De novo mutations in ATP1A3 cause alternating hemiplegia of childhood

Abstract

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.

Figure 1. Diagram of the ATP1A3 protein showing positions of AHC-causing and DYT12-causing mutation

AHC-causing mutations seen in a single case, in multiple cases and in a familial case are represented by black, red and blue dots, respectively. The white dots represent DYT12 mutations compiled from the HGMD database. ATP1A3 mutation coordinates are defined based on UniProt ID P13637 and Consensus CDS ID CCDS12594.1.

Figure 2. Pedigree of family with autosomal dominant AHC

Black shading indicates affectation status. An ATP1A3 mutation (c.821T>A;I274N) was identified in patients II-3, III-4, and III-6 where DNA was available (indicated by a plus sign). DNA was unavailable in the father and grandmother of patients III-4 and III-6. Details of the family were reported previously. Phenotypic details of the affected patients are provided in Supplementary Note.

Figure 3. Effects of disease-causing mutations on protein expression and enzyme activity in COS-7 cells

Panel a. shows the effects of AHC-causing mutations (left) to DYT12 (right) on ATP1A3 protein abundance compared to WT. Panel b. compares the ATPase activity of disease-causing mutations (AHC and DYT12, mean ± s.d.) to that of WT. *P < 0.05, **P < 0.01, ***P < 0.001, Student’s t-test (uncorrected for multiple testing), compared to WT