De novo mutations in ATP1A3 cause alternating hemiplegia of childhood
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 chi...
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Published in | Nature genetics Vol. 44; no. 9; pp. 1030 - 1034 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Nature Publishing Group US
01.09.2012
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | 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
. |
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Bibliography: | ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3 ObjectType-Article-1 ObjectType-Feature-2 These authors contributed equally to this work. |
ISSN: | 1061-4036 1546-1718 |
DOI: | 10.1038/ng.2358 |