L07

Question 1

what is a phenotype

Answer 1

An observable physical properties of an organism

Question 2

what are channelopathies

Answer 2

a group of disorders caused by dysfunction in ion channels

Question 3

how are channelopathies explained

Answer 3

genetics

acquired

Question 4

which disease has a monogenic channelopathy

Answer 4

cystic fibrosis

Question 5

give an example for an idiopathic channelopathy

Answer 5

postoperative pain

Question 6

give an example for acquired channelopathy

Answer 6

myasthenia gravis

Question 7

what are the features of cystic fibroses

Answer 7

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

Question 8

what happens in CF class 1

Answer 8

no creation of the protein (CFTR) from mRNA

Question 9

what happens in CF class 2

Answer 9

CFTR is made but it fails to fold or get trafficked to the cell membrane

Question 10

what happens in CF class 3

Answer 10

CFTR gating fails due to a mutation in the residues that control it

Question 11

what happens in CF class 4

Answer 11

faulty CFTR is produced

Question 12

what happens in CF class 5

Answer 12

insufficient quantities of CFTR

Question 13

what happens in CF class 6

Answer 13

CFTR stability is reduced at the cell membrane

Question 14

what are the methods of investigating genetic linkage

Answer 14

LINKAGE MAPPING

ASSOCIATION MAPPING

Question 15

CF is Autosomal recessive

Answer 15

yes

Question 16

what does 100% penetrance mean

Answer 16

Got the allele → Got the trait

Question 17

what gene encodes voltage gated Na channel subtype 1.7

Answer 17

SCN9A

Question 18

which genes encode which voltage gated Na channel subtype

Answer 18

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

Question 19

which subunit of the voltage gated Na channel does SCN9A encode

Answer 19

alpha

Question 20

what is the effect of Nav1.7- on action potential

Answer 20

Contributes to the rising phase and amplifies subthreshold stimuli

Question 21

what are the features of Nav1.7-

Answer 21

Low activation threshold (vs other NaV channels)

Fast kinetics

TTX responsive

Question 22

SCN9A (Nav1.7) is highly expressed by sensory neurons of the Dorsal Root Ganglion DRG

Answer 22

yea

Question 23

what does Q10R MEAN

Answer 23

R substituted for Q

Question 24

what conditions are associated with SCN9A mutations

Answer 24

Paroxysmal extreme
pain disorder (PEPD)

(Primary) inherited erythromelalgia (IEM)

Small-fibre neuropathy

Question 25

what are the features of Inherited Erythromelalgia (IEM)

Answer 25

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

Question 26

how do SCN9A mutations lead to IEM

Answer 26

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

Question 27

what are the features of Paroxysmal extreme pain disorder

Answer 27

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

Question 28

how do SCN9A mutations cause PEDP

Answer 28

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

Question 29

what are the features of Complete insensitivity to pain (CIP)

Answer 29

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

Question 30

which disease is associated with enhanced activation of SCN9A

Answer 30

IEM

Question 31

which disease is associated with impaired activation of SCN9A

Answer 31

PEPD

Question 32

what are the autonomic effects of IEM and what are they caused by

Answer 32

cutaneous vasomotor abnormality caused by sympathetic ganglion neuron being less excitable

Question 33

what are the autonomic effects of PEPD

Answer 33

skin flushing and watering of eyes and mouth

Question 34

what are the autonomic effects of CIP

Answer 34

there is non reported

Question 35

SNPs are studied to see if they are associated with a particular trait

Answer 35

yes

Question 36

which condition is associated with olfactory pathways

Answer 36

CIP

Question 37

how is anosmia caused in people with CIP

Answer 37

impaired signaling of olfactory sensory neuron