Differential expression of the actin-binding proteins, α-actinin-2 and-3, in different species:: implications for the evolution of functional redundancy
Differential expression of the actin-binding proteins, α-actinin-2 and-3, in different species:: implications for the evolution of functional redundancy
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DOI：
10.1093/hmg/10.13.1335
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发表时间：
2001-06-15
影响因子：
3.5
通讯作者：
North, KN
中科院分区：
文献类型：
--
作者：
Mills, MA;Yang, N;North, KN
α-肌动蛋白是由四种与肌营养不良蛋白相关的肌动蛋白结合蛋白组成的多基因家族。 α-肌动蛋白的两种骨骼肌亚型（ACTN2 和 ACTN3）是 Z 线的主要结构成分，参与锚定含肌动蛋白的细丝。在人类中，ACTN2 在所有肌纤维中表达，而 ACTN3 表达仅限于 2 型纤维的子集。我们最近证明，在一系列人群中，大约 18% 的个体不存在 α -actinin-3，并且过早终止密码子 (577X) 的纯合性是大多数真正的 α -actinin-3 缺陷病例的原因。 α-肌动蛋白-3的缺失与明显的疾病表型无关，这增加了ACTN3在人类中功能冗余的可能性，并且α-肌动蛋白-2能够补偿α-肌动蛋白-3的缺陷。我们现在提供有关其他物种中 ACTN3 表达的数据。非人类灵长类动物的基因分型表明，577X 无效突变很可能出现在人类身上。小鼠基因组包含四个直系同源物，它们全部映射到四个人类基因的进化保守的同线性区域。小鼠 Actn2 和 Actn3 在胚胎发育过程中在空间和时间上有差异表达，与人类相比，α -actinin-2 表达在出生后骨骼肌中并不完全与 α -actinin-3 重叠，表明其功能独立。此外，人类、小鼠和鸡的α-辅肌动蛋白基因的序列比较表明，ACTN3在很长一段进化过程中是保守的，这意味着该基因的持续功能对进化速度造成了限制。这些观察结果提供了一个真实的框架，可以在其中测试适用于人类的遗传冗余理论模型。此外，我们强调在动物基因敲除模型中根据功能丧失突变的表型后果得出有关基因功能的结论时需要谨慎。
The alpha -actinins are a multigene family of four actin-binding proteins related to dystrophin. The two skeletal muscle isoforms of alpha -actinin (ACTN2 and ACTN3) are major structural components of the Z-line involved in anchoring the actin-containing thin filaments. In humans, ACTN2 is expressed in all muscle fibres, while ACTN3 expression is restricted to a subset of type 2 fibres. We have recently demonstrated that alpha -actinin-3 is absent in similar to 18% of individuals in a range of human populations, and that homozygosity for a premature stop codon (577X) accounts for most cases of true alpha -actinin-3 deficiency. Absence of alpha -actinin-3 is not associated with an obvious disease phenotype, raising the possibility that ACTN3 is functionally redundant in humans, and that alpha -actinin-2 is able to compensate for alpha -actinin-3 deficiency. We now present data concerning the expression of ACTN3 in other species. Genotyping of non-human primates indicates that the 577X null mutation has likely arisen in humans. The mouse genome contains four orthologues which all map to evolutionarily conserved syntenic regions for the four human genes. Murine Actn2 and Actn3 are differentially expressed, spatially and temporally, during embryonic development and, in contrast to humans, alpha -actinin-2 expression does not completely overlap alpha -actinin-3 in postnatal skeletal muscle, suggesting independent function. Furthermore, sequence comparison of human, mouse and chicken a-actinin genes demonstrates that ACTN3 has been conserved over a long period of evolutionary time, implying a constraint on evolutionary rate imposed by continued function of the gene. These observations provide a real framework in which to test theoretical models of genetic redundancy as they apply to human populations. In addition we highlight the need for caution in making conclusions about gene function from the phenotypic consequences of loss-of-function mutations in animal knockout models.