METAXIN, A GENE CONTIGUOUS TO BOTH THROMBOSPONDIN-3 AND GLUCOCEREBROSIDASE, IS REQUIRED FOR EMBRYONIC-DEVELOPMENT IN THE MOUSE - IMPLICATIONS FOR GAUCHER-DISEASE
METAXIN, A GENE CONTIGUOUS TO BOTH THROMBOSPONDIN-3 AND GLUCOCEREBROSIDASE, IS REQUIRED FOR EMBRYONIC-DEVELOPMENT IN THE MOUSE - IMPLICATIONS FOR GAUCHER-DISEASE
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DOI：
10.1073/pnas.92.10.4547
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发表时间：
1995-05-09
影响因子：
11.1
通讯作者：
GINNS, EI
中科院分区：
文献类型：
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作者：
BORNSTEIN, P;MCKINNEY, CE;GINNS, EI
我们已经确定了一个小鼠基因，metaxin，跨越6 kb的间隔分离的葡萄糖脑苷脂酶基因（GC）的血小板反应蛋白3基因的染色体3E 3-F1。Metaxin和GC的转录收敛，其主要的聚腺苷酸化位点只有431 bp的距离。另一方面，metaxin和血小板反应蛋白3基因转录分歧，并共享一个共同的启动子序列。metaxin的cDNA编码317个氨基酸的蛋白质，没有信号序列或N-连接的糖基化的共识。Metaxin蛋白在年轻成年小鼠的组织中广泛表达，但在DNA或蛋白质数据库中没有发现密切的同源物。通过胚胎干细胞中的同源重组将靶向突变（外显子9中的A -> G）引入GC以建立轻度形式的戈谢病的小鼠模型。磷酸甘油酸激酶-新霉素基因盒也被插入GC的3 '侧翼区域作为选择标记，在后来被鉴定为metaxin的末端外显子的位点。对于联合突变纯合子的小鼠在妊娠早期死亡。由于人类相同的氨基酸突变与轻度1型戈谢病相关，我们认为metaxin蛋白可能是小鼠胚胎发育所必需的。显然，该位点的连续基因组织限制了戈谢病小鼠模型生产的靶向策略。
We have identified a murine gene, metaxin, that spans the 6-kb interval separating the glucocerebrosidase gene (GC) from the thrombospondin 3 gene on chromosome 3E3-F1. Metaxin and GC are transcribed convergently; their major polyadenylylation sites are only 431 bp apart. On the other hand, metaxin and the thrombospondin 3 gene are transcribed divergently and share a common promoter sequence. The cDNA for metaxin encodes a 317-aa protein, without either a signal sequence or consensus for N-linked glycosylation. Metaxin protein is expressed ubiquitously in tissues of the young adult mouse, but no close homologues have been found in the DNA or protein data bases. A targeted mutation (A --> G in exon 9) was introduced into GC by homologous recombination in embryonic stem cells to establish a mouse model for a mild form of Gaucher disease. A phosphoglycerate kinase-neomycin gene cassette was also inserted into the 3'-flanking region of GC as a selectable marker, at a site later identified as the terminal exon of metaxin. Mice homozygous for the combined mutations die early in gestation. Since the same amino acid mutation in humans is associated with mild type 1 Gaucher disease, we suggest that metaxin protein is likely to be essential for embryonic development in mice, Clearly, the contiguous gene organization at this locus limits targeting strategies for the production of murine models of Gaucher disease.