Neurodevelopmental Disorders (II) Flashcards
True/False? Females are also affected by FXS
True
Although it is X-linked, females are also affected (although incidence is rare)
Roughly the same symptoms are present, but much less pronounced
What gene mutation causes FRX? What does this gene code for?
Xq27.3, FMR1 gene
Codes for FMRP
What does FMRP do and what happens when it is knocked out?
FMRP is involved in hypermethylation of CCG islands (inhibition of protein synthesis)
KO of FMRP (as seen in FXS) leads to unregulated protein overexpression.
What was the previous hypothesis for protein expression localisation in neurons? What did FMRP prove?
It was thought that all expression occurs in the soma of the neuron and proteins were shuttled down the axon/dendrite to its desired location
It was discovered that FMRP forms a messenger ribonucleoprotein complex involved in local protein synthesis, disproving this theory
Besides hypermethylation, what is another role for FMRP?
FMRP can also associate with mRNAs in the nucleus to escort them into and out of the nucleus (associated with Nuclear Localisation Sequence and Nuclear Export Sequence)
What happens when mGlur5 is activated? What happens to this effect during FRX?
mGlur5 activation leads to Long Term Depression of synaptic responses
This effect is exaggerated in FRX KO mice
Are FXS symptoms due to a lack of effective connections or an excess?
An excess
What mGluR group is regulated by FMRP?
What happens when FRMP is KO as seen in FXS?
What class of drugs can treat this?
Group I mGluRs
FMRP KO = overespression of mGluR type I, too many connections
Pathway can be blocked with mGluR blockers
What are the abnormal phenotypes of FXS mouse that are corrected by mGluR5 blockers?
Audiogenic seizures Epileptiform bursts Open Field behavior Dendritic spine shape AMPA receptor internalization Excessive Protein synthesis
Name one mGluR5 blocker
MPEP
Why did MPEP fail?
It only worked in a mouse model (not in a human model)
Name an mGluR5 blocker that is effective in humans
Trick question: there are none (for now)
What drug seems to ameliorate core deficits in a mouse model of FXS? How does it work?
Metformin (Type II diabetes drug)
Mechanisms aren’t fully understood but it involves the inhibition of mTORC (which is related to FMRP)
What are the symptoms of Christianson Syndrome?
Non-verbalism Intellectual disability Epilepsy Truncal Ataxia Postnatal microcephaly Hyperkinesis Autistic Behaviour Cerebellar atrophy Regression >10yrs
What gene mutation causes Christianson Syndrome? What does this gene encode?
SLC9A6 gene mutation
Encodes Na/H Exchanger 6 (NHE6)
