CACNA2D3 is on the HEAL2 list of genes in ME - and CACNA2D3 is involved in hypersensitivity

The preprint of (1):

Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis

has a list of 115 genes.

Quote: " In this study, we present a multi-site ME/CFS whole-genome analysis, which is powered by a novel deep learning framework, HEAL2. We show that HEAL2 not only has predictive value for ME/CFS based on personal rare variants, but also links genetic risk to various ME/CFS-associated symptoms. Model interpretation of HEAL2 identifies 115 ME/CFS-risk genes that exhibit significant intolerance to loss-of-function (LoF) mutations."

One of the genes is CACNA2D3. 

This information is from AI via https://www.google.com/

The gene CACNA2D3 is a component of voltage-gated calcium channels that is crucial for regulating the startle response. Mutations in cacna2d3 lead to an increased sensitivity to stimuli, a lower startle threshold, and impaired habituation, meaning the individual startles more easily and has a harder time getting used to repeated sounds. 

Role of CACNA2D3 in the startle response

• Sensory filtering: CACNA2D3 acts as a sensory filter, controlling how sensitive an organism is to sensory input.
• Threshold regulation: It is essential for setting the threshold for the startle response, ensuring that the startle reflex is not triggered by every minor stimulus.
• Habituation: It plays a role in the ability of an organism to habituate to repeated, irrelevant stimuli.
• Effect of mutations: When cacna2d3 is mutated, the startle response threshold is lowered, making the individual hypersensitive to stimuli like sound. For example, a sound that is not startling to a normal individual can trigger a significant startle response in a mutant. 

Molecular mechanism

• Calcium channel subunit: CACNA2D3 is a subunit of voltage-gated calcium channels.
• Synaptic function: These channels are critical for modulating synaptic transmission, which is a key part of the neural circuits that mediate the startle reflex. 

Me: what is the startle response?

AI: The startle response is an involuntary, full-body reflex that happens in reaction to a sudden, intense stimulus, like a loud noise. It prepares the body for immediate action by triggering a rapid sequence of muscular contractions and autonomic reactions, such as an eyeblink, increased heart rate, and muscle tension. This is a primitive survival mechanism that is preserved across species. 

Characteristics of the startle response

• Involuntary and rapid: The response is automatic and happens very quickly, often with the entire sequence taking less than a second.
• Multiple physical components: While often measured by the eyeblink in humans, it is a whole-body reaction that can include a head and neck jerk, shoulder and arm movement, and a general body twitch.
• Autonomic effects: In addition to physical movement, the startle response can also cause a rapid heart rate, accelerated breathing, and increased muscle tension.
• Protective function: It serves as a defense mechanism, helping the organism to react to potential threats from predators or other dangers.
• Influenced by various factors: The intensity of the response can be affected by the stimulus, the individual's current emotional state, and other factors like fear or habituation. 

Examples and variations

• In newborns: The startle reflex, also called the Moro reflex, is a specific startle response seen in infants. It involves them flinging their arms and legs out and then pulling them back in as if to hug themselves.
• In animals: The startle response is crucial for survival in the animal kingdom, often appearing as a quick movement to escape a predator.
• In humans: Beyond a simple jump, the startle response can be heightened in situations involving trauma, such as post-traumatic stress disorder (PTSD). 

Me: Is the startle response affected in Myalgic encephalomyelitis?

AI: Yes, the startle response can be affected in Myalgic encephalomyelitis (ME/CFS), with many people reporting an exaggerated startle response. This may be due to the autonomic nervous system dysfunction, heightened sensory sensitivity, and general hyperarousal that can occur in ME/CFS. 

• Exaggerated startle: Some individuals with ME/CFS describe an "exaggerated startle response" to sounds and other stimuli.
• Autonomic nervous system dysfunction: Autonomic dysfunction, which affects the regulation of involuntary bodily functions like heart rate and blood pressure, is common in ME/CFS and can contribute to an abnormal startle reflex.
• Sensory hypersensitivity: Many people with ME/CFS experience increased sensitivity to light and sound. This hyperarousal can lead to a more intense startle response.
• Brainstem involvement: Research suggests that the inferior colliculus, a part of the brainstem that processes auditory information and is involved in the startle reflex, may be overactive in some conditions like ME/CFS, leading to an amplified response. 

Me: Is CACNA2D3 involved in hypersensitivity?

