L07 Flashcards
what is a phenotype
An observable physical properties of an organism
what are channelopathies
a group of disorders caused by dysfunction in ion channels
how are channelopathies explained
genetics
acquired
which disease has a monogenic channelopathy
cystic fibrosis
give an example for an idiopathic channelopathy
postoperative pain
give an example for acquired channelopathy
myasthenia gravis
what are the features of cystic fibroses
Monogenic- arises from mutations in the CFTR gene.
Dysfunction in the influx of chloride ions (and water).
Leads to mucus accumulation and inflammation.
Subtypes functionally classified on the effect of the mutation on the channel.
Identified by genetic linkage
what happens in CF class 1
no creation of the protein (CFTR) from mRNA
what happens in CF class 2
CFTR is made but it fails to fold or get trafficked to the cell membrane
what happens in CF class 3
CFTR gating fails due to a mutation in the residues that control it
what happens in CF class 4
faulty CFTR is produced
what happens in CF class 5
insufficient quantities of CFTR
what happens in CF class 6
CFTR stability is reduced at the cell membrane
what are the methods of investigating genetic linkage
LINKAGE MAPPING
ASSOCIATION MAPPING
CF is Autosomal recessive
yes
what does 100% penetrance mean
Got the allele → Got the trait
what gene encodes voltage gated Na channel subtype 1.7
SCN9A
which genes encode which voltage gated Na channel subtype
SCN1A – 1.1
SCN2A – 1.2
SCN3A – 1.3
SCN4A – 1.4
SCN5A – 1.5
SCN8A – 1.6
SCN9A – 1.7
SCN10A – 1.8
SCN11A – 1.9
which subunit of the voltage gated Na channel does SCN9A encode
alpha
what is the effect of Nav1.7- on action potential
Contributes to the rising phase and amplifies subthreshold stimuli
what are the features of Nav1.7-
Low activation threshold (vs other NaV channels)
Fast kinetics
TTX responsive
SCN9A (Nav1.7) is highly expressed by sensory neurons of the Dorsal Root Ganglion DRG
yea
what does Q10R MEAN
R substituted for Q
what conditions are associated with SCN9A mutations
Paroxysmal extreme
pain disorder (PEPD)
(Primary) inherited erythromelalgia (IEM)
Small-fibre neuropathy
what are the features of Inherited Erythromelalgia (IEM)
Mutation(s) in SCN9A (autosomal dominant)
Bilateral episodes of burning pain in feet & hands
Attacks triggered by exercise and/or heat
Onset in childhood and continued through adult life
how do SCN9A mutations lead to IEM
First mutation L858H, located in the second domain (Yang et al 2004).
The mutations lower the activation threshold, allowing the mutant channels to open more easily in response to smaller depolarizations.
They slow or impair fast inactivation, resulting in prolonged channel opening times.
The mutations enhance the ramp response, causing larger currents in response to small, slow depolarizations.
Some mutations also impair slow inactivation, leading to increased channel availability.
The mutations shift the voltage-dependence of activation and inactivation, making the channel activate at more hyperpolarized potentials.
Increased excitability correlates with symptom severity
what are the features of Paroxysmal extreme pain disorder
Mutation in SCN9A (autosomal dominant)
Severe pain in the rectal, ocular and mandibular areas
Attacks triggered by chewing and/or heat
Onset in childhood and continued through adult life
how do SCN9A mutations cause PEDP
Lowered threshold for channel activation - the channel opens more easily in response to small depolarizations
Delayed channel inactivation - the channel stays open longer than usual
Enhanced response to repetitive stimulations - the channel recovers more quickly between activations
Altered voltage-dependence - the relationship between membrane voltage and channel opening is shifted
what are the features of Complete insensitivity to pain (CIP)
Mutation in SCN9A (autosomal recessive)
Loss of all pain sensations
Tend to be non-sense mutations (within domains I & II) leading to a truncated protein
CIP patients often suffer major injuries as a result
which disease is associated with enhanced activation of SCN9A
IEM
which disease is associated with impaired activation of SCN9A
PEPD
what are the autonomic effects of IEM and what are they caused by
cutaneous vasomotor abnormality
caused by sympathetic ganglion neuron being less excitable
what are the autonomic effects of PEPD
skin flushing and watering of eyes and mouth
what are the autonomic effects of CIP
there is non reported
SNPs are studied to see if they are associated with a particular trait
yes
which condition is associated with olfactory pathways
CIP
how is anosmia caused in people with CIP
impaired signaling of olfactory sensory neuron
