OMIA 001786-9615 : Intestinal cobalamin malabsorption, CUBN-related in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s) (MIM number): 261100

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2013

Cross-species summary: Imerslund-Gräsbeck syndrome (I-GS); selective cobalamin malabsorption; megaloblastic anemia 1 (MGA1)

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. This phenotype can be caused by either mutations in the AMN or CUBN genes (locus heterogeneity).

Adapted from the corresponding entry by John Fyfe in [OMIA 000565-9615].

History: The phenotype can be caused by either mutations in the AMN gene [OMIA 000565-9615] or the CUBN gene [this entry]. He et al (2003 & 2005) mapped and identified two independent AMN mutations in Australian Shepherds and Giant Schnauzers [OMIA 000565-9615]. More recently, Owczarek-Lipska et al. (2013) identified a frameshift mutation in the CUBN gene as cause for inestinal cobalamin malabsorption in the Border Collie.

Mapping: Intestinal cobalamin malabsorption in Border Collies was mapped to CFA 2 in a genome wide association study (GWAS) using 7 cases and 7 controls. The best raw p-value in this analysis was 4.6E-6. The critical interval was defined by homozygosity mapping and spanned 3.53 Mb (Owczarek-Lipska et al. 2013).

Fyfe et al. (2013) conducted a genome scan on 19 Border Collies from families segregating for the disorder, using the Illumina 170K SNP chip. Homozygosity mapping highlighted a region on chromosome CFA2 centering on the CUBN gene.

Molecular basis: Whole genome re-sequencing of one affected Border Collie revealed 17 non-synonymous variants in the critical interval. Two of these variants were perfectly associated with intestinal cobalamin malabsorption in Border Collies. Based on the known functions of the corresponding genes the CUBN:c.8392delC frameshift variant is most likely causative for intestinal cobalamin malabsorption in Border Collies. This variant causes a premature stop codon in the open reading frame of cubilin (p.Gln2798Argfs*3) and is predicted to represent a complete loss of function allele (Owczarek-Lipska et al. 2013). CUBN and AMN form a transmembrane protein complex termed "cubam", which is essential in the uptake of cobalamin from the intestinal lumen. A defect in one of these two proteins therefore leads to intestinal cobalamin malabsorption. Other independent mutations in either the CUBN or the AMN gene very likely are responsible for this phenotype in other dog breeds.

By sequencing CUBN as a very strong positional candidate gene (see Mapping section), Fyfe et al. (2013) identified the same mutation (c.8392delC; p. Gln2798Argfs*3) in their Border Collie families.

By comparing sequence of the two candidate genes (AMN and CUBN) from the CanFam 3.1 reference genome assembly with sequence of the same two genes from the 15x whole-genome sequencing (WGS) of an affected Beagle, Drögemüller et al. (2014) identified "a single-base-pair deletion at Chr2:19,796,293 compared with the CanFam 3.1 reference genome assembly . . . . The variant lies within exon 8 of the CUBN gene and represents a frameshift mutation leading to an early premature stop codon (c.786delC). The predicted protein from the mutant allele contains <10% of the amino acids from the wild-type CUBN (p.Asp262Glufs*47). Thus, the identified variant most likely represents a complete loss-of-function allele."

Fyfe et al. (2014) reported the same c.786delC mutation in affected Beagles, as did Kook et al. (2014; J Vet Intern Med and J Small Anim Pract) in a single affected Beagle.

Fyfe et al. (2018): "Whole genome sequencing of two affected Komondor dogs of unknown relatedness and one parent and a clinically-normal littermate of an affected dog revealed a pathogenic single-base change in the CUBN intron 55 splice donor consensus sequence (NM_001003148.1: c.8746 + 1G > A) that was homozygous in affected dogs and heterozygous in the unaffected parents. Alleles of the variant co-segregated with alleles of the disease locus in the entire family and all more distantly-related sporadic cases. . . . This variant obliterates a splice donor consensus sequence in intron 55, predicting an abnormal RNA splicing pattern, and was thereby considered pathogenic. We confirmed the variant in all 6 affected Komondors by Sanger sequencing".

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).

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).

Prevalence: At the time of mutation discovery Owczarek-Lipska et al. (2013) estimated the carrier frequency of the CUBN:c.8392delC defect at 6% in a cohort of 203 European Border Collies.

Drögemüller et al. (2014) estimated the carrier frequency of the Beagle mutation (c.786delC) to be 9%.

Mizukami et al. (2016) reported the frequency of the c.8392delC allele as 0.015 in 500 Border collies in Japan.

Fyfe et al. (2018): "A population study using a simple allele-specific DNA test indicated mutant allele frequencies of 8.3 and 4.5% among North American and Hungarian Komondors, respectively."

Genetic testing: Genetic testing for the causative mutation is available. Genetic testing is recommended to confirm the clinical diagnosis in suspected cases. Genetic testing is also recommended for breeding animals to avoid the accidental mating of two carriers, which might lead to affected offspring.

