Tuesday, November 17, 2015

in vivo RNAi used to validate at gene level hits in genome-wide deficiency screen for enhancers and suppressors of Na (+) /K (+) ATPase alleles

Talsma AD, Chaves JF, LaMonaca A, Wieczorek ED, Palladino MJ. Genome-wide screen for modifiers of Na (+) /K (+) ATPase alleles identifies critical genetic loci. Mol Brain. 2014 Dec 5;7:89. doi: 10.1186/s13041-014-0089-3. PMID: 25476251; PMCID: PMC4302446.

From the abstract: "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. ... We performed a genome-wide deficiency screen ... 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. ... 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."

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