title: Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene.
abstract: Hereditary juvenile megaloblastic anemia due to vitamin B12 (cobalamin) deficiency is caused by intestinal malabsorption of cobalamin. In Imerslund-Grasbeck syndrome (IGS), cobalamin absorption is completely abolished and not corrected by the administration of intrinsic factor (IF); if untreated, the disease is fatal. Biallelic mutations either in the cubilin (CUBN) or amnionless (AMN) gene cause IGS. In a series of families clinically diagnosed with likely IGS, at least six displayed no evidence of mutations in CUBN or AMN. A genome-wide search for linkage followed by mutational analysis of candidate genes was performed in five of these families. A region in chromosome 11 showed evidence of linkage in four families. The gastric IF (GIF) gene located in this region harbored homozygous nonsense and missense mutations in these four families and in three additional families. The disease in these cases therefore should be classified as hereditary IF deficiency. Clinically, these patients resembled those with typical IGS; radiocobalamin absorption tests had been inconclusive regarding the nature of the defect. In the diagnosis of juvenile cobalamin deficiency, mutational analysis of the CUBN, AMN, and GIF genes provides a molecular characterization of the underlying defect and may be the diagnostic method of choice.
authors.affiliation: Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Tanner
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Li
authors.forename: James D
authors.initials: JD
authors.lastname: Perko
authors.forename: Cihan
authors.initials: C
authors.lastname: Oner
authors.forename: Mualla
authors.initials: M
authors.lastname: Cetin
authors.forename: Cigdem
authors.initials: C
authors.lastname: Altay
authors.forename: Zekiye
authors.initials: Z
authors.lastname: Yurtsever
authors.forename: Karen L
authors.initials: KL
authors.lastname: David
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.forename: Essam A
authors.initials: EA
authors.lastname: Ismail
authors.forename: Ralph
authors.initials: R
authors.lastname: Gräsbeck
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D005260:Female; D006801:Humans; D007437:Intrinsic Factor / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D010375:Pedigree; D014805:Vitamin B 12 / Q000378:metabolism*; D014806:Vitamin B 12 Deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D007437:Intrinsic Factor; D014805:Vitamin B 12
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