Breeds: Beagle, Border Collie, Komondor.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
CUBN cubilin (intrinsic factor-cobalamin receptor) Canis lupus familiaris 2 NC_006584.3 (19784125..20041840) CUBN Homologene, Ensembl, NCBI gene

Variants

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
Beagle Intestinal cobalamin malabsorption due to CUBN mutation CUBN deletion, small (<=20) CanFam 3.1 2 g.19796293delC c.786delC p.Asp262Glufs*47 2014 24164695
Komondor Intestinal cobalamin malabsorption, CUBN-related CUBN splicing CanFam 3.1 2 g.19981457 c.8746 + 1G>A Fyfe et al. (2018): NM_001003148.1: c.8746 + 1G > A 2018 30591068
Border Collie Intestinal cobalamin malabsorption due to CUBN mutation CUBN deletion, small (<=20) CanFam3.1 2 g.19974334delC c.8392delC p.Gln2798Argfs*3 2013 23613799

References


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.
2018 Fyfe, J.C., Hemker, S.L., Frampton, A., Raj, K., Nagy, P.L., Gibbon, K.J., Giger, U. :
Inherited selective cobalamin malabsorption in Komondor dogs associated with a CUBN splice site variant. BMC Vet Res 14:418, 2018. Pubmed reference: 30591068. DOI: 10.1186/s12917-018-1752-1.
2016 Mizukami, K., Yabuki, A., Kohyama, M., Kushida, K., Rahman, M.M., Uddin, M.M., Sawa, M., Yamato, O. :
Molecular prevalence of multiple genetic disorders in Border collies in Japan and recommendations for genetic counselling. Vet J 214:21-3, 2016. Pubmed reference: 27387721. DOI: 10.1016/j.tvjl.2016.05.004.
2014 Drögemüller, M., Jagannathan, V., Howard, J., Bruggmann, R., Drögemüller, C., Ruetten, M., Leeb, T., Kook, P.H. :
A frameshift mutation in the cubilin gene (CUBN) in Beagles with Imerslund-Gräsbeck syndrome (selective cobalamin malabsorption). Anim Genet 45:148-50, 2014. Pubmed reference: 24164695. DOI: 10.1111/age.12094.
Fyfe, J.C., Hemker, S.L., Venta, P.J., Stebbing, B., Giger, U. :
Selective Intestinal Cobalamin Malabsorption with Proteinuria (Imerslund-Gräsbeck Syndrome) in Juvenile Beagles. J Vet Intern Med :, 2014. Pubmed reference: 24433284. DOI: 10.1111/jvim.12284.
Kook, P.H., Drögemüller, M., Leeb, T., Hinden, S., Ruetten, M., Howard, J. :
Hepatic fungal infection in a young beagle with unrecognised hereditary cobalamin deficiency (Imerslund-Gräsbeck syndrome). J Small Anim Pract :, 2014. Pubmed reference: 25131805. DOI: 10.1111/jsap.12251.
Kook, P.H., Drögemüller, M., Leeb, T., Howard, J., Ruetten, M. :
Degenerative Liver Disease in Young Beagles with Hereditary Cobalamin Malabsorption Because of a Mutation in the Cubilin Gene. J Vet Intern Med :, 2014. Pubmed reference: 24467303. DOI: 10.1111/jvim.12295.
2013 Fyfe, J.C., Hemker, S.L., Venta, P.J., Fitzgerald, C.A., Outerbridge, C.A., Myers, S.L., Giger, U. :
An exon 53 frameshift mutation in CUBN abrogates cubam function and causes Imerslund-Gräsbeck syndrome in dogs. Mol Genet Metab 109:390-6, 2013. Pubmed reference: 23746554. DOI: 10.1016/j.ymgme.2013.05.006.
Lutz, S., Sewell, A.C., Reusch, C.E., Kook, P.H. :
Clinical and laboratory findings in border collies with presumed hereditary juvenile cobalamin deficiency. J Am Anim Hosp Assoc 49:197-203, 2013. Pubmed reference: 23535754. DOI: 10.5326/JAAHA-MS-5867.
Owczarek-Lipska, M., Jagannathan, V., Drögemüller, C., Lutz, S., Glanemann, B., Leeb, T., Kook, P.H. :
A frameshift mutation in the cubilin gene (CUBN) in Border Collies with Imerslund-Gräsbeck syndrome (selective cobalamin malabsorption). PLoS One 8:e61144, 2013. Pubmed reference: 23613799. DOI: 10.1371/journal.pone.0061144.
2005 Battersby, IA., Giger, U., Hall, EJ. :
Hyperammonaemic encephalopathy secondary to selective cobalamin deficiency in a juvenile Border collie. J Small Anim Pract 46:339-44, 2005. Pubmed reference: 16035451.
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.
1999 Morgan, L.W., McConnell, J. :
Cobalamin deficiency associated with erythroblastic anemia and methylmalonic aciduria in a border collie Journal of the American Animal Hospital Association 35:392-395, 1999. Pubmed reference: 10493414.
1996 Giger, U., Outerbridge, C.A., Myers, S.L. :
Hereditary cobalamin deficiency in border collie dogs. Journal of Veterinary Internal Medicine 10:169, 1996.
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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