Genome-wide screen for modifiers of Na (+) /K (+) ATPase alleles identifies critical genetic loci.
Genome-wide screen for modifiers of Na (+) /K (+) ATPase alleles identifies critical genetic loci.
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DOI：
10.1186/s13041-014-0089-3
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发表时间：
2014-12-05
期刊：
影响因子：
3.6
通讯作者：
Palladino MJ
中科院分区：
文献类型：
--
作者：
Talsma AD;Chaves JF;LaMonaca A;Wieczorek ED;Palladino MJ
影响Na+/ K+ ATP酶的突变（a.k.a.钠-钾泵）基因在苍蝇中引起条件性运动表型和在人类中引起三种不同的复杂神经疾病。已经鉴定了超过50种影响人类ATP 1A 2和ATP 1A 3基因的突变，已知这些突变引起快速发作的肌张力障碍性帕金森综合征、家族性偏瘫性偏头痛、儿童交替性偏瘫以及具有神经系统并发症（包括癫痫发作和各种情绪障碍）的家族性偏瘫性偏头痛的变体。在苍蝇中，影响ATPalpha基因的突变具有显着的表型，包括寿命改变、神经功能障碍、神经变性、肌肉变性和严重的运动障碍。运动缺陷可以表现为条件性爆炸敏感（BS）或温度敏感（TS）麻痹：非常适合遗传筛查的表型。我们进行了全基因组的缺陷屏幕使用三个不同的错义等位基因的ATPalpha和条件运动功能测定，以确定新的修饰基因座。二次筛选证实了相互作用的等位基因特异性，并且许多相互作用被映射到单个基因并随后被验证。我们成功地鉴定了64个修饰基因位点，并使用经典突变和RNAi证实了50个单基因相互作用。所鉴定的基因包括那些具有已知功能的基因、几个具有未知功能的基因或其他未表征的基因，以及许多没有描述与运动或Na+/K+ ATP酶功能相关的基因座。我们使用无偏的全基因组筛选来寻找基因组中含有对ATPalpha功能障碍的遗传调节重要的元件的区域。我们已经确定了许多关键区域，并将其中几个缩小到单个基因。这些数据表明，有许多基因座能够改变ATPalpha功能障碍，这可能提供了基础，用于改善偏头痛，运动和癫痫发作功能障碍的动物。本文的在线版本（doi：10.1186/s13041-014-0089-3）包含补充材料，可供授权用户使用。
Mutations affecting the Na+/ K+ATPase (a.k.a. the sodium-potassium pump) genes cause conditional locomotor phenotypes in flies and three distinct complex neurological diseases in humans. More than 50 mutations have been identified affecting the human ATP1A2 and ATP1A3 genes that are known to cause rapid-onset Dystonia Parkinsonism, familial hemiplegic migraine, alternating hemiplegia of childhood, and variants of familial hemiplegic migraine with neurological complications including seizures and various mood disorders. In flies, mutations affecting the ATPalpha gene have dramatic phenotypes including altered longevity, neural dysfunction, neurodegeneration, myodegeneration, and striking locomotor impairment. Locomotor defects can manifest as conditional bang-sensitive (BS) or temperature-sensitive (TS) paralysis: phenotypes well-suited for genetic screening. We performed a genome-wide deficiency screen using three distinct missense alleles of ATPalpha and conditional locomotor function assays to identify novel modifier loci. A secondary screen confirmed allele-specificity of the interactions and many of the interactions were mapped to single genes and subsequently validated. We successfully identified 64 modifier loci and used classical mutations and RNAi to confirm 50 single gene interactions. The genes identified include those with known function, several with unknown function or that were otherwise uncharacterized, and many loci with no described association with locomotor or Na+/K+ ATPase function. We used an unbiased genome-wide screen to find regions of the genome containing elements important for genetic modulation of ATPalpha dysfunction. We have identified many critical regions and narrowed several of these to single genes. These data demonstrate there are many loci capable of modifying ATPalpha dysfunction, which may provide the basis for modifying migraine, locomotor and seizure dysfunction in animals. The online version of this article (doi:10.1186/s13041-014-0089-3) contains supplementary material, which is available to authorized users.
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