Genetic evidence of an accessory activity required specifically for cubilin brush-border expression and intrinsic factor-cobalamin absorption

Cubilin is a high molecular weight multiligand receptor that mediates intes tinal absorption of intrinsic factor-cobalamin and selective protein reabso rption in renal tubules. The genetic basis of selective intestinal cobalami n malabsorption with proteinuria was investigated in a canine model closely resembling human Imerslund-Grasbeck syndrome caused by cubilin mutations. Canine CUBN cDNA was cloned and sequenced, showing high identity with human and rat CUBN cDNAs, An intragenic CUBN marker was identified in the canine family and used to test the hypothesis of genetic linkage of the disease a nd CUBN loci. Linkage was rejected, indicating that the canine disorder res embling Imerslund-Grasbeck syndrome is caused by defect of a gene product o ther than cubilin. These results imply that there may be locus heterogeneit y among human kindreds with selective intestinal cobalamin malabsorption an d proteinuria and that normal brush-border expression of cubilin requires t he activity of an accessory protein. (C) 1999 by The American Society of He matology.