Jones J M, Huang J D, Mermall V, Hamilton B A, Mooseker M S, Escayg A, Copeland N G, Jenkins N A, Meisler M H
Department of Human Genetics, 4708 Medical Science II, University of Michigan, Ann Arbor, MI 48109-0618, USA.
Hum Mol Genet. 2000 Mar 22;9(5):821-8. doi: 10.1093/hmg/9.5.821.
Exon shuffling is thought to be an important mechanism for evolution of new genes. Here we show that the mouse neurological mutation flailer (flr) expresses a novel gene that combines the promoter and first two exons of guanine nucleotide binding protein beta 5 (Gnb5) with the C-terminal exons of the closely linked Myosin 5A (MyoVA) gene (Myo5a). The flailer protein, which is expressed predominantly in brain, contains the N-terminal 83 amino acids of Gnb5 fused in-frame with the C-terminal 711 amino acids of MyoVA, including the globular tail domain that binds organelles for intracellular transport. Biochemical and genetic studies indicate that the flailer protein competes with wild-type MyoVA in vivo, preventing the localization of smooth endoplasmic reticulum vesicles in the dendritic spines of cerebellar Purkinje cells. The flailer protein thus has a dominant-negative mechanism of action with a recessive mode of inheritance due to the dependence of competitive binding on the ratio between mutant and wild-type proteins. The chromosomal arrangement of Myo5a upstream of Gnb5 is consistent with non-homologous recombination as the mutational mechanism. To our knowledge, flailer is the first example of a mammalian mutation caused by germ line exon shuffling between unrelated genes.
外显子改组被认为是新基因进化的一种重要机制。在此我们表明，小鼠神经学突变摆臂（flr）表达一种新基因，该基因将鸟嘌呤核苷酸结合蛋白β5（Gnb5）的启动子和前两个外显子与紧密连锁的肌球蛋白5A（MyoVA）基因（Myo5a）的C端外显子结合在一起。主要在脑中表达的摆臂蛋白包含Gnb5的N端83个氨基酸，与MyoVA的C端711个氨基酸框内融合，包括结合细胞器用于细胞内运输的球状尾部结构域。生化和遗传学研究表明，摆臂蛋白在体内与野生型MyoVA竞争，阻止小脑浦肯野细胞树突棘中光滑内质网囊泡的定位。因此，由于竞争结合对突变蛋白与野生型蛋白比例的依赖性，摆臂蛋白具有显性负性作用机制和隐性遗传模式。Myo5a在Gnb5上游的染色体排列与作为突变机制的非同源重组一致。据我们所知，摆臂是由种系中外显子在不相关基因之间改组引起的哺乳动物突变的首个例子。
