L7: Channelopathies Flashcards
What is a channelopathy?
- a dysfunction of a channel (either voltage-gated or ligand-gated ion channels)
- caused by genetic mutations, autoantibody destruction, or exposure to toxins
What are the causes of mutations in channelopathies?
- radiation (UV, X-rays)
- infections (virus, bacteria)
- chemical toxins (e.g., tobacco tar)
-germline errors in DNA replication - somatic errors in development
- scientific interference
Name three types of mutations in genetic diseases
- Point mutation: Involves a change in a single amino acid.
- Nonsense mutation: Causes insertion of a stop codon, leading to a truncated and non-functional protein.
- Frameshift mutation: Involves the insertion/deletion of nucleotides, resulting in a shift of the reading frame and a completely different protein sequence.
What are the types of genetic diseases?
- Autosomal dominant: disease expressed in individuals who have one copy of the mutated gene (heterozygote).
- Autosomal recessive: disease expressed only in individuals who have two copies of the mutated gene (homozygote), while heterozygotes are carriers without showing symptoms.
- Dominant negative: Mutant proteins disrupt the function of normal proteins, leading to a dominant disease phenotype.
- Haploinsufficiency: Both copies of the gene are required for full function, and one copy is not sufficient to maintain normal function
Provide examples of channelopathies and the affected ion channels
- Hyperekplexia (startle disease/stiff baby syndrome): Affects ligand-gated channels (glycine receptors).
- Generalized Epilepsy with Febrile Seizures (GEFS) and Benign Familial Neonatal Seizures (BFNS): Affect voltage-gated ion channels (sodium channels).
- Sickle cell anemia: Affects enzymes (hemoglobin).
- Cystic fibrosis: Affects transporters (chloride transporter)
Describe the symptoms and genetics of hyperekplexia.
- Symptoms: Muscle spasms, increased response to unexpected stimuli, rigidity, hypertonia in infants.
- Genetics: Autosomal dominant with a genetic linkage to chromosome 5q32, caused by a point mutation (R271Q) in the GLRA1 gene (glycine receptor alpha 1 subunit).
How does reduced glycine entry in hyperekplexia cause exaggerated reflexes and hypertonia?
- reduced glycine entry at glycine receptor of motor nerve leads to decreased release of acetylcholine due to negative feedback
- causes exaggerated reflexes, hypertonia, and an exaggerated startle response
What is Generalized Epilepsy with Febrile Seizures (GEFS)?
- a genetic disorder characterized by convulsions and fever, with onset typically in childhood but can also develop later in life
What are the symptoms of GEFS?
-convulsions, fever, and other seizure-related manifestations
How does the mutation in GEFS affect sodium channel function?
- C121W mutation in the Na+ channel beta 1 subunit causes a loss of disulfide bridges, leading to reduced inactivation of sodium channels
- results in persistent Na+ current, causing membrane to become more depolarized and hyperexcitable (especially at ↑ temperatures)
What is the effect of slow inactivation and persistent sodium current on GEFS?
- slow inactivation & subsequent persistent Na+ current ↑ neuronal excitability
- making neurons more prone to firing AP & contributing to the development of seizures in GEFS patients
What are the symptoms of Benign Familial Neonatal Seizure (BFNS)?
- BFNS characterized by recurrent seizures that occur in early life (usually within first days after birth)
- seizures resolve spontaneously within three months
- increased risk of epilepsy in 10-15% of affected individuals later in life
What is the genetic basis of BFNS?
- caused by haploinsufficiency
- genetic linkage for BFNS is located on chromosome 20q13.3
- gene affected is KCNQ2 (codes for a K+ channel) - mutation involved is a frameshift mutation, resulting in a 300 amino acid deletion.
How does the mutation in BFNS affect Kv7 channel function?
- frameshift mutation in BFNS causes a 300 AA deletion in the C-terminus tail of the KCNQ2 subunit, resulting in a non-functional Kv7 K+ channel
- leads to hyperexcitability of the NS due to impaired regulation of neuronal firing & contributes to occurrence of neonatal seizures
What is the impact of Kv7 channel dysfunction on BFNS?
- results in altered neuronal excitability, leading to recurrent seizures in the neonatal period
- seizures resolve spontaneously within few months but ↑ risk of epilepsy in some affected individuals later in life
What is the composition of the Kv7 channel and where is it predominantly found in neurons?
- composed of KCNQ2 and KCNQ3 subunits
- mainly found in the axon hillock of neurons
What are the functional properties of voltage-gated K channels and their role in cell physiology?
- VG K+ channels are delayed rectifying channels responsible for the hyperpolarization of the cell
- play a crucial role in regulating the resting membrane potential & repolarization of the cell after an AP
What specific function do Kv7 channels serve in neuronal activity?
- responsible for generating M current - which is crucial for repetitive firing in neurons
- the M current plays a role in regulating excitability of neurons and is important for fine-tuning their firing pattern
Where is the mutation that causes BFNS located, and what is its effect on the Kv7 channel?
- located in the C-terminus tail of the KCNQ2 subunit of the Kv7 channel
- mutation leads to the production of a non-functional Kv7 potassium channel.
How does the non-functional Kv7 channel impact neuronal excitability in BFNS?
- results in altered neuronal excitability
- this dysregulation contributes to occurrence of recurrent seizures in the neonatal period
- seizures resolve spontaneously within few months but ↑ risk of epilepsy in some affected individuals later in life
What is the genetic basis of GEFS?
- inherited in an autosomal dominant pattern and is linked to chromosome 19q13.1
Which gene is responsible for GEFS, and where is it located?
- SCN1B, which codes for the sodium channel beta 1 subunit
- located on chromosome 19q13.1
What specific mutation is associated with GEFS, and what amino acid change does it cause?
- point mutation at position C121W
- leads to the replacement of cysteine (C) with tryptophan (W) in the Na+ channel beta 1 subunit
How does the mutation in the sodium channel beta 1 subunit impact the function of sodium channels?
- the Na+ beta 1 subunit can coassemble with the large alpha subunit of Na+ channel
- mutation at C121W affects the disulfate bridges in the beta subunit’s large extracellular loop, leading to a ↓ in inactivation of the Na+ channel
- results in slow inactivation & a persistent Na+ current, causing cell membrane to become more depolarized & excitable
How does the altered sodium channel function contribute to the symptoms of GEFS?
- ↑ excitability of neurons due to the altered Na+ channel function can lead to recurrent convulsions - particularly triggered by fever
- temp dependency of the Na+ channel dysfunction explains why fever can be significant trigger for seizures in GEFS sufferers
- the condition may manifest in childhood, but it can also develop later in life.
