Synaptic Ras GTPase-activating protein 1, also known as synaptic Ras-GAP 1 or SYNGAP1, is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in
humans
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
is encoded by the ''SYNGAP1''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
SYNGAP1 is a
ras GTPase-activating protein that is critical for the development of cognition and proper
synapse
In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell.
Synapses are essential to the transmission of nervous impulses from ...
function. Mutations in humans can cause
intellectual disability,
epilepsy
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...
,
autism
The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
and
sensory processing deficits.
Function
SynGAP1 is a complex protein with several functions that may be regulated temporally via complex
isoforms
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
.
A well-documented function of SynGAP1 involves
NMDA receptor
The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...
-mediated synaptic plasticity and membrane insertion of
AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synapse, synap ...
s through the suppression of upstream signaling pathways.
However, SynGAP1 has also been shown to function cooperatively with
Unc51.1 in
axon formation.
One way SynGAP1 affects these processes is through the
MAP kinase signaling pathway by attenuation of
Ras
Ras or RAS may refer to:
Arts and media
* RAS Records Real Authentic Sound, a reggae record label
* Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service
* Rás 1, an Icelandic radio station
* Rás 2, an Icelandic radio stati ...
signalling.
However,
alternative splicing
Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...
and multiple translational start sites have been shown to cause opposing effects, illustrating the importance of multiple functional domains that reside within the c- and n-termini. For example, the expression of an α1 or α2 c-terminal variant of SynGAP1 will either increase or decrease synaptic strength, respectively.
Overall, SynGAP1 is essential for development and survival, which is evident as
knockout mice
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
die perinatally.
Dendritic spine development and maturation
SynGAP1 is shown to localize at the
postsynaptic density on the
dendritic spines of excitatory synapses.
Cultured neurons of SynGAP heterozygotic and homozygotic knockout mice display accelerated maturation of
dendritic spines, including an increase in overall spine size, which produces more mushroom shaped and less stubby spines.
Spine heads are enlarged due to the increased
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of
cofilin, leading to a decrease in F-
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
severing and turnover. The increased size of the dendritic spines also corresponded to an increase in membrane bound AMPARs or a decrease in
silent synapses
In neuroscience, a silent synapse is an excitatory glutamatergic synapse whose postsynaptic membrane contains NMDA-type glutamate receptors but no AMPA-type glutamate receptors. These synapses are named "silent" because normal AMPA receptor-media ...
. These neurons displayed a higher frequency and larger amplitudes of miniature
excitatory postsynaptic potentials
In neuroscience, an excitatory postsynaptic potential (EPSP) is a postsynaptic potential that makes the postsynaptic neuron more likely to fire an action potential. This temporary depolarization of postsynaptic membrane potential, caused by the ...
(mEPSP).
Mice models with domain specific mutations led to neonatal hyperactivity of the hippocampal trisynaptic circuit.
Mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s had the greatest impact during the first 3 weeks of development, and reversal of mutations in adults did not improve behavior and cognition.
Clinical significance
Several mutations in the SYNGAP1 gene were identified as the cause of intellectual disability. Intellectual disability is sometimes associated with
syndromes
A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek σύνδρομον, meaning "concurrence". When a syndrome is paire ...
of other defects caused by the same gene, but SYNGAP1-associated intellectual disability is not; it is therefore called non-syndromic intellectual disability. Since neither of the parents of children with this condition have the mutation, this means it was a sporadic mutation that occurred during division of the parents' gametes (
meiosis
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately resu ...
) or fertilization of the egg. It is a
dominant mutation, which means that the individual will be developmentally disabled even if only one
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
is mutated.
Mutations in this gene have also been found associated to cases of developmental and epileptic
encephalopathies,
autism spectrum disorder, and touch-related sensory processing deficits.
Epilepsy in this disorder is distinctive, combining eyelid myoclonia with absences and myoclonic-atonic seizures. Seizures are often triggered by eating.
A causal therapy was the first successful worldwide by the group of Prof. Gerhard Kluger tested at the
Schön Klinik
Schön Klinik founded in 1985, is a clinic group based in Prien am Chiemsee (Bavaria) with 17 clinics in Germany and 10,000 employees. In 2016 approximately 100,000 patients were treated in the clinics. Michael Porter described the Schön Klinik as ...
in
Vogtareuth
Vogtareuth is a Municipalities of Germany, municipality in the district of Rosenheim (district), Rosenheim in Bavaria in Germany. It lies on the river Inn (river), Inn.
References
Rosenheim (district)
Populated places on the Inn (river) ...
with
statins. In the process, the
RAS pathway
Ras, from "Rat sarcoma virus", is a family of related proteins that are expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals ...
, which is overactive in SYNGAP1-associated intellectual disability is inhibited by
statins. Further clinical studies by the group of Prof. Gerhard Kluger are in preparation.
Interactions
SYNGAP1 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with
DLG3 and
ULK1.
References
Further reading
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External links
* {{PDBe-KB2, F6SEU4, Mouse Ras/Rap GTPase-activating protein SynGAP