Even I thought this post was rather a long slog, but I kept finding more and more evidence to support the basic premise, so I covered all the genes that came up for completeness.
I have been going on about the relevance of calcium channels in autism for years. I have also pointed out that while you
can have severe autism for a single mutated gene, you can also “just” have a
miss-expression of that same gene, without any error in the code in your DNA. You
can have a little bit of that severe autism phenotype. You can even have the opposite dysfunction, which would usually be over-expression of that gene.
Once you have miss-expression
of a gene it will cause a cascade of other effects.
This means that while you
may not be able to correct the initial genetic dysfunction, you may well be able
to treat what comes further down the cascade.
I like to look for associations, so I skip quickly through the research papers, but take note when I see links to things like:-
·
Epilepsy /
seizures
· Headaches, particularly episodic
·
Mental retardation
/ intellectual disability
·
Mathematical ability
·
High educational
attainment
·
Big Heads
·
Epilepsy /
seizures
·
Pain threshold
·
Speech development
(or lack thereof)
·
Sleep
disturbance
·
IBD (Inflammatory
Bowel Disease)
It is very easy to look up the significance of any gene.
Open the site below and just type in the name of the gene.
Today’s post does touch on complex subjects, but you can happily read it on a superficial level and get the key insights.
You have about 20,000 genes in your DNA and each
gene encodes a protein. That protein
could be something important like an ion channel or a transcription factor. Today we are mainly looking at ion channels,
the plumbing of the brain.
These 20,000 genes/proteins interact with each
other and clever people called Bioinformaticians collect
and map this data. These maps can then
show you the cascade of events that might happen if one gene/protein is
miss-expressed, perhaps due to a mutation.
Today I start with 2 genes CACNB1 and CACNA1C.
CACNB1 was only recently identified as an
autism gene
Genome-wide detection of tandem DNA repeats that are expanded in autism
CACNA1C is the gene that encode the calcium ion channel Cav1.2. It is the gene behind Timothy Syndrome and the gene that I followed to Verapamil, a key part of my son’s PolyPill therapy.
The reason the gene/protein interactions are
important is that the same therapy can be applied to different dysfunctional genes/proteins.
A person with a genetic defect in a sodium ion channel might get a therapeutic benefit
from a drug targeting a calcium ion channel.
The top 5 interactions with CACNA1C (in red):
Note CACNB1 (in blue)
There is already
lot in this blog about the calcium channel Cav1.2 (encodeded by
CACNA1C).
CACNA1C is associated with Autism, schizophrenia, anorexia nervosa, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), Tourette syndrome, unipolar depression and bipolar disorder.
Today we look at the “new” autism gene CACNB1.
It is actually much more interesting that you might
imagine, especially if you have to deal with epilepsy or periodic headaches at
home. You also might also have some Math
Whizz back there in your family tree.
We know that brainy people, particularly mathematicians, have elevated risk of autism in their family.
Having a maths protégé in the family may not be good for your kids.
We also know that bright mathematicians are very
likely to have some feature’s of Asperger’s.
The chart below expresses
the top 25 interactions with the gene CACNB1 which encodes voltage-dependent L-type
calcium channel subunit beta-1. It is the pink circle in the middle.
Click on the link for a higher resolution image, or on the image itself.
https://version11.string-db.org/cgi/network.pl?taskId=KBcDrcBSd4X6
If you look at the above chart you can spot the
genes that relate to calcium channels, they start with CAC.
At the top of the chart we 6 genes starting
with SCN. These genes relate to sodium ion channels.
SCN9A
It was interesting to me that the gene SCN9A, which encodes the ion channel Nav1.7 is associated with
insensitivity to pain. Reduced sensitivity
to pain is very common in autism. This
is a feature of Monty’s autism.
A mutation in SCN9A can also cause epilepsy. Often these seizures
are fever associated.
Local anesthetics such as lidocaine, but also the anticonvulsant phenytoin,
mediate their analgesic effects by non-selectively blocking voltage-gated
sodium channels. Nav1.7.
Other sodium channels involved in pain
signalling are Nav1.3, Nav1.8, and Nav1.9.
You would think that SCN9A would encode Nav1.9,
but it seems to really be Nav1.7. Nav1.9
is encoded by the gene SCN11A, just to see who is paying attention.
SCN8A
The SCN8A gene encodes the sodium ion channel Nav1.6. It is the primary voltage-gated sodium
channel at the nodes of Ranvier.
The channels are highly concentrated in sensory and motor axons in the peripheral nervous system and cluster at the nodes in the central nervous system.
If you have a mutation is in SCN8A you may face Cute
syndrome. You will have some severe
challenges including treatment resistant epilepsy and may include autism and
intellectual disability.
https://www.thecutesyndrome.com/about-scn8a.html
Not such a cute syndrome.
SCN4A
The Nav1.4 voltage-gated sodium
channel is
encoded by the SCN4A gene.
