A Deep Dive into Closely Interacting Genes/Proteins that Account for Numerous Autism/Epilepsy Syndromes – (all Calcium or Sodium ion channels)

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.

https://www.genecards.org/

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 Na_v1.7 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. Na_v1.7.

Other sodium channels involved in pain signalling are Na_v1.3, Na_v1.8, and Na_v1.9.

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 Na_v1.4 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 Na_v1.3 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 (Na_V1.3) 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 Na_V1.3. Pathogenic Na_V1.3 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 (Na_V1.1) 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.

 

 SCN2A

The Na_v1.2 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

 The Na_v1.1 sodium ion channel is encoded by the SCN1A gene.

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 Ca_v2.1 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 Ca_v1.2.   Ca_v1.2 is a subunit of the L-type voltage-dependent calcium channel.

 

CACNA1S

The CACNA1S gene encodes Ca_v1.1 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 Ca_v1.3.

Ca_v1.3 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 Ca_v1.3 Ca²⁺ channels contribute to the death of dopaminergic neurones in patients with Parkinson's disease

Inhibition of L-type channels, in particular Ca_v1.3 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 Cav_2.3 , 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 Ca_v1.4.

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.

 

If you do invest in genetic testing, you would be well advised to look up any affected genes yourself. From what I have seen, do not rely on your DAN Doctor to do this thoroughly.