AI: Yes, CACNA2D3 is involved in hypersensitivity, particularly acoustic and tactile hypersensitivity, as well as a broader role in pain processing and sensory filtering. Mutations or loss of CACNA2D3 function lead to an increase in sensitivity to certain stimuli, suggesting it plays a crucial role in normal sensory processing and habituation. 

• Acoustic hypersensitivity: Studies in zebrafish and mice show that loss of cacna2d3 results in an exaggerated startle response to sounds and an inability to habituate (get used to) repeated stimuli.
• Tactile and thermal hypersensitivity: Research indicates that CACNA2D3 is involved in transmitting pain signals in the brain, with some studies showing reduced thermal pain sensitivity in knockout mice, while others suggest a role in pain sensitization and transmission in mammals.
• Cross-sensory activation: In mice, the absence of CACNA2D3 has been linked to "cross-sensory activation," where sensory stimuli (like a sound) trigger responses in unrelated sensory areas of the brain (like the visual or olfactory systems).
• Human relevance: Mutations in the CACNA2D3 gene have been identified as potentially contributing to neurodevelopmental disorders like autism spectrum disorder (ASD), which can involve sensory processing challenges. It is also associated with allergic diseases in children, like asthma and atopic dermatitis. 

Reference

1) Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis

Sai Zhang, Fereshteh Jahanbani, Varuna Chander, Martin Kjellberg, Menghui Liu, Katherine A. Glass, David S. Iu, Faraz Ahmed, Han Li, Rajan Douglas Maynard, Tristan Chou, Johnathan Cooper-Knock, Martin Jinye Zhang, Durga Thota, Michael Zeineh, Jennifer K. Grenier, Andrew Grimson, Maureen R. Hanson, Michael P. Snyder

medRxiv 2025.04.15.25325899; doi: https://doi.org/10.1101/2025.04.15.25325899

This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

Interaction between HTT, RABGAP1L and GPR52

Answers from Artificial Intelligence about HTT, RABGAP1L and GPR52.

I used Artificial Intelligence (AI) via https://www.google.com/

Me: What is the function of huntingtin?

AI: Huntingtin's primary function is to regulate neuronal survival, development, and transport within the cell, with its highest activity in the brain. It is crucial for processes like intracellular signaling, transporting vesicles containing crucial molecules like BDNF, and protecting neurons from self-destruction (apoptosis). Normal huntingtin is essential for development, but a mutated form is linked to Huntington's disease. 

Key functions of huntingtin

• Neuronal survival: It has anti-apoptotic properties, protecting neurons from dying.
• Intracellular transport: It is involved in moving vesicles along the cell's internal structures (microtubules). This is vital for transporting molecules like Brain-Derived Neurotrophic Factor (BDNF), which is critical for neuronal health and function.
• Cellular signaling: The protein plays a role in chemical signaling pathways within the cell.
• Protein binding: It can bind to other proteins and structures, acting as a scaffold for protein complexes.
• Development: Huntingtin is critical during embryonic development for processes like neurogenesis (the formation of neurons). 

Huntingtin and disease

• The huntingtin protein is produced by the HTT gene.
• A mutation in this gene that causes a long polyglutamine tract is the cause of Huntington's disease (HD).
• While normal huntingtin is essential, the mutated protein disrupts normal functions and contributes to neurodegeneration. 

Me: What is the function of RABGAP1L?

AI: RABGAP1L is a protein that regulates intracellular membrane trafficking, playing a role in processes like endosomal transport and cellular immunity. It does this by inactivating specific RAB GTPases, which are key proteins in vesicle transport. In the immune system, RABGAP1L helps regulate cell-autonomous immunity by inhibiting Rab7A and Rab10 to expel bacteria and suppress autophagy. It also functions as an antiviral protein by disrupting endosomal function, which can inhibit viral entry. 

Key functions

• Membrane trafficking: RABGAP1L regulates the transport of vesicles within the cell, which is crucial for organizing cellular processes and logistics.
• Cell-autonomous immunity: It is involved in the cell's defense against pathogens.
  • It inactivates Rab7A and Rab10 during infections, which promotes the expulsion of bacteria from the cell.
  • This inactivation also suppresses autophagy, a process where the cell breaks down its own components.
• Antiviral activity: RABGAP1L can act as a restriction factor against certain viruses, such as the influenza A virus (IAV).
  • It disrupts the endosomal pathway that viruses use for entry, inhibiting their ability to replicate. 

Me: What is the function of GPR52?

