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
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
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)
