title: Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East.
abstract: Selective intestinal malabsorption of vitamin B(12) causing juvenile megaloblastic anemia (MGA; MIM# 261100) is a recessively inherited disorder that is believed to be rare except for notable clusters of cases in Finland, Norway, and the Eastern Mediterranean region. The disease can be caused by mutations in either the cubilin (CUBN; MGA1; MIM# 602997) or the amnionless (AMN; MIM# 605799) gene. To explain the peculiar geographical distribution, we hypothesized that mutations in one of the genes would mainly be responsible for the disease in Scandinavia, and mutations in the other gene in the Mediterranean region. We studied 42 sibships and found all cases in Finland to be due to CUBN (three different mutations) and all cases in Norway to be due to AMN (two different mutations), while in Turkey, Israel, and Saudi Arabia, there were two different AMN mutations and three different CUBN mutations. Haplotype evidence excluded both CUBN and AMN conclusively in five families and tentatively in three families, suggesting the presence of at least one more gene locus that can cause MGA. We conclude that the Scandinavian cases are typical examples of enrichment by founder effects, while in the Mediterranean region high degrees of consanguinity expose rare mutations in both genes. We suggest that in both regions, physician awareness of this disease causes it to be more readily diagnosed than elsewhere; thus, it may well be more common worldwide than previously thought.
authors.affiliation: Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Tanner
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Li
authors.forename: Ryan
authors.initials: R
authors.lastname: Bisson
authors.forename: Ceren
authors.initials: C
authors.lastname: Acar
authors.forename: Cihan
authors.initials: C
authors.lastname: Oner
authors.forename: Reyhan
authors.initials: R
authors.lastname: Oner
authors.forename: Mualla
authors.initials: M
authors.lastname: Cetin
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Abdelaal
authors.forename: Essam A
authors.initials: EA
authors.lastname: Ismail
authors.forename: Willy
authors.initials: W
authors.lastname: Lissens
authors.forename: Ralf
authors.initials: R
authors.lastname: Krahe
authors.forename: Harald
authors.initials: H
authors.lastname: Broch
authors.forename: Ralph
authors.initials: R
authors.lastname: Gräsbeck
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D000749:Anemia, Megaloblastic / Q000235:genetics*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D006239:Haplotypes; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008565:Membrane Proteins; D008877:Middle East; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D012537:Scandinavian and Nordic Countries; D014806:Vitamin B 12 Deficiency / Q000175:diagnosis / Q000235:genetics*
chemical_list: C484714:AMN protein, human; D008565:Membrane Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor