Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia.
The amnionless gene, Amn, on mouse chromosome 12 encodes a type I transmembrane protein that is expressed in the extraembryonic visceral layer during gastrulation. Mice homozygous with respect to the amn mutation generated by a transgene insertion have no amnion. The embryos are severely compromised, surviving to the tenth day of gestation but seem to lack the mesodermal layers that normally produce the trunk. The Amn protein has one transmembrane domain separating a larger, N-terminal extracellular region and a smaller, C-terminal cytoplasmic region. The extracellular region harbors a cysteine-rich domain resembling those occurring in Chordin, found in Xenopus laevis embryos, and Sog, found in Drosophila melanogaster. As these cysteine-rich domains bind bone morphogenetic proteins (Bmps), it has been speculated that the cysteine-rich domain in Amn also binds Bmps. We show that homozygous mutations affecting exons 1-4 of human AMN lead to selective malabsorption of vitamin B12 (a phenotype associated with megaloblastic anemia 1, MGA1; OMIM 261100; refs. 5,6) in otherwise normal individuals, suggesting that the 5' end of AMN is dispensable for embryonic development but necessary for absorption of vitamin B12. When the 5' end of AMN is truncated by mutations, translation is initiated from alternative downstream start codons.
Tanner
Stephan M
SM
Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Aminoff
Maria
M
Wright
Fred A
FA
Liyanarachchi
Sandya
S
Kuronen
Mervi
M
Saarinen
Anne
A
Massika
Orit
O
Mandel
Hanna
H
Broch
Harald
H
de la Chapelle
Albert
A
D000650:Amnion / Q000002:abnormalities; D000749:Anemia, Megaloblastic / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005775:Gastrula; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree
C424167:Amn protein, mouse; D008565:Membrane Proteins; D004247:DNA