An exon 53 frameshift mutation in CUBN abrogates cubam function and causes Imerslund-Gräsbeck syndrome in dogs

John C. Fyfe, Shelby L. Hemker, Patrick J. Venta, Caitlin A. Fitzgerald, Catherine A Outerbridge, Sherry L. Myers, Urs Giger

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Cobalamin malabsorption accompanied by selective proteinuria is an autosomal recessive disorder known as Imerslund-Gräsbeck syndrome in humans and was previously described in dogs due to amnionless (AMN) mutations. The resultant vitamin B12 deficiency causes dyshematopoiesis, lethargy, failure to thrive, and life-threatening metabolic disruption in the juvenile period. We studied 3 kindreds of border collies with cobalamin malabsorption and mapped the disease locus in affected dogs to a 2.9Mb region of homozygosity on canine chromosome 2. The region included CUBN, the locus encoding cubilin, a peripheral membrane protein that in concert with AMN forms the functional intrinsic factor-cobalamin receptor expressed in ileum and a multi-ligand receptor in renal proximal tubules. Cobalamin malabsorption and proteinuria comprising CUBN ligands were demonstrated by radiolabeled cobalamin uptake studies and SDS-PAGE, respectively. CUBN mRNA and protein expression were reduced ~10 fold and ~20 fold, respectively, in both ileum and kidney of affected dogs. DNA sequencing demonstrated a single base deletion in exon 53 predicting a translational frameshift and early termination codon likely triggering nonsense mediated mRNA decay. The mutant allele segregated with the disease in the border collie kindred. The border collie disorder indicates that a CUBN mutation far C-terminal from the intrinsic factor-cobalamin binding site can abrogate receptor expression and cause Imerslund-Gräsbeck syndrome.

Original languageEnglish (US)
Pages (from-to)390-396
Number of pages7
JournalMolecular Genetics and Metabolism
Volume109
Issue number4
DOIs
StatePublished - Aug 2013
Externally publishedYes

Keywords

  • Amnionless
  • Animal model
  • Cubilin
  • Inborn error
  • Methylmalonic aciduria
  • Vitamin B

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

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