L7 - channelopathies Flashcards
define channelopathy
dysfucntion in io channels
what can cause channelopathies
genetics
antibodies
toxins
channels themselves
what can cause genetic mutations in channels
radiation (UV, X-rays) viruses chemicals and toxins germ line (errors in DNA replication) Somatic (errors in DNA replication)
what is a point mutation
mutation where one nucleotide in the codon is replaced by another
may or may not change the AA (silent)
what is a nonsense mutation
a point mutation that results in STOP codon being encoded
when is a point mutation likely to / not likely to be silent?
if the mutation occurs in the last nucleotide its possible it may be silent.
if it occurs in the first 2 it is more likely to change the AA thats encoded
what is a frameshift mutation
insertion or deletion of a nucleotide in the sequence which changes all downstream codons
define autosomal dominant disease
disease expressed in heterozygote, only one allele needed for disease to present
define autosomal recessive disease
disease only expressed in homozygote - two alleles needed
heterozygotes are carriers
define dominant negative disease
where the mutant protein disrupts the function of the normal protein
define haploinsufficiency
both genes ( so each allele) are required for full function
for most cases we only require the genes from one allele for full fucntion
where does the mutation in Hyperekplexia occur
the gene encoding glycine receptor
nAChR like receptor
symptoms of Hyperekplexia (stiff baby syndrome)
muscle spasm in response to unexpected stimuli
-> become rigid and fall over
increased muscle tone as infant (hypertonic)
describe the genetics of hyperekplexia
dom/res, linkage
- autosomal dominant
- genetic linkage on chromosome 5q32 (same place as the glycine receptor)
describe the mutation and where it occurs in hyperekplexia
what does it result in regarding to the channel activity
R271Q in GLRA1
this means point mutation at residue 271 - arginine to glutamine in the glycine receptor, alpha 1 subunit gene
the mutation occurs on TMD2 which is involved in the pore of the channel -> causes channel to lose its ability to respond to glycine, less Cl flow
how does the change in channel activity (in hyperekplexia) lead to the symptoms observed in the disease
usually in the spinal cord there is glycinergic inhibition of ACh release (from motor neurones to skeletal muscle) via ACh acting on renshaw cells to release glycine (negative feedback)
however in hyperekplexia the glycine receptor no longer responds efficiently to this glycine released, so there is less inhibition and more ACh released to muscles
what channel is affected in Generalised Epilepsy with Febrile Seizures (GEFS)
voltage gated Na channel
symptoms of GEFS
convulsions
fever
could result in generalised epilepsy in later life
childhood disease usually resolves with age
describe the genetics of GEFS
dom/res, linkage
autosomal dominant
linkage chromosome 19q13.1
same place as SCN1B ( sodium channel Beta 1 subunit gene)
which is the long and which is the short arm of the chromosome ?
P -> short
q -> long
(how to remember: tail of q goes down, it is the bottom long section of the chromosome)
describe the mutation in GEFS
point mutation C121W (cysteine at 121 replaced by tyrptophan)
what is the normal function of the B subunit of the VG Na channel and how does the mutation in GEFS affect this
the B subunit has no role in the pore or voltage sensing but can sometimes bind to the (very long) alpha subunit regulating its function
the mutation and loss of cysteine means a disulfide bond cant form in the mutated version where it normally would in the wild type protein
leads to slower inactivation of the channel, so increased Na entry and longer lasting depolarisation (hyperexcitability
what channel is affected in Benign Familial Neonatal Seizures (BFNS)
ligand gated K channel
symptoms of BFNS
- recurrent seizures in early life#
- starts within first 3 days and resolves within 3 months
- increased epilepsy in later life
describe the genetics of BFNS
location of mutation etc
linkage to 20q13.3 (same place as KCNQ2) a gene for K channel
frameshift mutation that leads to ~300AA deletion
leads to haploinsufficiency (one gene isnt sufficient - too few channels)
where are KCNQ2 channels found and what is their usual function?
nodes of ranvier
axon hillock
they are involved in controlling the M current (amount of recurring APs generated - like refractory period)
how does the mutation in BFNS alter aactivity of the channel
the mutation isnt in the pore or voltage sensor
the deletion occurs on the C terminal resulting in a non functional protein - not enough K channels expressed
causes repeated AP firing (seizures)
what might explain why childhood channelopathies (BFNS and GEFS) resolve on their own?
by the body altering expression of the mutated subunit type ( there are several types of each a and B subunit, one of the others may not be mutated)
gene therapy could be an option in channelopathies, what are its limitations
have to consider:
- how to get gene into cell
- how to get gene into correct cell
- how to insert a gene without disrupting other genes in the genome
- how is it ensured that the gene is under normal cellular controls