Mutations in the gene are associated with hypokalemic periodic paralysis, hyperkalemic periodic paralysis, paramyotonia congenita, and potassium-aggravated myotonia.
I have covered hypokalemic periodic paralysis and hypokalemic sensory overload
previously in this blog. I showed that I
could reduce Monty’s sensitivity to the sound of a baby crying by giving a
modest potassium supplement.
Mutations in SCN4A are also associated with
abnormal height and abnormalities of the head, mouth or neck.
SCN3A
The Nav1.3 voltage-gated sodium
channel is
encoded by the SCN3A gene
It has recently been shown that speech
development is affected by this ion channel.
Many people with severe autism never fully develop speech.
Sodium channel SCN3A (NaV1.3) regulation of human cerebral
cortical folding and oral motor development
Channelopathies are disorders caused by abnormal ion channel function in differentiated excitable tissues. We discovered a unique neurodevelopmental channelopathy resulting from pathogenic variants in SCN3A, a gene encoding the voltage-gated sodium channel NaV1.3. Pathogenic NaV1.3 channels showed altered biophysical properties including increased persistent current. Remarkably, affected individuals showed disrupted folding (polymicrogyria) of the perisylvian cortex of the brain but did not typically exhibit epilepsy; they presented with prominent speech and oral motor dysfunction, implicating SCN3A in prenatal development of human cortical language areas. The development of this disorder parallels SCN3A expression, which we observed to be highest early in fetal cortical development in progenitor cells of the outer subventricular zone and cortical plate neurons and decreased postnatally, when SCN1A (NaV1.1) expression increased. Disrupted cerebral cortical folding and neuronal migration were recapitulated in ferrets expressing the mutant channel, underscoring the unexpected role of SCN3A in progenitor cells and migrating neurons.
The Nav1.2 sodium ion channel is
encoded by the SCN2A gene.
Mutations in this gene have been implicated in
cases of autism, infantile spasms bitemporal glucose hypometabolism,
and bipolar disorder and epilepsy.
SCN1A
Mutations to the SCN1A gene most often results
in different forms of seizure disorders, the most common forms of seizure
disorders are Dravet Syndrome (DS), Intractable childhood epilepsy with
generalized tonic-clonic seizures (ICEGTC), and severe myoclonic epilepsy
borderline (SMEB).
Mutations are also associate with
·
Febrile
seizures up to 6 years of age
·
MMR-related febrile seizures
·
Sleep
duration
·
Educational
attainment
Now the Calcium ion channels:-
CACNB1
The gene CACNB1
encodes the Voltage-dependent
L-type calcium channel subunit beta-1.
CACNB1
regulates the activity of L-type calcium channels that contain CACNA1A, CACNA1C
or CACNA1B. Required for functional expression
L-type calcium channels that contain CACNA1D.
The
gene is associated with headaches, asthma, mathematical ability and acute myeloid leukemia
CACNB2
The
gene CACNB2 encodes the Voltage-dependent L-type calcium channel subunit beta-2.
Mutation
in the CACNB2 gene are associated with Brugada
syndrome, autism, attention deficit-hyperactivity
disorder (ADHD), bipolar disorder, major depressive disorder, and schizophrenia.
CACNB3
The gene CACNB3 encodes the Voltage-dependent L-type calcium channel
subunit beta-3.
Diseases associated with CACNB3 include Headache and Lambert-Eaton Myasthenic Syndrome.
Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder characterized by muscle weakness of the limbs.
CACNA1A
The Cav2.1 P/Q voltage-dependent calcium channel is encoded by the CACNA1A gene.
Mutations in this gene are associated with
multiple neurologic disorders, many of which are episodic, such as familial hemiplegic migraine, movement disorders such as episodic
ataxia, and epilepsy with multiple seizure types.
CACNA1B
The voltage-dependent N-type calcium
channel subunit alpha-1B is encoded by the CACNA1B gene. Diseases associated with CACNA1B include Neurodevelopmental
Disorder With Seizures And Nonepileptic Hyperkinetic Movements and Undetermined Early-Onset Epileptic
Encephalopathy.
CACNA1C (covered earlier in this blog)
The CACNA1C gene encodes the calcium
channel Cav1.2. Cav1.2
is a subunit of the L-type voltage-dependent
calcium channel.
CACNA1S
The CACNA1S gene encodes Cav1.1 also known as the calcium channel,
voltage-dependent, L type, alpha 1S subunit.
This gene encodes one of the five subunits of
the slowly inactivating L-type voltage-dependent
calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic
paralysis, thyrotoxic periodic
paralysis and malignant hyperthermia susceptibility.
Mutations
are associated with inflammatory bowel disease (IBD) and ulcerative colitis.
Note that Rezular or R-Verapamil was a drug
developed to treat IBD.
