Potassium Channel, Calcium-Activated, Large Conductance, Subfamily M, Alpha Member 1

Alternative Names

  • KCNMA1
  • Slowpoke, Drosophila, Homolog of
  • SLO
  • SLO1
  • SLO-Alpha resulting in
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OMIM Number

600150

Gene Map Locus
10q22.3

Description

The KCNMA1 gene encodes the pore-forming alpha subunit of the voltage-gated potassium channel.  This channel can be activated by both membrane depolarization as well as by intracellular calcium ions and it allows strong conductance of potassium ions through cell membranes.  By carrying out this function, the potassium channel is responsible for the regulation of smooth muscle contraction and the apoptotic process as well as the response to osmotic stress, hypoxia and carbon monoxide. 

The KCNMA1 gene is associated with Generalized Epilepsy and Paroxysmal Dyskinesia (GEPD), an autosomal dominant disorder characterized by epileptic seizures, paroxysmal nonkinesigenic dyskinesia and developmental delay.

Molecular Genetics

KCNMA1 is located on the long arm of chromosome 10.  It consists of 768 kb of DNA and its coding sequence is spread across 45 exons.  The protein product encoded by this gene is 137 kDa in mass and is made up of 1236 amino acids.  Multiple isoforms of the protein exist due to alternative splicing.  The gene is ubiquitously expressed with highest expression seen in brain, aorta and spinal cord.  Mutations in KCNMA1 include heterozygous missense mutations that result in the gain-of-function phenotype of GEPD as well as homozygous loss-of-function mutations such as duplications resulting in a frameshift. 

Epidemiology in the Arab World

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Other Reports

Saudi Arabia

Tabarki et al. (2016) described two sisters suffering from severe developmental delay, myoclonic seizures, diffuse hypotonia and severe cerebellar atrophy starting from the age of 8 months.  The patients were born to healthy second-cousin parents.  A combined exome/autozygome analysis uncovered a novel homozygous frameshift duplication (c.2026dupT, p.Tyr676Leufs*7) in the KCNMA1 gene of both patients.  The parents were heterozygous for the mutation.  The mutation was also not found in 1500 Saudi exomes and was scored as pathogenic based on ACMG guidelines.  The authors suggested this to be a new autosomal recessive, loss-of-function phenotype distinct from the previously reported autosomal dominant, gain-of-function GEPD phenotype associated with KCNMA1 mutations.

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