A frameshift mutation in the cubilin gene (CUBN) in Beagles with Imerslund–Gräsbeck syndrome (selective cobalamin malabsorption). (27th October 2013)

• Record Type: Journal Article
• Authors: Drögemüller, Michaela; Jagannathan, Vidhya; Howard, Judith; Bruggmann, Rémy; Drögemüller, Cord; Ruetten, Maja; Leeb, Tosso; Kook, Peter H.
• Is Part Of: Animal genetics. Volume 45:Number 1(2014:Feb.)
• Page Start: 148
• Page End: 150
• Publication Date: 2013-10-27
• Subjects: Animal genetics -- Periodicals; 572.8
• DOI: 10.1111/age.12094
• Languages: English
• ISSNs: 0268-9146

Abstract

<abstract abstract-type="main" id="age12094-abs-0001"> <title>Summary</title> <p>Mammals are unable to synthesize cobalamin or vitamin B<sub>12</sub> and rely on the uptake of dietary cobalamin. The cubam receptor expressed on the intestinal endothelium is required for the uptake of cobalamin from the gut. Cubam is composed of two protein subunits, amnionless and cubilin, which are encoded by the <italic>AMN</italic> and <italic>CUBN</italic> genes respectively. Loss‐of‐function mutations in either the <italic>AMN</italic> or the <italic>CUBN</italic> gene lead to hereditary selective cobalamin malabsorption or Imerslund–Gräsbeck syndrome (IGS). We investigated Beagles with IGS and resequenced the whole genome of one affected Beagle at 15× coverage. The analysis of the <italic>AMN</italic> and <italic>CUBN</italic> candidate genes revealed a homozygous deletion of a single cytosine in exon 8 of the <italic>CUBN</italic> gene (c.786delC). This deletion leads to a frameshift and early premature stop codon (p.Asp262Glufs*47) and is, thus, predicted to represent a complete loss‐of‐function allele. We tested three IGS‐affected and 89 control Beagles and found perfect association between the IGS phenotype and the <italic>CUBN:c.786delC</italic> variant. Given the known role of cubilin in cobalamin transport, which has been firmly established in humans and dogs, our data strongly suggest that the <italic>CUBN:c.786delC</italic> variant is causing IGS in the investigated Beagles.</p> </abstract>