title: Luminal expression of cubilin is impaired in Imerslund-Grasbeck syndrome with compound AMN mutations in intron 3 and exon 7.
abstract: Juvenile megaloblastic anaemia 1 (OMIM # 261100) is a rare autosomic disorder characterized by selective cobalamin mal-absorption and inconstant proteinuria produced by mutations in either CUBN or AMN genes. Amnionless, the gene product of AMN, is a transmembrane protein that binds tightly to the N-terminal end of cubilin, the gene product of CUBN. Cubilin binds to intrinsic factor-cobalamin complex and is expressed in the distal intestine and the proximal renal tubule. We report a compound AMN heterozygosity with c.742C>T, p.Gln248X and c.208-2A>G mutations in 2 siblings that led to premature termination codon in exon 7 and exon 6, respectively. It produced a dramatic decrease in receptor activity in urine, despite absence of CUBN mutation and normal affinity of the receptor for intrinsic factor binding. Heterozygous carriers for c.742T and c.208-2G had no pathological signs. These results indicate that amnionless is essential for the correct luminal expression of cubilin in humans.
authors.affiliation: Faculté de Médecine, INSERM U954 Nutrition, Genetics, and Environmental Risk Exposure, Vandoeuvre Les Nancy, France. b.namour@chu-nancy.fr
authors.forename: Fares
authors.initials: F
authors.lastname: Namour
authors.forename: Gabriele
authors.initials: G
authors.lastname: Dobrovoljski
authors.forename: Celine
authors.initials: C
authors.lastname: Chery
authors.forename: Sandra
authors.initials: S
authors.lastname: Audonnet
authors.forename: François
authors.initials: F
authors.lastname: Feillet
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Gueant
mesh_terms: D000293:Adolescent; D000328:Adult; D000749:Anemia, Megaloblastic; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D005091:Exons / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics*; D008286:Malabsorption Syndromes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D035781:Siblings; D014806:Vitamin B 12 Deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: C484714:AMN protein, human; D018389:Codon, Nonsense; D008565:Membrane Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor