Mutations in CUBN, encoding the intrinsic factor-vitamin B-12 receptor, cubilin, cause hereditary megaloblastic anaemia 1

Megaloblastic anaemia 1 (MGA1, OMIM 261100) is a rare, autosomal recessive disorder characterized by juvenile megaloblastic: anaemia, as well as neuro logical symptoms that may be the only manifestations(1,2). At the cellular level, MGA1 is characterized by selective intestinal vitamin B-12 (B-12, co balamin) malabsorption-2. MGA1 occurs worldwide, but its prevalence is high er in several Middle Eastern countries(3-6) and Norway(1,7), and highest in Finlands (0.8/100,000). We previously mapped the MGA1 locus by linkage ana lysis in Finnish and Norwegian families to a 6-cM region on chromosome 10p1 2.1 (ref. 8). A functional candidate gene encoding the intrinsic factor (IF )-B-12 receptor, cubilin, was recently cloned(9,10); the human homologue, C UBN, was mapped to the same region(10). We have now refined the MGA1 region by linkage disequilibrium (LD) mapping, fine-mapped CUBN and identified tw o independent disease-specific CUBN mutations in 17 Finnish MGA1 families. Our genetic and molecular data indicate that mutations in CUBN cause MGA1.