Alternating Hemiplegia of Childhood-Related Neural and Behavioural Phenotypes in Na+,K+-ATPase α3 Missense Mutant Mice

Greer S Kirshenbaum,Susan H Fox,John C Roder,Jonathan G L Mullins,Ian J Edwards,Jonathan M Brotchie,Tom H Johnston,Mark J Drinkhill,Neil Dawson,Judith A Pratt,Steven J Clapcote

doi:10.1371/journal.pone.0060141

Abstract

Missense mutations in ATP1A3 encoding Na+,K+-ATPase α3 have been identified as the primary cause of alternating hemiplegia of childhood (AHC), a motor disorder with onset typically before the age of 6 months. Affected children tend to be of short stature and can also have epilepsy, ataxia and learning disability. The Na+,K+-ATPase has a well-known role in maintaining electrochemical gradients across cell membranes, but our understanding of how the mutations cause AHC is limited. Myshkin mutant mice carry an amino acid change (I810N) that affects the same position in Na+,K+-ATPase α3 as I810S found in AHC. Using molecular modelling, we show that the Myshkin and AHC mutations display similarly severe structural impacts on Na+,K+-ATPase α3, including upon the K+ pore and predicted K+ binding sites. Behavioural analysis of Myshkin mice revealed phenotypic abnormalities similar to symptoms of AHC, including motor dysfunction and cognitive impairment. 2-DG imaging of Myshkin mice identified compromised thalamocortical functioning that includes a deficit in frontal cortex functioning (hypofrontality), directly mirroring that reported in AHC, along with reduced thalamocortical functional connectivity. Our results thus provide validation for missense mutations in Na+,K+-ATPase α3 as a cause of AHC, and highlight Myshkin mice as a starting point for the exploration of disease mechanisms and novel treatments in AHC.

Highlights

Alternating hemiplegia of childhood (AHC) is a rare but severe disease that is difficult to diagnose and even more challenging to treat
Mechanisms for deleterious effects can be readily postulated for all the Myshkin, AHC and rapid-onset dystonia-parkinsonism (RDP) mutations, though there is a consistent pattern of the AHC mutations and Myshkin
A consistent structure-phenotype relationship emerged from our comparative molecular modelling of AHC and RDP mutations affecting the same positions in Na+,K+-ATPase a3

Summary

Introduction

Alternating hemiplegia of childhood (AHC) is a rare but severe disease that is difficult to diagnose and even more challenging to treat. Onset of AHC usually occurs before the age of 6 months, manifesting mainly as ocular movements and dystonic attacks or an episode of marked hypotonia [2]. Patients have bouts of hemiplegia or hemiparesis that last a few minutes to several days [1]. Other paroxysmal symptoms, such as tonic/dystonic spells or autonomic disturbances, including alterations in skin colour, temperature, and sweating, are present, either concurrent with hemiplegia or in isolation. Proven therapies for amelioration of episode frequency and duration are extremely limited, and the long-term impact of even the most frequently prescribed drug treatment, flunarizine, is unknown [3]

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Conclusion