Channelopathies of Muscle Contraction Flashcards
What are (/importance) of channelopathies?
=ion channel diseases
Frequency in general population is very low
Gives useful insights into structure/function relationships and physiological roles
Many are genetically heterogenous with same clinical phenotype resulting from mutations in different genes
(e.g. Long QT syndrome - mutations in 3 different ion channel genes)
Different mutations in same gene may cause very different clinical phenotypes
(e.g. episodic ataxia type 2 / familial hemiplegic migraine both cause by mutations in a P-type VGCC)
What types of molecular pathology result in channelopathies?
Mutated Genes
= abnormal / absent channel protein
= altered function
= genetic channelopathies
= e.g. neuromuscular disorders
Antibodies, toxins
= bind to channels
= altered function
= autoimmune and toxic channelopathies
= e.g. Myasthenia gravis (AchR)
Abnormal transcription of normal genes
= abberrant expression of normal proteins
= altered function
= transcriptional channelopathies
= e.g. Multiple Sclerosis (Na+ channel)
What are the different genetics of disease involved?
Monogenic
= disease produced by single gene
Polygenic
= multiple genes contribute to the disease phenotype
Autosomal dominant disease
= phenotype arises from possession of a single mutant allele on a non sex chromosome (autosome)
= if one parent carries a dominant mutation = offspring has 50% chance of inheriting it
Autosomal recessive disease
= only homozygotes carrying two mutant alleles are symptomatic
= heterozygotes are carriers
Mutations can result in gain of function or loss of function
Most channelopathies are monogenic
What are the ion channels involved in skeletal muscle contraction? (+examples of human disease due to mutation)
- Nerve voltage-gated sodium channel
= Multiple sclerosis (loss of motor function) - KCNA voltage-gated potassium channel
= Myokymia (involuntary contractions) - Nerve voltage-gated calcium channel
= Familial Hemiplegic Migraine - Nicotinic acetylcholine receptor
= Myasthenia Gravis - Skeletal muscle voltage-gated sodium channel
= Myotonia (prolonged muscle contraction) - Skeletal muscle voltage-gated chloride channel
= Myotonia - Transverse tubule voltage-gated calcium channel
= Hypokalemic periodic paralysis (flaccid / weak muscles) - Sarcoplasmic reticulum calcium release channel
= Human malignant hyperthermia / central core disease
What is Myokymia
= spontaneous / involuntary muscle contractions
= most commonly reported as mild facial muscle twitching
(can be more severe and associated with ataxia and epilepsy)
= results from genetic mutations (around 12) in voltage gated potassium channel = loss of function (Autosomal dominant)
- nerve cell is left in a depolarised state = poised to fire action potentials spontaneously
- action potential is prolonged = excessive and uncontrolled release of neurotransmitter
= also referred to as episodic ataxia type 1
What is Myotonia?
= prolonged muscle contraction
= mutated chloride channel is less open than WT
= Cl- influx and membrane repolarisation is impaired
= leads to hyperexcitability of muscle
= results in multiple action potentials
= also K+ accumulation in T-tubules (increased by each action potential)
= K+ conductance is dominant (over Cl-)
= depolarises membrane and triggers further action potentials
Describe Myotonia in animals.
e.g. Myotonic goats
= extreme muscle stiffness when attempting quick forceful movements
= caused by genetic mutation (Ala885Pro substitution of skeletal muscle chloride channel gene - CLC1)
e.g. Myotonic mice
= cannot get up off of back
= “arrested development of righting response”
= also mutations in CLC1
= used as model to study human disease
Describe Myotonia in Humans.
