Channelopathies

Question 0

Mutational mechanisms that lead to defective ion channel function

Answer 0

Mutation-> nucleotide change that occurs in 1% of pop-> more frequent Polymorphisms-> multiple isoforms
Point mutations ->
conservative-> biochemically similar to type of AA coded -> little functional effect or silent
Missence-> different type of AA coded-> function may be adversely effected
First two positions of codon of greater impact than third
Frameshift->
insertion-> truncation
deletion-> nonsense

Question 1

Channelopathy

Answer 1

Problems with channel expression or channel properties
Disease condition or pathology associated with ion channel dysfunction-> associated with genetic mutations
Ion channel itself-> permeation pathway, gating characteristics, pharmacology, regulation/ligand binding sites
Accessory protein->
-> accessory subunits-> regulation
-> chaperones-> trafficking
-> localisation

Question 2

How do mutations effect channel function

Answer 2

Alter tertiary structure
Alter permeation pathways-> ion movement altered
Change channel activities
Change inactivation process

Question 3

Investigations of channelopatheis

Answer 3

For many chromosomal loci and gene/s are known 
Unique case studies
Familial studies
Linkage analysis
Functional assays
Screen against human genome

Question 4

Clinical symptoms of channelopatheis

Answer 4

Tissue function-> EMG, ENG,EEG,ECG
Cell function-> electrophysiology, bio physiology, membrane function, EMG
Molecular screening techniques to identify ion channel and gene-> blood samples, PCR, sequencing

Question 5

Type so channelopatheis CNS

Answer 5

Generalised epilepsy GE:Nav
Familial hemiplegic migraine FHM:Cav
Cerebellar ataxia
Hyperexplexia-> excessive startle

Question 6

PNS channelopatheis

Answer 6

Inherited erythromelagia IE:Nav

Question 7

Muscle system channelopatheis

Answer 7

Skeletal muscle and NMJ-> prolonged contraction in response to stimuli-> Congenital myotonia -> Nav:Clc
Myasthenia-> muscle weakness-> Cav:Kv, AchR-> autoimmune
Cardiac muscle-> long QT syndrom-> Nav Kv, Cav, ankrin B
SIDS-> Nav, Kv -> short QT, arythmias, AF, brugaden syndrome,, CPNT

Question 8

Other channelopatheis

Answer 8

Endocrine eg pancreas B cell-> neonatal diabetes -> Kiv
Sensory organs-> retinitis pigmentosa-> CNG
Epithelial-> cystic fibrosis-> CFTR

Question 9

How common are channelopatheis

Answer 9

Most are inherited, very few spontaneous
>60 ion channel related genes are known
CFTR-> most common inherited disease -> CF transmembrane Regulator -> 1 in 25 Caucasian carriers, 1 in 2500 births
-> over 1000 mutations >2/3 have a common mutation
-> regulates Cl secretion
-> prone to chest infections, sinusitis, infertility, excessive salty sweat
-> recessive
-> so common because it’s advantageous? -> protective against excessive fluid loss in diarrhoea -> less dehydration

Question 10

How rare are channelopathies

Answer 10

Least common-> spontaneous
-> timothy syndrome -> 1 in 200,000 births-> wide spectrum of disorders-> autism, LQT, syndactyly, immune deficiency, cognitive abnormalities, every tissue
Cav1.2-> identified by long QT, gain of function-> loss of v.d. Handel inactivation
Can be lethal

Question 11

Long QT

Answer 11

1:5,000
Manifests in children and teenagers
Precipitated by arousal, loud noises, excise
Symptoms-> LQT prolongation of ECG QT interval-> life threatening arythrmias, prolonged V repolarisation-? VF
8 different genes-> 7 inherited, 1 spontaneous

Question 12

Dominant negative effect LQT 1

Answer 12

Most common, least severe 35%
Multiple mutations
KCNQ1 KvLQT1-> slow delayed rectifier K+ current-> mayor re polarising current of phase 3 cardiac AP
Decrease ability to re polarise-> slow->Increased QT times
Mutated monomer formers tetramer with wt K+ channel subunits-> heteromerisation-> 50% wt, 50% mt
Random association->
-> no or 1 mt-> wt hemomeric
-> 2-3 mt-> heteromeric
-> all 4 -> nt-
All channels with mutant subunits strongly effected
Decreased number of fully effective channels
Effect depends on deleterious effect of mt

Question 13

Diversity of channelopathies

Answer 13

Clinical phenotype and severity are multi factoral
Genetic background
Environment
Location-> specific organ
Pharmacologically unmasked-> malignant hypothermia

Question 14

Nav mutations

Answer 14

Most lead to hyper excitability 
SkM-> myotonia
CNS -> epilepsy
PNS-> pain syndromes
Gain of function-> loss of inactivation 
-> leak current-> constant depolarisation
-> reduce relative refractory period
-> hyper excitability

Question 15

Generalised epilepsy

Answer 15

Mutation in SCN1A-> codes for Nav 1
Persist at non inactivating current
Facilitates neuronal hyper excitability 
2-5% change is enough to cause disorder
Na channels always open 
Treat with Na channel blocker-> lamotrigene

Question 16

SCN9A mutation

Answer 16

Nav 1.7
Gain of function due to Missence mutation
Unique to noiceptor -> noiception and AP generation
Primary erthermalgia-> burning pain. Redness, exacerbated by heat
Lowered activation threshold in c fibres-> neuronal hyperexcitability-> spontaneous AP

Question 17

Nav loss of function

Answer 17

Lack of pain
SCN9A Nav 1.7
Complete loss of function on c fibres

Question 18

SCN4A

Answer 18

Nav 1.4
Unique to skeletal muscle
Necessary for AP generation 
Hypothermic periodic paralysis 
Limb weakness for serval days
Impaired inactivation-> persistent back ground current-> repetitive APs