L7: Channelopathies

Question 1

What is a channelopathy?

Answer 1

• a dysfunction of a channel (either voltage-gated or ligand-gated ion channels)
• caused by genetic mutations, autoantibody destruction, or exposure to toxins

Question 2

What are the causes of mutations in channelopathies?

Answer 2

• radiation (UV, X-rays)
• infections (virus, bacteria)
• chemical toxins (e.g., tobacco tar)
  -germline errors in DNA replication
• somatic errors in development
• scientific interference

Question 3

Name three types of mutations in genetic diseases

Answer 3

1. Point mutation: Involves a change in a single amino acid.
2. Nonsense mutation: Causes insertion of a stop codon, leading to a truncated and non-functional protein.
3. Frameshift mutation: Involves the insertion/deletion of nucleotides, resulting in a shift of the reading frame and a completely different protein sequence.

Question 4

What are the types of genetic diseases?

Answer 4

1. Autosomal dominant: disease expressed in individuals who have one copy of the mutated gene (heterozygote).
2. Autosomal recessive: disease expressed only in individuals who have two copies of the mutated gene (homozygote), while heterozygotes are carriers without showing symptoms.
3. Dominant negative: Mutant proteins disrupt the function of normal proteins, leading to a dominant disease phenotype.
4. Haploinsufficiency: Both copies of the gene are required for full function, and one copy is not sufficient to maintain normal function

Question 5

Provide examples of channelopathies and the affected ion channels

Answer 5

1. Hyperekplexia (startle disease/stiff baby syndrome): Affects ligand-gated channels (glycine receptors).
2. Generalized Epilepsy with Febrile Seizures (GEFS) and Benign Familial Neonatal Seizures (BFNS): Affect voltage-gated ion channels (sodium channels).
3. Sickle cell anemia: Affects enzymes (hemoglobin).
4. Cystic fibrosis: Affects transporters (chloride transporter)

Question 6

Describe the symptoms and genetics of hyperekplexia.

Answer 6

• 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).

Question 7

How does reduced glycine entry in hyperekplexia cause exaggerated reflexes and hypertonia?

Answer 7

• 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

Question 8

What is Generalized Epilepsy with Febrile Seizures (GEFS)?

Answer 8

• a genetic disorder characterized by convulsions and fever, with onset typically in childhood but can also develop later in life

Question 9

What are the symptoms of GEFS?

Answer 9

-convulsions, fever, and other seizure-related manifestations

Question 10

How does the mutation in GEFS affect sodium channel function?

Answer 10

• 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)

Question 11

What is the effect of slow inactivation and persistent sodium current on GEFS?

Answer 11

• slow inactivation & subsequent persistent Na+ current ↑ neuronal excitability
• making neurons more prone to firing AP & contributing to the development of seizures in GEFS patients

Question 12

What are the symptoms of Benign Familial Neonatal Seizure (BFNS)?

Answer 12

• 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

Question 13

What is the genetic basis of BFNS?

Answer 13

• 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.

Question 14

How does the mutation in BFNS affect Kv7 channel function?

Answer 14

• 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

Question 15

What is the impact of Kv7 channel dysfunction on BFNS?

Answer 15

• 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

Question 16

What is the composition of the Kv7 channel and where is it predominantly found in neurons?

Answer 16

• composed of KCNQ2 and KCNQ3 subunits
• mainly found in the axon hillock of neurons

Question 17

What are the functional properties of voltage-gated K channels and their role in cell physiology?

Answer 17

• 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

Question 18

What specific function do Kv7 channels serve in neuronal activity?

Answer 18

• 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

Question 19

Where is the mutation that causes BFNS located, and what is its effect on the Kv7 channel?

Answer 19

• 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.

Question 20

How does the non-functional Kv7 channel impact neuronal excitability in BFNS?

Answer 20

• 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

Question 21

What is the genetic basis of GEFS?

Answer 21

• inherited in an autosomal dominant pattern and is linked to chromosome 19q13.1

Question 22

Which gene is responsible for GEFS, and where is it located?

Answer 22

• SCN1B, which codes for the sodium channel beta 1 subunit
• located on chromosome 19q13.1

Question 23

What specific mutation is associated with GEFS, and what amino acid change does it cause?

Answer 23

• point mutation at position C121W
• leads to the replacement of cysteine (C) with tryptophan (W) in the Na+ channel beta 1 subunit

Question 24

How does the mutation in the sodium channel beta 1 subunit impact the function of sodium channels?

Answer 24

• 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

Question 25

How does the altered sodium channel function contribute to the symptoms of GEFS?

Answer 25

• ↑ 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.