Alternating hemiplegia of childhood-related neural and behavioural phenotypes in Na+,K+-ATPase α3 missense mutant mice

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

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

LanguageEnglish
Article numbere60141
Number of pages15
JournalPLOS One
Volume8
Issue number3
DOIs
Publication statusPublished - 20 Mar 2013

Fingerprint

sodium-potassium-exchanging ATPase
childhood
Adenosine Triphosphatases
Phenotype
phenotype
mutants
mice
missense mutation
Missense Mutation
Molecular modeling
Cell membranes
mutation
Mutation
Binding Sites
sodium-translocating ATPase
Alternating hemiplegia of childhood
epilepsy
Learning Disorders
Frontal Lobe
Ataxia

Keywords

  • analysis of variance
  • animals
  • blood pressure
  • female
  • gait
  • hemiplegia
  • humans
  • locomotion
  • male
  • mice
  • mice, mutant strains
  • models, molecular
  • mutation, missense
  • phenotype
  • protein conformation
  • sodium-potassium-exchanging ATPase
  • species specificity

Cite this

Kirshenbaum, G. S., Dawson, N., Mullins, J. G. L., Johnston, T. H., Drinkhill, M. J., Edwards, I. J., ... Clapcote, S. J. (2013). Alternating hemiplegia of childhood-related neural and behavioural phenotypes in Na+,K+-ATPase α3 missense mutant mice. PLOS One, 8(3), [e60141]. https://doi.org/10.1371/journal.pone.0060141
Kirshenbaum, Greer S ; Dawson, Neil ; Mullins, Jonathan G L ; Johnston, Tom H ; Drinkhill, Mark J ; Edwards, Ian J ; Fox, Susan H ; Pratt, Judith A ; Brotchie, Jonathan M ; Roder, John C ; Clapcote, Steven J. / Alternating hemiplegia of childhood-related neural and behavioural phenotypes in Na+,K+-ATPase α3 missense mutant mice. In: PLOS One. 2013 ; Vol. 8, No. 3.
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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.",
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Kirshenbaum, GS, Dawson, N, Mullins, JGL, Johnston, TH, Drinkhill, MJ, Edwards, IJ, Fox, SH, Pratt, JA, Brotchie, JM, Roder, JC & Clapcote, SJ 2013, 'Alternating hemiplegia of childhood-related neural and behavioural phenotypes in Na+,K+-ATPase α3 missense mutant mice' PLOS One, vol. 8, no. 3, e60141. https://doi.org/10.1371/journal.pone.0060141

Alternating hemiplegia of childhood-related neural and behavioural phenotypes in Na+,K+-ATPase α3 missense mutant mice. / Kirshenbaum, Greer S; Dawson, Neil; Mullins, Jonathan G L; Johnston, Tom H; Drinkhill, Mark J; Edwards, Ian J; Fox, Susan H; Pratt, Judith A; Brotchie, Jonathan M; Roder, John C; Clapcote, Steven J.

In: PLOS One, Vol. 8, No. 3, e60141, 20.03.2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Alternating hemiplegia of childhood-related neural and behavioural phenotypes in Na+,K+-ATPase α3 missense mutant mice

AU - Kirshenbaum, Greer S

AU - Dawson, Neil

AU - Mullins, Jonathan G L

AU - Johnston, Tom H

AU - Drinkhill, Mark J

AU - Edwards, Ian J

AU - Fox, Susan H

AU - Pratt, Judith A

AU - Brotchie, Jonathan M

AU - Roder, John C

AU - Clapcote, Steven J

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N2 - 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.

AB - 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.

KW - analysis of variance

KW - animals

KW - blood pressure

KW - female

KW - gait

KW - hemiplegia

KW - humans

KW - locomotion

KW - male

KW - mice

KW - mice, mutant strains

KW - models, molecular

KW - mutation, missense

KW - phenotype

KW - protein conformation

KW - sodium-potassium-exchanging ATPase

KW - species specificity

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DO - 10.1371/journal.pone.0060141

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VL - 8

JO - PLOS One

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JF - PLOS One

SN - 1932-6203

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M1 - e60141

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Kirshenbaum GS, Dawson N, Mullins JGL, Johnston TH, Drinkhill MJ, Edwards IJ et al. Alternating hemiplegia of childhood-related neural and behavioural phenotypes in Na+,K+-ATPase α3 missense mutant mice. PLOS One. 2013 Mar 20;8(3). e60141. https://doi.org/10.1371/journal.pone.0060141