Genetically altered animal models for ATP1A3-related disorders.
Genetically altered animal models for ATP1A3-related disorders.
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DOI：
10.1242/dmm.048938
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发表时间：
2021-10-01
影响因子：
4.3
通讯作者：
Clapcote SJ
中科院分区：
文献类型：
--
作者：
Ng HWY;Ogbeta JA;Clapcote SJ
在过去的20年里，特别是随着外显子组测序技术的出现，编码Na+，K+-ATP酶（NKA α3）泵的神经元特异性α3亚基（ATP 1A 3）的基因中的常染色体显性和新生突变已被确定为罕见神经系统疾病表型连续体的原因。 ATP 1A 3的这些等位基因疾病包括（按严重程度/残疾和儿童期发病的大致顺序）：多脑回症;儿童期交替性偏瘫;小脑共济失调、反射消失、高脚、视神经萎缩和感觉神经性听力损失综合征;复发性脑病伴小脑共济失调;和速发型肌张力障碍-帕金森综合征。一些患者呈现中间、非典型或组合表型。由于这些疾病目前难以治疗，因此对更有效的疗法存在未满足的需求。ATP 1A 3突变导致广泛神经症状的分子机制知之甚少。然而，使用基因改变的模式生物体进行的体内比较研究可以深入了解NKA α3致病突变的生物学后果。在此，我们回顾了现有的小鼠，斑马鱼，果蝇和秀丽隐杆线虫模型用于研究ATP 1A 3相关的疾病，并讨论其对疾病机制的理解和新的治疗方法的发展的潜在贡献。总结：本文综述了用于研究ATP 1A 3相关疾病的动物模型，并讨论了它们对更好地理解病理机制和新疗法的贡献。
Within the past 20 years, particularly with the advent of exome sequencing technologies, autosomal dominant and de novo mutations in the gene encoding the neurone-specific α3 subunit of the Na+,K+-ATPase (NKA α3) pump, ATP1A3, have been identified as the cause of a phenotypic continuum of rare neurological disorders. These allelic disorders of ATP1A3 include (in approximate order of severity/disability and onset in childhood development): polymicrogyria; alternating hemiplegia of childhood; cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss syndrome; relapsing encephalopathy with cerebellar ataxia; and rapid-onset dystonia-parkinsonism. Some patients present intermediate, atypical or combined phenotypes. As these disorders are currently difficult to treat, there is an unmet need for more effective therapies. The molecular mechanisms through which mutations in ATP1A3 result in a broad range of neurological symptoms are poorly understood. However, in vivo comparative studies using genetically altered model organisms can provide insight into the biological consequences of the disease-causing mutations in NKA α3. Herein, we review the existing mouse, zebrafish, Drosophila and Caenorhabditis elegans models used to study ATP1A3-related disorders, and discuss their potential contribution towards the understanding of disease mechanisms and development of novel therapeutics. Summary: This Review provides an overview of the animal models used to study the spectrum of ATP1A3-related disorders and discusses their contribution towards better understanding of pathological mechanisms and novel therapeutics.
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通讯作者：
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