GPR52 is a G protein-coupled receptor that functions in the brain and liver, playing a role in regulating brain function, fatty acid metabolism, and potentially treating neuropsychiatric and neurodegenerative diseases. In the brain, it is involved in processes like cognition and psychiatric disorders such as schizophrenia. In the liver, it is linked to the biosynthesis of fatty acids. 

Brain function and potential therapeutic applications

• Regulation of cAMP: GPR52 is involved in various brain functions through its activation of the cAMP pathway.
• Schizophrenia: Stimulating GPR52 with agonists shows potential for treating schizophrenia, including positive and negative symptoms, by acting as a novel mechanism to complement existing dopamine-targeting drugs.
• Huntington's disease: Inhibiting GPR52 activity may be beneficial for Huntington's disease, as it is linked to the abnormal expression of huntingtin in the disorder.
• Cognitive function: Agonists for GPR52 have shown pro-cognitive properties in studies.
• Substance use disorders: GPR52 is a target for the treatment of substance use disorders. 

Other functions

• Fatty acid biosynthesis: GPR52 accelerates fatty acid biosynthesis in liver cells, especially in response to excessive fat intake.
• Immune function: GPR52 regulates cAMP in T cells, which can be relevant in the context of immune responses. 

Me: What is the interaction between HTT, RABGAP1L and GPR52?

AI:The interaction is a regulatory pathway where GPR52, a G-protein coupled receptor, modulates the levels of huntingtin (HTT) protein, with the RABGAP1L gene's location and function being crucial to this process. GPR52, located within an intron of the RABGAP1L gene, helps regulate HTT levels by activating RAB39B to move HTT to the endoplasmic reticulum, thus preventing its degradation. In contrast, RABGAP1L can inhibit GPR52's effect, highlighting a complex "epistatic" relationship between the two. This interaction is particularly relevant to Huntington's disease (HD), as modulating GPR52 levels can impact the severity of the disease. 

Detailed interaction

• GPR52's role: GPR52 is a striatal-enriched receptor that helps reduce the levels of both normal and mutant HTT. It does this by promoting the activity of RAB39B, a protein that helps move HTT to the endoplasmic reticulum. This process protects HTT from degradation, which can otherwise lead to the buildup of toxic mutant HTT in the brain.
• RABGAP1L's role: The RABGAP1L gene contains the GPR52 gene within one of its introns. This means that the RABGAP1L gene can influence GPR52's function. Specifically, RABGAP1L can inhibit GPR52-mediated modulation of HTT levels by blocking its substrate, RAB39B.
• Combined effect: The interaction between GPR52 and RABGAP1L is complex and appears to be a form of regulation where they act in opposition to control HTT levels.
• Relevance to Huntington's disease: This interaction is a potential therapeutic target for Huntington's disease. Reducing GPR52 levels has been shown to rescue disease-related phenotypes in both cell and animal models.

Me: How does huntingtin support synapses?

AI: Huntingtin supports synapses by facilitating the transport of crucial vesicles and proteins throughout the neuron and stabilizing receptors at the postsynaptic membrane. It does this by interacting with molecular motors, like kinesin and dynein, to move synaptic components and neurotrophic factors to their correct locations. Additionally, huntingtin is involved in processes like endocytosis and autophagy, which help maintain synaptic homeostasis. 

Detailed roles in synaptic support

• Transport of synaptic vesicles and organelles: Wild-type huntingtin (wtHTT) is essential for the transport of synaptic vesicle precursors along axons to the presynaptic terminal. It also moves other organelles, including mitochondria, and cargo, such as neurotrophic factors like BDNF, along axons and dendrites.
• Regulation of receptor localization: In the postsynaptic neuron, huntingtin, through its interactions with other proteins, helps stabilize synaptic receptors in the postsynaptic density (PSD). Loss of function disrupts the clustering of these receptors, which are critical for signal reception.
• Endocytosis and vesicle recycling: Huntingtin interacts with proteins involved in endocytosis, such as HIP1 and HIP1R, which helps regulate the formation of new vesicles at the synapse by supporting the assembly of the clathrin coating on the membrane.
• Regulation of synaptic plasticity: Huntingtin is important for synaptic plasticity, which is the ability of synapses to strengthen or weaken over time. It is involved in both presynaptic and postsynaptic functions that are crucial for long-term memory storage and learning, notes this PLOS article.
• Synaptic homeostasis: The protein plays a role in autophagy, a process that removes damaged components and helps maintain synaptic homeostasis. It also regulates the activity of transcription factors, like NF-κB, which helps to ensure proper communication between the synapse and the nucleus.