Abstract
ABSTRACTWithin the past 20 years, particularly with the advent of exome sequencing technologies, autosomal dominant and de novo mutations in the gene encoding the neurone-specific α3 subunit of the Na+,K+-ATPase (NKA α3) pump, ATP1A3, have been identified as the cause of a phenotypic continuum of rare neurological disorders. These allelic disorders of ATP1A3 include (in approximate order of severity/disability and onset in childhood development): polymicrogyria; alternating hemiplegia of childhood; cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss syndrome; relapsing encephalopathy with cerebellar ataxia; and rapid-onset dystonia-parkinsonism. Some patients present intermediate, atypical or combined phenotypes. As these disorders are currently difficult to treat, there is an unmet need for more effective therapies. The molecular mechanisms through which mutations in ATP1A3 result in a broad range of neurological symptoms are poorly understood. However, in vivo comparative studies using genetically altered model organisms can provide insight into the biological consequences of the disease-causing mutations in NKA α3. Herein, we review the existing mouse, zebrafish, Drosophila and Caenorhabditis elegans models used to study ATP1A3-related disorders, and discuss their potential contribution towards the understanding of disease mechanisms and development of novel therapeutics.
Highlights
Na+,K+-ATPase structure and function The sodium-potassium pump, Na+,K+-ATPase (NKA), actively transports three Na+ ions out of the cell and two K+ ions into the cell against their concentration gradients, utilising energy derived from adenosine 5′-triphosphate (ATP) hydrolysis (Kaplan, 2002)
Altered NKA α3 mouse models have enhanced our understanding of the phenotypic effects of mutations causing ATP1A3-related disorders
The replication of alternating hemiplegia of childhood (AHC) features in Myshkin, Mashlool, Matoub and Atp1a3D801Y mice (Table 3), and the access provided to their neurophysiology, highlight these models as valuable tools for the exploration of pathophysiological mechanisms and potential treatments
Summary
Na+,K+-ATPase structure and function The sodium-potassium pump, Na+,K+-ATPase (NKA), actively transports three Na+ ions out of the cell and two K+ ions into the cell against their concentration gradients, utilising energy derived from adenosine 5′-triphosphate (ATP) hydrolysis (Kaplan, 2002). AdCORD, autosomal-dominant cone-rod dystrophy; AHC, alternating hemiplegia of childhood; ARA, adult rapid-onset ataxia; ASD, autism spectrum disorder; CAPOS, cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss; COS, childhood-onset schizophrenia; CRA, childhood rapid-onset ataxia; DDEMØ, dystonia, dysmorphism of the face, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia (Ø); EIEE, early infantile epileptic encephalopathy; PMG, polymicrogyria; RDP, rapid-onset dystonia-parkinsonism; RECA, relapsing encephalopathy with cerebellar ataxia.
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