Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East.
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.
Tanner
Stephan M
SM
Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Li
Zhongyuan
Z
Bisson
Ryan
R
Acar
Ceren
C
Oner
Cihan
C
Oner
Reyhan
R
Cetin
Mualla
M
Abdelaal
Mohamed A
MA
Ismail
Essam A
EA
Lissens
Willy
W
Krahe
Ralf
R
Broch
Harald
H
Gräsbeck
Ralph
R
de la Chapelle
Albert
A
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*
C484714:AMN protein, human; D008565:Membrane Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor