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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. [Copyright &y& Elsevier]

Imerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder clinically characterized by megaloblastic anemia, benign mild proteinuria, and other nonspecific symptoms. Several pathogenetic variants in the amnionless (AMN) or cubilin (CUBN) genes have been described in IGS. We describe a case of IGS with urinary tract infection and mild but persistent proteinuria at onset in an 11-month-old female child. With the appearance of macrocytic anemia, aphthous stomatitis, and neurological signs, IGS was clinically suspected, and vitamin B12 parenteral therapy was started. Sequence analysis showed the presence of a novel intronic variant c.513+5G>A of AMN, never before described in the literature, that was in compound heterozygosity with the known pathogenetic variant c.1006+34_1007-31del. Analysis extension to the parents revealed the presence of variant c.1006+34_1007-31 in the father and c.513+5G>A in the mother. In the present case with IGS, the novel intronic variant of AMN was identified in "trans" with a known pathogenic variant (c.1006-31 del) and the new variant was interpreted to be pathogenetic since it was not found in the public database of polymorphisms and because it was predicted to alter a donor splicing site. Our case underlines the relevance in detecting certain subtle symptoms, such as mild but persistent proteinuria associated with megaloblastic anemia, to reach a correct diagnosis of a rare but treatable disorder. [ABSTRACT FROM AUTHOR]