= loss of function disease, mutations in CLC1
(CLC1 exclusively expressed in skeletal muscle = dominant conductance required for membrane repolarisation)
= >120 mutations in the 23 exons (exon 8 most common)
= prevalence = 1:100,000
= muscle stiffness
(due to continued firing of action potentials in muscle after cessation of voluntary effort)
Autosomal recessive
= generalised myotonia / Becker’s disease
= more severe form, severity develops gradually
= often results in muscle hypertrophy
= BUT not lethal = ?other CLC members compensate (?CLC2 co-assembles with CLC1)
= females have milder phenotypes
Autosomal dominant
= myotonia congenita / Thomsen’s disease
= milder symptoms from birth
= symptoms worsened by rest / cold + improved by exercise = ‘warm up’ phenomenon
EXTRA READING - WHY NOT LETHAL?
= Becker’s disease also known as Becker muscular dystrophy
= mutations in DMD gene
= less severe than DMD but same gene
What is HypoPP (Hypokalemic perioidic paralysis)?
Symptoms
= flaccid muscles and muscle weakness lasting several hours to days
Prevalece
= 1 in 100,000 births
Mutations
= L-type VGCC in skeletal muscle
= 3 most common all in S4 domains
Pathophysiology
= voltage sensor malfunction
= VGCC fails to sense action potential delivered by the axon and fails to open
What is MH (Human Maligant Hyperthermia)?
= not actually a disease = BUT an abnormal reaction to volatile anesthetic (e.g. halothane)
Clinical symptoms
= high fever
= skeletal muscle rigidity
= hyper-metabolism leading to hyper-ventilation
= hypoxia and lactic acidosis in muscle
(if not treated immediately = death within minutes = heart attack)
Prevalence
= 1 in 20,000
Autosomal dominant
= genetic channelopathy arising from mutations in the ryanodine receptor (RYR1)
= 100s of disease-causing point mutations known
= affect regulation of channel gating by Ca2+, ryanodine, caffeine and ATP
= most common mutation = Arg614Cys
= mutant RYR channel is open more often than the WT (in response to cytosolic calcium)
Treatment
= Dantrolene - a potent inhibitor of Ca2+ release from the sarcoplasmic reticulum
What is the structure of RYR1?
= very complex with many domains
Central domain
= has Ca2+ binding site
= conformational changes directly tilt the S6 TMS to the open and closed state
Helical domain
= participates in interaction with Ca2+ channels in the plasma membrane
Channel domain
= resembles that for voltage ion channels with 6 TMS
Hotspot for disease causing mutations (own domain)
What is CCD (central core disease)?
Clinical symptoms
= manifests in infants
= ‘floppy infants’
Diagnosis
= muscle biopsy
Autosomal dominant disorder
= most common mutation = Arg2435His
Prevalence
= 1 in 20,000
Pathophysiology
= in the length of each fibre making up the muscle = the core is unstructured, inactive and devoid of mitochondria
= can be seen with NADH staining (a marker of mitochondrial function)
MH vs CCD?
CCD sufferers also susceptible to MH
= led to identification of RYR as mutated gene
= many mutations of RYR causing MH , also cause CCD
BUT they differ in severity
MH = transient Ca2+ leak = eventually regulated
CCD = persistent Ca2+ leak = if unregulated leads to muscle atrophy
What is Long QT Syndrome?
= cardiac syndrome
Clinical symptoms
= abnormal heartbeat which can lead to sudden cardiac arrest and death
Prevalence
= 1 in 7,000 (in USA)
Genetically heterogenous
= 2 arise from mutations in 2 different voltage-gated K+ channels (LQT1, LQT2)
= 1 arises from voltage gated Na+ channel (LQT3)
= all result in extended QT phase and irregilar heart beat
= longer action potentials which can overlap when heartbeat increases
= reduced pumping efficiency of heart (unconscious) and can result in cardiac arrest
Describe the cardiac action potential.
= has discrete phases
- Na+ influx via Na+ channels
- Activated K+ (mediate K+ efflux) and Ca2+ channels (mediate Ca2+ influx_
Length of QT phase reflects balance between K+ and Ca2+ channels
- K+ channel activation and Ca2+ channel inactivation leads to membrane repolarisation
