Epilepsy mutations Flashcards
Two states of ion channel
- Intrinsic: mutations in ion channel.
- Extrinsic: normal ion channel sequence
Intrinsic mutations:
Mis-sense
A single point mutation in the coding region of DNA
Causing a change in the triplet codon leading to a change in the amino acid (N->S).
Incorporated into the protein during translation
Known as mis-sense
Intrinsic mutation:
Non-sense?
If the codon change generates a stop codon.
Translation is terminated at this point
Generates a short protein.
Intrinsic mutations
Frame shift 1: insertion?
Mutation is an addition of a single base.
the reading frame is altered.
Completely unrelated protein to the parental DNA.
Intrinsic mutations:
Frame shift 2 (deletion)
A frame-shift occurs upon the deletion of a single base.
A stop codon is encountered that exist out of frame in the parental DNA.
What is the resting potenetial of a neuron?
-70mV
What does glutamate do to this resting potential?
Make it more positive
Depolarises the cell
What does the GABAA do the resting potential of a neurone?
Makes it more negative
Hyperpolarisation
Action potential?
Excitation and inhibition balance.
Moves towarsd depolarisation to fire AP.
Multiple inputs are required to make this happen
Therefore AP is not just erratic but buffered
The shape of the graph for an AP?
AS7
Wave effect?
AP move as a wave from the cell body down the dendrites onto post-synpases.
Propagation?
During the AP sodium channels are open.
Downstream: channels are inactivated- takes time for them to be reactivated.
Upstream:sodium channels are closed.
Wave effect: leaving behind a trail of inactivated sodium channels
What is the percentage of population that has anxiety disorders?
Name the 3 types of anxiety disorders?
25% of population
Phobias
Panic disorders
Post-traumatic stress
What is the treatment for anxiety?
Diazepam
Increases GABAA receptor function
What genetic variation is responsible for anxiety?
Decrease gamma2 expression
Increase in anxiety levels
Name the 3 post-translational processing related to protein biogenesis?
- Protein glycosylation
- Disulphide bond formation
- Protein folding(2nd-3rd) and oligomerisation (4th- coming together to produce a protein receptor)
Glycosylation?
In ER and Golgi
the formation of linkages with glycosyl groups.
BiP/calnexin?
Fomrs tertiary and quaternary structures.
Aided by chaperone proteins
Disulphide bonds?
Essnetial disulphide bonds are needed
Only when the correct disulphide bond is formed will the substrate be released
GABAA receptor?
5 TM
GABA binding site at the interface between alpha and beta subunits.
Benzodiapin binds between the alpha and gamma
What is the success rate of getting the correct confirmation for the GABAA receptor?
20-30%
Chaperon
a family of proteins that aid in the folding of target proteins.
Name the 2 epilepsy mutations?
Gamma2 subunit mutation
Alpha1 subunit mutations
Name the 3 types of gamma2 subunit mutations?
R43Q
K289M
Q351X
Name the type of alpha1 subunit mutation
A322D
Other mechanisms that cause epilepsy?
- Channel function
- Rasmussen’s encephalitis
- Stargazin mutation
- Environmental contaminants
R43 forms?
Inter-subunits contacts.
Interaction between the alpha-beta and gamma-alpha.
Loss of interaction between gamma and beta.
Some activity still there but efficiency is decreased.
R82Q and P83S?
Similar effects of gamma2.
Name the 3 epilepsy mutations?
R43Q
R82Q
P83S
Gamma 2 (R117G)
Reduces current density.
Gamma2 subunit is quiet but the alpha and beta subunits can still make a receptor.
A332D mutation?
Unstable regardless of assembly.
Alpha1 subunit no longer expressed.
R46W muation?
Associated with childhood absense epilepsy.
Affects receptor channel gating and expression.
Sodium channels?
Voltage gated
Generalised epilepsy with febrile seizures- convulsions and fever.
Hyper excitability- therefore these channels are easier to activate therefore seizures.
Potassium channels?
Voltage gated.
Episodic ataxia.
Decreased function of potassium channels-AP is now prolonged.
ataxia?
describes a group of neurological disorders that affect co-ordination, balance and speech
Migraine?
What channels
Prevalence figures
Symptoms
calcium channels
Prevalence: 24% females; 12% males.
Headaches, nausea, vomiting, sensitivity to light
Calcium channels?
Voltage gated
alpha1A mutation:
Types of mutation
What channel does it affect?
It affects calcium channels
Cause: missense, nonsense, aberrant splicing and insertion.
Familial Hemiplegic Migraine?
Rare
Paralysis to half of body.
Progressive cerebellar atrophy.
Decrease function of all channels due to missense voltage sensor
Episodic ataxia?
Type of mutations?
Neurodegenerative.
Lack of response.
Non-functional
Types of mutations: frameshift and subsitution
Spinocerebellar ataxia?
Slow progressive cerebellar ataxia.
Severe neuronal loss in cerebellum
Expansion of the mutation at each generation.
Alpha1 subunit mutations?
Tottering mice
Absence/motor seizures
Ataxia.
Leaner mice
Absense/motor seizures
Beta subunit mutations?
Lethargic mice
Absence seizures
Ataxia
Gamma subunit mutation?
Stargazer mice
Epilepsy
Rasmussen’s encephalitis?
Progressive: only in a single cerebral hemisphere.
Causes severe epilepsy.
Hemiplegia (paralysis in one side)
Dementia
Brain inflammation
Environmental triggers
Extrinsic factors?
When neuronal activity applies there is an increase in lateral diffusion of the neurotransmitter.
Therefore can reach more receptors.
Stargazer mutation?
Head tossing
Epileptic seizure
Ataxic
Effects the gamma subunit of the calcium channel (intrinsic mutation)
Intrinsic mutation?
situated entirely within or pertaining exclusively to this receptor.
Extrinsic?
Affects the postsynaptic receptors instead of the presynaptic receptors in which it originates from
Environmental excitotoxins for glutamate recepotrs?
Shellfish
Ibotenic acid
MSG
BMAA
Environmental excitotoxins for the GABAA receptors?
RDX explosives.
Organochlorine pesticides
PCBs
