes with cubilin to ensure apical membrane localization of IF-Cbl receptors in enterocytes. It also regulates endocytic functions. Without functional amnionless, the IF-Cbl receptors do not localize to the brush-border, and dogs cannot absorb cobalamin (Fyfe et al., 2003).
Dogs are born with cobalamin stores, but they are rapidly used up during postnatal growth unless replaced from the diet. This is when signs become apparent (Fyfe et al., 1991).Control: Parents and siblings of affected dogs should be tested. Breeding of affected is not recommended. Carriers should only be bred to tested dogs that are not carriers. Genetic testing: A DNA test for the disorder is included in the OFA's list at http://www.offa.org/dna_alltest.html, which directs enquiries to PennGen at the University of Pennsylvania (http://research.vet.upenn.edu/Default.aspx?alias=research.vet.upenn.edu/penngen). Breeds: Australian Shepherd, Giant Schnauzer, Hungarian komondor. Associated gene:
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|AMN||amnion associated transmembrane protein||Canis lupus familiaris||8||NC_006590.3 (70800435..70807835)||AMN||Homologene, Ensembl, NCBI gene|
By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.
WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
|Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Year Published||PubMed ID(s)||Acknowledgements|
|Giant Schnauzer||Intestinal cobalamin malabsorption, AMN-related||AMN||deletion, gross (>20)||c.1113_1145del||2005||15845892|
|Australian Shepherd||Intestinal cobalamin malabsorption, AMN-related||AMN||regulatory||8||c.3G>A||2005||15845892|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2015||Gold, A.J., Scott, M.A., Fyfe, J.C. :|
|Failure to thrive and life-threatening complications due to inherited selective cobalamin malabsorption effectively managed in a juvenile Australian shepherd dog. Can Vet J 56:1029-34, 2015. Pubmed reference: 26483576.|
|2005||He, Q., Madsen, M., Kilkenney, A., Gregory, B., Christensen, E.I., Vorum, H., Højrup, P., Schäffer, A.A., Kirkness, E.F., Tanner, S.M., de la Chapelle, A., Giger, U., Moestrup, S.K., Fyfe, J.C. :|
|Amnionless function is required for cubilin brush-border expression and intrinsic factor-cobalamin (vitamin B12) absorption in vivo. Blood 106:1447-53, 2005. Pubmed reference: 15845892. DOI: 10.1182/blood-2005-03-1197.|
|2004||Fyfe, J.C., Madsen, M., Højrup, P., Christensen, E.I., Tanner, S.M., de la Chapelle, A., He, Q., Moestrup, S.K. :|
|The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. Blood 103:1573-9, 2004. Pubmed reference: 14576052. DOI: 10.1182/blood-2003-08-2852.|
|2003||He, Q., Fyfe, JC., Schaffer, AA., Kilkenney, A., Werner, P., Kirkness, EF., Henthorn, PS. :|
|Canine Imerslund-Grasbeck syndrome maps to a region orthologous to HSA14q. Mamm Genome 14:758-64, 2003. Pubmed reference: 14722725. DOI: 10.1007/s00335-003-2280-1.|
|2000||Fordyce, H.H., Callan, M.B., Giger, U. :|
|Persistent cobalamin deficiency causing failure to thrive in a juvenile beagle Journal of Small Animal Practice 41:407-410, 2000. Pubmed reference: 11023127.|
|1991||Batt, RM., Horadagoda, NU., Simpson, KW. :|
|Role of the pancreas in the absorption and malabsorption of cobalamin (vitamin B-12) in dogs. J Nutr 121:S75-6, 1991. Pubmed reference: 1941244.|
|Fyfe, J.C., Giger, U., Hall, C.A., Jezyk, P.F., Klumpp, S.A., Levine, J.S., Patterson, D.F. :|
|Inherited Selective Intestinal Cobalamin Malabsorption and Cobalamin Deficiency in Dogs Pediatric Research 29:24-31, 1991. Pubmed reference: 1848001.|
|Fyfe, J.C., Ramanujam, K.S., Ramaswamy, K., Patterson, D.F., Seetharam, B. :|
|Defective Brush-Border Expression of Intrinsic Factor- Cobalamin Receptor in Canine Inherited Intestinal Cobalamin Malabsorption Journal of Biological Chemistry 266:4489-4494, 1991. Pubmed reference: 1999430.|
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