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Genome sequencing identifies a novel mutation in ATP1A3 in a family with dystonia in females only.

Authors: Wilcox, R  Braenne, I  Bruggemann, N  Winkler, S  Wiegers, K  Bertram, L  Anderson, T  Lohmann, K 
Citation: Wilcox R, etal., J Neurol. 2015 Jan;262(1):187-93. doi: 10.1007/s00415-014-7547-9. Epub 2014 Oct 31.
Pubmed: (View Article at PubMed) PMID:25359261
DOI: Full-text: DOI:10.1007/s00415-014-7547-9

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements or postures. Several genetic causes of dystonia have been elucidated but genetic causes of dystonia specifically affecting females have not yet been described. In the present study, we investigated a large dystonia family from New Zealand in which only females were affected. They presented with a generalized form of the disorder including laryngeal, cervical, and arm dystonia. We found a novel, likely disease-causing, three base-pair deletion (c.443_445delGAG, p.Ser148del) in ATP1A3 in this family by combining genome and exome sequencing. Mutations in ATP1A3 have previously been linked to rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and CAPOS syndrome. Therefore, we re-examined our patients with a specific focus on typical symptoms of these conditions. It turned out that all patients reported a rapid onset of dystonic symptoms following a trigger suggesting a diagnosis of RDP. Notably, none of the patients showed clear symptoms of parkinsonism or symptoms specific for AHC or CAPOS. The ATP1A3 gene is located on chromosome 19q13.2, thus, providing no obvious explanation for the preponderance to affect females. Interestingly, we also identified one unaffected male offspring carrying the p.Ser148del mutation suggesting reduced penetrance of this mutation, a phenomenon that has also been observed for other RDP-causing mutations in ATP1A3. Although phenotypic information in this family was initially incomplete, the identification of the p.Ser148del ATP1A3 mutation elicited clinical re-examination of patients subsequently allowing establishing the correct diagnosis, a phenomenon known as "reverse phenotyping".

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CRRD Object Information
CRRD ID: 11055714
Created: 2016-04-13
Species: All species
Last Modified: 2016-04-13
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.