lecture 07 ppCNS: channelopathies

define channelopathies

a channel dysfunction; can be caused by genetics, antibodies, toxins, or channels acting as lethal agents

how can channelopathies be caused ?

1. radiation
2. infection
3. chems & toxins
4. germline (error in DNA rep)
5. somatic (error in development)
6. experiments

what types of mutations can occur in genes (3)?

point mutation

nonsense mutation

frameshift mutation

define point mutation

single base code change causing a.a to change

define nonsense mutation

single base change, but produces STOP codon; produces biologically inactive channel

define frameshift mutation

single base insert changes rest of codon seq, altering a.a seq from point of insert (also can cause premature STOP codon)

what are 4 types of genetic disease categories?

1. autosomal dominant
2. autosomal recessive
3. dominant negative
4. haploinsufficiency

define the 4 types of genetic diseases

1. autosomal dom: disease expressed in heterozygote
2. autosomal rec: disease expressed in homozygote (hetero is carrier)
3. dom neg: mutant protein disrupts function of normal protein
4. haploinsufficiency: both genes req for full function

what are 3 specific channelopathies which can affect the nervous system?

1. hyperkplexia
2. generalised epilepsy w febrile seizures (GEFS)
3. benign familial neonatal seizures (BFNS)

what is hyperkplexia?

* stiff baby syndrome
* muscle spasm in response to unexpected stimuli; muscle tone increased so become rigid

what type of mutation is hyperkplexia?

autosomal dominant point mutation

what does the mutation cause on a molecular level in hyperkplexia?

* activation of motor neuron causes ACh release for contraction
* Renshaw Cells also release Gly to conduct -ve feedback on ACh release (to stop over activation)
* in hyperkeplexia patients, the __GlyR is INACTIVE__, so tons of ACh AND Gly get released, but as receptor is non-functioning, motor neuron w GlyR is NOT active and response is wrong for ACh release

hyperekeplexia is an example of WHAT type of lesion?

UMN lesion due to the symptoms exhibited

* inhibition of spinal arc reflex in **corticospinal** tract

overall, what happens in hyperkplexia (and what 3 responses do we see)?

* reduced glycinergic inhibition in SC leading to exaggerated reflex & hypertonia due to **defect in GlyR**
* protein still in cell, but is __non-functioning;__ result is Cl- channel opening less freq when exposed to Gly, result in less inhibition


1. exaggerated reflexes
2. hypertonia
3. exaggerated startle response

how do Renshaw Cells operate normally ?

Renshaw Cells directly inhibits the alpha MN, releasing **glycine** on **GlyRs** to in**h**ibit **ACh** **release** from GlyRs causing negative feedback to control reflexes

what is (generalised epilepsy w febrile seizures) GEFS? 

* convulsions
* fever
* for children

what type of mutation is GEFS? 

autosomal dominant point mutation , acts as “gain of function” mutation

what happens in GEFS on a molecular level?

* ß subunits, which coassemble w large alpha-subunit, can alter inactivation kinetics of the alpha subunit
* disulphide bond no longer formed bc sys → trp; structure of protein changes
* subunits can still assoc w channel, but are slower inactivation leading to persistent inward Na+ current

overall, what happens in GEFS?

* slower inactivation of Na+ channel, persistent INWARD Na+ current
* more depolarised membrane & hyperexcitability leading to seizures

what is BFNS?

benign familial neonatal seizures

* recurrent seizures in early life
* starts within first 3 days
* resolves spontaneously within 3 months
* (increased risk of epilepsy in 10-15% of individuals later in life)

what type of mutation is BFNS? 

frameshift mutation, haploinsufficiency (300 a.a deletion)

what happens in BFNS on a molecular level? 

* 2 subunits of KCNQ2 & KCNQ3 channels make K+ channel (Kv7) in CNS & PNS; subunits come together to make functional channel
* M current, which Kv7 generates, controls repetitive firing in neurons to make them fire in controlled matter
* we get a non-functional K+ channel from ONE allele, and one gene cannot produce enough for normal function, so we have a lack of M-current (get too much firing)

overall, what happens in BFNS? 

* non-functional Kv7 channel
* No M-current, leading to high neuronal firing and seizures

what 2 receptors are involved in hyperkplexia and what SPECIFIC cell is involved ?

as we know, hyperkplexia is caused by **reduced glycinergic inhibit in the SC.**

* NAChRs work FINE
* GlyRs are IMPLICATED

GlyRs release Glycine AND ACh on MN AND **Renshaw Cells**.

* GlyRs triggers activation of MNs in the SC for contraction
* Renshaw Cells release Gly on GlyRs to inhibit overreaction (-ve feedback)

*in* ***hyperkplexia,*** *GlyR is INACTIVE, so tons of ACh is released on skeletal muscle.*

what are the limitations of gene therapy?

* how do we get gene intones cell
* how do we get correct cell
* how do we insert gene into genome w/o disrupting other genes
* how do we ensure gene is under normal cellular controls