CACNA1D
The CACNA1D gene encodes Cav1.3.
Cav1.3 is required for proper hearing.
Some mutations in CACNA1D) cause excessive aldosterone production in aldosterone-producing
adenomas (APA) resulting in primary aldosteronism,
which causes treatment - resistant arterial
hypertension. These mutations allow increased Ca2+ influx
through Cav1.3, which in turn triggers Ca2+ - dependent aldosterone production. The
number of validated APA mutations is constantly growing. In rare cases, APA mutations have also been
found as germline mutations in
individuals with neurodevelopmental
disorders of different severity, including autism spectrum disorder.
Recent evidence suggests that L-type Cav1.3
Ca2+ channels contribute to the death of dopaminergic neurones
in patients with Parkinson's disease
Inhibition of L-type channels, in particular Cav1.3
is protective against the pathogenesis of Parkinson's in some animal models
CACNA1D is highly expressed in prostate cancers compared with
benign prostate tissues. Blocking L-type channels or knocking down gene
expression of CACNA1D significantly
suppressed cell-growth in prostate cancer cells
CACNA1E
CACNA1E encodes the calcium channel Cav2.3 ,
also known as the calcium channel, voltage-dependent, R type, alpha 1E
subunit.
These channels mediate the entry of calcium
ions into excitable cells, and are also involved in a variety of
calcium-dependent processes, including muscle contraction, hormone or
neurotransmitter release, gene expression, cell motility, cell division and
cell death.
Mutations are associated with epilepsy, acute myeloid leukemia, mathematical ability and having a big
head.
CACNA1F
The gene CACNA1F encodes Cav1.4.
Mutations in this gene can cause X-linked eye
disorders, including congenital stationary night blindness type 2A, cone-rod
dystropy, and Aland Island eye disease
Mutations
are associated with astigmatism
and other eye conditions.
CACNA2D1
The CACNA2D1 gene encodes the voltage-dependent calcium channel subunit
alpha-2/delta-1.
Alpha2/delta proteins are believed to be the molecular
target of the gabapentinoids gabapentin and pregabalin, which are used to treat epilepsy and neuropathic pain.
Genomic aberrations of
the CACNA2D1 gene in three patients with epilepsy and intellectual
disability
CACNA2D2
The CACNA2D2 gene encodes
the voltage-dependent
calcium channel subunit alpha2delta-2 is a protein that in humans is encoded by.
The Calcium Channel Subunit Alpha2delta2 Suppresses Axon Regeneration in the Adult CNS
CACNA2D3
The CACNA2D3 gene encodes the Calcium channel alpha2/delta subunit 3.
Cacna2d3 has been associated with CNS disorders including autism.
Synaptic, transcriptional and chromatin genes disrupted in autism
CACNA2D4
Calcium channel, voltage-dependent, alpha
2/delta subunit 4 is a protein that is encoded by the CACNA2D4 gene.
Mutations
in CACNA2D4 are associated with mathematical ability and educational
attainment.
CACHD1
CACHD1 (Cache Domain Containing 1) is not well researched, it
may regulate voltage-dependent calcium channels. It is moderately associated with anxiety.
CACNG1
The CACNG1 gene encodes the Voltage-dependent
calcium channel gamma-1 subunit
Diseases associated with
CACNG1 include hypokalemic periodic paralysis, type 1 and Malignant
Hyperthermia.
REM1
The protein encoded by this
gene is a GTPase and member of the RAS-like GTP-binding protein family. The
encoded protein is expressed in endothelial cells, where it promotes
reorganization of the actin cytoskeleton and morphological changes in the cells.
Recall my posts about
RASopathies and MR/ID.
Diseases associated with
REM1 include Mental Retardation and late onset Parkinson’s disease.
NALCN
NALCN (Sodium Leak Channel, Non-Selective) gene
encodes a voltage-independent, nonselective cation channel which belongs to a
family of voltage-gated sodium and calcium channels that regulates the resting
membrane potential and excitability of neurons.
It is highly associated with an abnormality in
the process of focusing of light by the eye in order to produce a sharp image
on the retina.
It is associated with mental or behavioral disorders
and unusual body height.
GEM
GEM encodes a protein that belongs to the RAD/GEM family of GTP-binding
proteins.
It is associated with heart disease.
Conclusion
I was really surprised just how many autism/epilepsy
genes are so closely related to the newly recognised autism gene CACNB1.
I hope you can see that a child without a mutation in CACNB1 can be affected by several of today's genes. What matters is differentially expressed genes (DEGS).
In my simplification of autism, I have a category
called channelopathies and differentially expressed genes (DEGS). I did add the DEG part a while back, but this
chart has stood the test of time.
I think many people with severe autism are affected
by the genes in today’s post.
Headaches and epilepsy are an integral part of autism and better not considered as comorbidities. The same is true with big/small heads and indeed high/low IQ.
