Hi Jimmy,
Thanks for your question. There are a vast number of signal
transduction pathways in the Central Nervous System (CNS) neurons, so
I will try to spread the 4 answers over the classes you gave as
examples (receptors/neurotransmitter malfunction, ion channel
malfunction, heterotrimeric/small G-proteins, and kinases).
1. Receptors / Neurotransmitter malfunction: A specific molecular
mutation in the Dopamine receptor DRD2 (Dopamine Receptor, subtype
D2), in which an Adenosine (A) is substituted for a Guanidine (G) at
the first base of codon 154, results in a substitution of Isoleucine
for Valine in the translated protein (a missense mutation). This may
seem insignificant, but this Valine is highly conserved across many
species, implying that it serves an important function. This position
lies in the middle of a transmembrane domain of the receptor, likely
important in agonist binding. Some studies have suggested that the
mutation disrupts signal transduction between the receptor's agonist
binding site and it's intracellular domain, which is linked to a
G-protein.
So, how does this relate to disease? In this particular case, it
likely results in myclonus dystonia, a disease in which muscles
contract uncontrollably and painfully, thought to be due to the effect
of the mutated DRD2 receptor in the basal ganglia in the brain. It
may also play a role in mood disorders and addiction. Here's some
more info from the paper below:
"Dopamine is the predominant catecholamine neurotransmitter in the
central nervous system. Disturbances of the dopaminergic system are
relevant in the etiology of various movement disorders, such as
Parkinson’s disease, the dopa-responsive dystonias, and early-onset
torsion dystonia. Among the five dopamine receptors (D1–D5) identified
so far, DRD2 is a particularly attractive candidate to cause MD, as it
is known to control various functions of the central nervous system,
including movement, positive reinforcement/addiction, and possibly
emotion, all of which are affected to a certain extent in at least
some patients with MD [Myoclonus Dystonia]."
See, for example, the following paper (full text) from the NIH PubMed
service:
http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=10220438
2. Ion channels: The sodium channel is important in the propagation
of action potentials in neurons, both in the CNS and in the peripheral
nervous system. A missense mutation in the alpha subunit of the
Sodium Channel, Neuronal Type I (SCN1A) at several possible locations
results in Generalized Epilepsy with Febrile Seizures (GEFS), which
can run in families. Two possible mutations are a substitution of
Threonine at position 875 or a substitution of a Arginine at position
1648. See the site below for other possibilities. These positions,
like the example above, have been conserved in many different species,
implying that they serve an important functional purpose. See the
site below for other possibilities. The NIH site below also mentions
the currently accepted molecular mechanism by which these mutations
all cause disease. Here’s an excerpt:
"SCN1A mutations altered channel inactivation, resulting in persistent
inward sodium current. This gain-of-function abnormality was expected
to enhance excitability of neuronal membranes by causing prolonged
membrane depolarization, a plausible underlying biophysical mechanism
responsible for autosomal dominant generalized epilepsy with febrile
seizures plus."
NIH OMIM GEFS+ page:
http://www.ncbi.nlm.nih.gov:80/entrez/dispomim.cgi?id=182389
3. G-proteins: The first example above is, to some extent, involved
in a G-protein malfunction (in that the signal doesn't get form the
receptor to the G-protein). Here's some background from the 1st site
below:
"Heterotrimeric G proteins bind to cell surface receptors and are
integral in transmission of signals from outside the cell. Upon
activation of the G-alpha subunit by binding of GTP, the G-alpha and
G-beta-gamma subunits dissociate and interact with effector proteins
for signal transduction."
An important class of G-protein coupled receptors in the CNS are the
opioid receptors. One of these, the Mu-1 receptor, may have several
allelic variations in the human population. One of these, a
substitution of Aspartic Acid for Asparagine at position 40 confers 3
times greater binding of the receptor to the endogenous opiod
beta-endorphin. Clinically, this is seen as a reduced response to
morphine (less pupillary constriction, etc.). See the second site
below for more details.
Heterotrimeric G protein page at NIH OMIM:
http://www.ncbi.nlm.nih.gov:80/entrez/dispomim.cgi?id=602513
Mu-1 receptor page:
http://www.ncbi.nlm.nih.gov:80/entrez/dispomim.cgi?id=600018
4. Kinases: William's Syndrome (aka William-Beuren Syndrome) is a
disease in which the genes for both elastin and LIM kinase are
deleted. Deletion of the elastin gene primarily causes peripheral
defects, including supravalvular aortic stenosis, mental retardation,
elfin facies, and transient hypercalcemia in infancy. Deletion of the
LIM kinase is thought to cause impaired visuospatial constructive
abilities. Individuals with deletion of only the elastase gene do not
share the visuospatial difficulties of William's Syndrome patients.
The LIM Kinase-I is most highly expressed in the cerebral cortex. The
NIH OMIM site also gives the following information on the
developmental ramifications of this deletion:
"The behavioral phenotype in Williams syndrome suggests a dorsal
and/or ventral developmental dissociation, with defects in dorsal but
not the ventral hemispheric visual stream. A shortened extent of the
dorsal central sulcus had been observed in autopsy specimens."
NIH William's Disease page:
http://www.ncbi.nlm.nih.gov/disease/Williams.html
NIH OMIM William's Disease page:
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=194050
Visuospatial construction paper:
http://www.journals.uchicago.edu/AJHG/journal/issues/v65n5/990624/990624.html
William's Disease Literature survey:
http://www.indiana.edu/~pietsch/williams-contents.html
Also, a generally very good place to look for information on genetic
diseases, mutations, signaling abnormalities, etc., is the NIH Online
Mendelian Inheritance in Man (OMIM) Database:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
I hope this was helpful. Feel free to post if you require
clarification.
-Frank [welte-ga] |
