De novo mutations in ATP1A3 cause alternating hemiplegia of childhood
Top Cited Papers
Open Access
- 29 July 2012
- journal article
- case report
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 44 (9), 1030-1034
- https://doi.org/10.1038/ng.2358
Abstract
David Goldstein, Mohamad Mikati and colleagues report identification of de novo mutations in ATP1A3 in alternating hemiplegia of childhood, which is a rare neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurologic manifestations. Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.Keywords
This publication has 29 references indexed in Scilit:
- Using ERDS to Infer Copy-Number Variants in High-Coverage GenomesAmerican Journal of Human Genetics, 2012
- SVA: software for annotating and visualizing sequenced human genomesBioinformatics, 2011
- Mutation I810N in the α3 isoform of Na + ,K + -ATPase causes impairments in the sodium pump and hyperexcitability in the CNSProceedings of the National Academy of Sciences, 2009
- Crystal structure of the sodium-potassium pump (Na + ,K + -ATPase) with bound potassium and ouabainProceedings of the National Academy of Sciences, 2009
- RAPID-ONSET DYSTONIA-PARKINSONISM IN A CHILD WITH A NOVEL ATP1A3 GENE MUTATIONNeurology, 2009
- The Sequence Alignment/Map format and SAMtoolsBioinformatics, 2009
- The consensus coding sequence (CCDS) project: Identifying a common protein-coding gene set for the human and mouse genomesGenome Research, 2009
- Fast and accurate short read alignment with Burrows–Wheeler transformBioinformatics, 2009
- Infrastructure for the life sciences: design and implementation of the UniProt websiteBMC Bioinformatics, 2009
- Human Gene Mutation Database (HGMD®): 2003 updateHuman Mutation, 2003