Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia
Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia
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DOI：
10.1038/ng1098
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发表时间：
2003-03-01
期刊：
影响因子：
30.8
通讯作者：
de la Chapelle, A
中科院分区：
文献类型：
--
作者：
Tanner, SM;Aminoff, M;de la Chapelle, A
小鼠12号染色体上的无羊膜基因Amn编码一种I型跨膜蛋白，该蛋白在原肠胚形成期间在胚胎外内脏层表达(1)。与转基因插入产生的羊膜突变相关的纯合小鼠没有羊膜（2,3）。胚胎严重受损，存活到妊娠第10天，但似乎缺乏通常产生躯干的中胚层(4)。Amn蛋白有一个跨膜结构域，将较大的n端胞外区域和较小的c端胞质区域分开。细胞外区域含有一个富含半胱氨酸的区域，类似于非洲爪蟾胚胎中的Chordin和黑腹果蝇胚胎中的Sog。由于这些富含半胱氨酸的结构域与骨形态发生蛋白（Bmps）结合，因此推测Amn中富含半胱氨酸的结构域也与Bmps结合(4)。我们发现影响人类AMN外显子1-4的纯合突变导致维生素B-12的选择性吸收不良（一种与巨幼细胞性贫血相关的表型1，MGA1; OMIM 261100；参考文献）。这表明AMN的5'端对于胚胎发育是必不可少的，但对于维生素B-12的吸收却是必需的。当AMN的5端被突变截断时，从下游的起始密码子开始翻译。
The amnionless gene, Amn, on mouse chromosome 12 encodes a type I transmembrane protein that is expressed in the extraembryonic visceral layer during gastrulation(1). Mice homozygous with respect to the amn mutation generated by a transgene insertion have no amnion(2,3). The embryos are severely compromised, surviving to the tenth day of gestation but seem to lack the mesodermal layers that normally produce the trunk(4). 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(4). We show that homozygous mutations affecting exons 1-4 of human AMN lead to selective malabsorption of vitamin B-12 (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 B-12. When the 5 end of AMN is truncated by mutations, translation is initiated from alternative downstream start codons.