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.