Mutations in the KCNA1 gene associated with episodic ataxia type‐1 syndrome impair heteromeric voltage‐gated K+ channel function

@article{DAdamo1999MutationsIT,
  title={Mutations in the KCNA1 gene associated with episodic ataxia type‐1 syndrome impair heteromeric voltage‐gated K+ channel function},
  author={Maria Cristina D’Adamo and Paola Imbrici and F. Sponcichetti and Mauro Pessia},
  journal={The FASEB Journal},
  year={1999},
  volume={13},
  pages={1335 - 1345}
}
Episodic ataxia type‐1 syndrome (EA‐1) is an autosomal dominant neurological disorder that manifests itself during infancy and results from point mutations in the voltage‐gated potassium channel gene hKv1.1. The hallmark of the disease is continuous myokymia and episodic attacks of spastic contractions of the skeletal muscles, which cause permanent disability. Coexpression of hKv1.1 and hKv1.2 subunits produces heteromeric potassium channels with biophysical and pharmacological properties… 
Episodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human potassium channels Kv1.4‐1.1/Kvβ1.1 and Kv1.4‐1.1/Kvβ1.2
TLDR
The results demonstrate that the human Kvβ1.1 and Kv β1.2 subunits modulated the functional properties of tandemly linked Kv1.4.4‐1.x subunits, and alter the fast inactivation and repriming properties of the channels by decreasing both the rate and degree of N‐type in activation and by accelerating the recovery from fast in activation.
Functional characterization of an episodic ataxia type-1 mutation occurring in the S1 segment of hKv1.1 channels
TLDR
It is demonstrated that both reduced current levels and specific gating defects are the likely causes of EA-1 symptoms in patients bearing the I177N mutation and the data suggest that the I 177N substitution may alter the gating properties of the channel that is specifically defined by the S1 segment.
Episodic ataxia type 1 mutations affect fast inactivation of K+ channels by a reduction in either subunit surface expression or affinity for inactivation domain.
TLDR
It is proposed that EA1 mutations affect the rate of N-type inactivation either by reduced subunit surface expression, giving rise to a reduced number of Kv1.4 inactivation particles, as set by the precise subunit stoichiometry, and to test this hypothesis, quantified amounts of mRNA were injected into Xenopus laevis oocytes and the relative rates of inactivation and stoichiometric were determined.
Episodic ataxia type 1 mutation F184C alters Zn2+-induced modulation of the human K+ channel Kv1.4-Kv1.1/Kvbeta1.1.
TLDR
It is demonstrated that the EA1 mutation F184C will not only sensitize the homomeric Kv1.1 channel to extracellular Zn(2+), but it will also endow heteromeric channels with a higher sensitivity to this metal ion.
Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene
TLDR
A 31-year-old man displaying markedly atypical symptoms, including long-lasting attacks of jerking muscle contractions associated with hyperthermia, severe migraine, and a relatively short-sleep phenotype is described, highlighting a possibly unrecognized relationship between K+ channel dysfunction,hyperthermia and migraine in EA1.
Identification of a New de Novo Mutation Underlying Regressive Episodic Ataxia Type I
TLDR
The clinical phenotype of an EA1 patient characterized by ataxia attacks that decrease in frequency with age, and eventually leading to therapy discontinuation is reported, corroborate the notion that EA1 also results from de novo variants and point out that regardless of the mutation-induced deleterious loss of Kv1.1 channel function the atAXia phenotype may improve spontaneously.
Episodic Ataxia Type-1 Mutations in the Kv1.1 Potassium Channel Display Distinct Folding and Intracellular Trafficking Properties*
TLDR
Results suggest that as in many neurodegenerative disorders, intracellular aggregation of misfolded Kv1.1-containing channels may contribute to the pathophysiology of EA-1.
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References

SHOWING 1-10 OF 41 REFERENCES
Episodic ataxia type‐1 mutations in the hKv1.1 cytoplasmic pore region alter the gating properties of the channel
TLDR
The results demonstrate that the highly conserved residues Val408 and Glu325 play a pivotal role in several gating processes of a human potassium channel, and suggest a pathogenetic mechanism by which the impairment of the delayed‐rectifier function of affected neurons is related to the type and number of mutated subunits which make up the hKv1.1 channels.
Episodic Ataxia Mutations in Kv1.1 Alter Potassium Channel Function by Dominant Negative Effects or Haploinsufficiency
TLDR
Results show that the different mutations in Kv1.1 affect channel function and indicate that both dominant negative effects and haplotype insufficiency may result in the symptoms of EA.
Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1
TLDR
Mutation analysis of the KCNA1 coding region in families identified four different missense point mutations present in the heterozygous state, indicating that EA/myokymia can result from mutations in this gene.
A gene for episodic ataxia/myokymia maps to chromosome 12p13.
TLDR
Using a group of Genethon markers from one such region--chromosome 12p--the authors found evidence of linkage in four EA/myokymia families, and tested markers near known K+ channel genes for linkage.
Episodic ataxia and myokymia syndrome: A new mutation of potassium channel gene Kv1.1
TLDR
A novel mutation within this gene in a newly diagnosed family is described, located at chromosome 12p13.1, which is associated with point mutations in the potassium channel gene Kv1.1.
Episodic ataxia and channelopathies
  • N. Gordon
  • Medicine, Psychology
    Brain and Development
  • 1998
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