A novel <i>KCNA1</i> mutation associated with global delay and persistent cerebellar dysfunction

Demos, Michelle; Macri, Vincenzo; Farrell, Kevin; Nelson, Tanya N.; Chapman, Kristine; Accili, Eric A.; Armstrong, Linlea

doi:10.1002/mds.22467

Cited by 49 publications

(41 citation statements)

References 20 publications

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“…Genetic mutations in Kv1 channels in humans, or depletion of the Kv1.1 gene in mice, result in hyperexcitability, episodic ataxia, myokymia and epilepsy [1, 17, 18, 25, 29, 83, 132, 156, 160], consistent with a role for Kv1 channels in limiting action potential generation. However, Kv1.1 and Kv1.2 channels can also be found in the AIS and axon terminals, and deletion of the Kv1.1 gene produces only a small prolongation of the compound action potential in mature nerves [132], making its loss at the juxtaparanode an unlikely explanation for the dramatic phenotypes observed in humans and mice.…”

Section: Pathologies Of the Juxtaparanodementioning

confidence: 94%

The node of Ranvier in CNS pathology

2014

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Healthy nodes of Ranvier are crucial for action potential propagation along myelinated axons, both in the central and in the peripheral nervous system. Surprisingly, the node of Ranvier has often been neglected when describing CNS disorders, with most pathologies classified simply as being due to neuronal defects in the grey matter or due to oligodendrocyte damage in the white matter. However, recent studies have highlighted changes that occur in pathological conditions at the node of Ranvier, and at the associated paranodal and juxtaparanodal regions where neurons and myelinating glial cells interact. Lengthening of the node of Ranvier, failure of the electrically resistive seal between the myelin and the axon at the paranode, and retraction of myelin to expose voltage-gated K+ channels in the juxtaparanode, may contribute to altering the function of myelinated axons in a wide range of diseases, including stroke, spinal cord injury and multiple sclerosis. Here, we review the principles by which the node of Ranvier operates and its molecular structure, and thus explain how defects at the node and paranode contribute to neurological disorders.

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Section: Pathologies Of the Juxtaparanodementioning

confidence: 94%

The node of Ranvier in CNS pathology

2014

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“…One important mutation locus is at site V408, which is in the ion permeation pathway. When expressed in heterologous systems, V408A (Adelman et al, 1995;D'Adamo et al, 1998) and V408L (Demos et al, 2009) show accelerated decay of outward potassium current during prolonged depolarization of the membrane potential. However, the molecular mechanism by which mutations at this site lead to faster current decay is unclear.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Accelerated Current Decay Caused by an Episodic Ataxia Type-1-Associated Mutant in a Potassium Channel Pore

Peters

Werry²,

Gill³

et al. 2011

J. Neurosci.

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In Kv1.1, single point mutants found below the channel activation gate at residue V408 are associated with human episodic ataxia type-1, and impair channel function by accelerating decay of outward current during periods of membrane depolarization and channel opening. This decay is usually attributed to C-type inactivation, but here we provide evidence that this is not the case. Using voltage-clamp fluorimetry in Xenopus oocytes, and single-channel patch clamp in mouse ltk؊ cells, of the homologous Shaker channel (with the equivalent mutation V478A), we have determined that the mutation may cause current decay through a local effect at the activation gate, by destabilizing channel opening. We demonstrate that the effect of the mutant is similar to that of trapped 4-aminopyridine in antagonizing channel opening, as the mutation and 10 mM 4-AP had similar, nonadditive effects on fluorescence recorded from the voltagesensitive S4 helix. We propose a model where the Kv1.1 activation gate fails to enter a stabilized open conformation, from which the channel would normally C-type inactivate. Instead, the lower pore lining helix is able to enter an activated-not-open conformation during depolarization. These results provide an understanding of the molecular etiology underlying episodic ataxia type-1 due to V408A, as well as biophysical insights into the links between the potassium channel activation gate, the voltage sensor and the selectivity filter.

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“…Additionally, there is only one report of cerebral atrophy in EA1. 14 Thus the proband underwent extensive diagnostic tests for Wilson's disease, Huntington's disease, Sydenham's chorea, epilepsy and Curschmann-Steinert myotonic dystrophy, but these did not establish a diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing as a Diagnostic Tool in a Family With Episodic Ataxia Type 1

Tacik

Guthrie

Strongosky

et al. 2015

Mayo Clinic Proceedings

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Complex neurological phenotypes are inherently difficult to diagnose. Whole-exome sequencing (WES) is a new tool in the neurologist's diagnostic armamentarium. WES can be applied to investigate the “diagnostic odyssey” cases. These cases involve patients with rare diseases of likely genetic etiology who have failed to obtain a diagnosis by clinical evaluation and targeted gene testing. The 22-year-old adopted proband presented with episodes of jerking ataxic movements that affected his whole body and mild intellectual developmental disability. He underwent numerous multidisciplinary and multicentric evaluations throughout his life that failed to establish a clear diagnosis. Following his visit to the Mayo Clinic, WES was applied for genetic determination of the unknown disorder in the proband, his biological parents and sister. Besides, four other paternal relatives were reported to have similar complaints. Additional clinical evaluation, and magnetic resonance neuroimaging (MRI), electromyography (EMG) and electroencephalography (EEG) of the proband were performed to verify the phenotype after the WES results were available. Eleven months after the proband's initial visit, WES identified the c.1210G>A (p.V404I) mutation in the potassium voltage-gated channel, shaker-related subfamily, member 1 gene in the proband, his father, and his sister, and thus the diagnosis of episodic ataxia type 1 was established. The proband's MRI demonstrated mild vermian hypoplasia, EMG myokymic discharges, and EEG generalized background slowing. Acetazolamide therapy was beneficial for him at the daily dose of 500 mg.

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A novel KCNA1 mutation associated with global delay and persistent cerebellar dysfunction

Cited by 49 publications

References 20 publications

The node of Ranvier in CNS pathology

The node of Ranvier in CNS pathology

Mechanism of Accelerated Current Decay Caused by an Episodic Ataxia Type-1-Associated Mutant in a Potassium Channel Pore

Whole-Exome Sequencing as a Diagnostic Tool in a Family With Episodic Ataxia Type 1

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