Categories: Haematopoietic system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 618882 (trait) , 605799 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2005

Cross-species summary: Imerslund-Gräsbeck syndrome (IGS2); megaloblastic anemia, Norwegian type

Species-specific description: Intestinal cobalamin malabsorption is a metabolic disorder characterized by failure to thrive, neutropenia, decreased serum cobalamin (Cbl), and nonregenerative anemia. Other signs include chronic inappetance, megaloblastic changes of the bone marrow, methylmalonic aciduria, and homocysteinemia. It occurs in the giant schnauzer, Australian shepherd, border collie, Hungarian komondor, and beagle. In giant schnauzers and Australian shepherds intestinal cobalamin malabsorption is due to absence of receptors for the intrinsic factor-Cbl complex at the brush border of enterocytes in the ileum. A specific defect has not yet been demonstrated in other breeds. The mode of inheritance is autosomal recessive. The two known causative mutations are a deletion in AMN in the giant schnauzer, and a nucleotide substitution in AMN in the Australian shepherd. Tests are available to detect the known causative mutations. Parents and siblings of affected dogs should be tested. Breeding of affected dogs is not recommended. Carriers should be bred only to clinically normal dogs demonstrated to be non carriers. 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 (Dog) (VBO_0200095), Giant Schnauzer (Dog) (VBO_0200604), Komondor (Dog) (VBO_0200779).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: