ion channel disorders

• channelopathy

  Disease condition or pathology associated with ion channel dysfunction

  • Associated with mutation in channel gene
• POINT MUTATIONS:

  silent - no effect

  conserved point mutation: amino acid with similar properties - no effect

  missense - change
• frameshift mutations:

  • insertion - leads to nonsense
  • deletion - leads to truncation
• how mutations alter ion channels - (loss or gain of function)

  • ion pathway altered - no longer selective for specific ion
  • effect activation process - change membrane potential - more/less sensitive to stimulus
  • change inactivation process
• long QT syndrome

  • long QT interval
  • slow repolarisation phase of action potential
  • elongated AP
• LQT1

  mutation in KCNQ1 gene encoding for VG potassium channels important for repolarisation
• What channelopathy underlies LQTS

  LQT1

  (KVLQT1) activation causes major repolarising current of  phase 3 of the cardiac AP

  –Mutation causes loss of function = slow repolarisation
• dominant negative effect

  potassium channel has 4 subunits

  • heterozygous mutation
  • 50 wild type and 50 mutant
  • randomly associated in cell
  • all with the mutant is effected

  
• EPILEPSY

  mutations in voltage-gated and ligand-gated ion channels

  Generalized epilepsy

  • mutation in VD sodium channel - SCN1A in brain
  • Severe myoclonic epilepsy in infancy (SMEI) = Dravet Syndrome
  • mutaions in SCN1A and gene that codes Nav1.1
• Nav loss of function = painless

  • mutation in SCN9A in periphery neurones
• Nav gain of function in skeletal muscles

  • mutation in SCN4A for Nav1.4
  • unique to skeletal muscle
  • for AP generation

  Hyperkalemic Periodic Paralysis

  • Weakness of limbs
  • gain of function mutation in NAv1.4
  • Slows down inactivation process
  • High extracellular potassium