Mutations in the RCCX gene may be the diathesis in the stress diathesis model of disease.

Jul 10, 2019

Over the past few years there has been increasing evidence for a disabling epidemic involving a large number of syndromes/symptoms/diseases with overlapping symptoms affecting many young, vibrant, talented people (predominantly women) and if you look, many, but not all, have joint hypermobility (double jointedness, ligament laxity).  

These are to name a few;


  • Ehlers-Danlos Syndrome, Hypermobility Type (EDS-HT)
  • Chronic fatigue Syndrome (CFS)/Myalgic Encephalomyelitis (ME)
  • Fibromyalgia (FM)
  • Mast Cell Activation Syndrome (MCAS): histamine intolerance, migraines, diarrhea, sinus pain, burning eyes, syncope, distractibility, brain fog, irritability, interstitial cystitis, hyper-adrenergic POTS, etc., depending on location of the mast cells
  • Postural Orthostatic Tachycardia (POTS), Dysautonomia, Orthostatic Intolerance, Low Blood volume
  • Pain Syndromes: Neuropathic Pain Syndromes/Chronic Regional Pain Syndrome/Myofascial Pain Disorder/Frequent Dislocations/Dysmenorrhea/Chronic Headache/Migraines/Interstitial Cystitis/Vulvodynia/Temporomandibular Joint Disorder (TMJ)
  • GI Syndromes: Irritable Bowel Syndrome/Cyclical Vomiting/Gastroparesis/Food Intolerance/Gut dysbiosis/Candida overgrowth/Leaky Gut Syndromes/Malabsorption Syndromes
  • Raised Intracranial Pressure Conditions: Pseudotumor Cerebri/Benign Intracranial Hypertension/Posterior Reversible Encephalopathy/Acquired
  • Chiari Malformation
  • Neurological Issues
  • Mitochondrial Disorders
  • Immune Dysregulation:
  • Psychiatric Issues:
  • Hormonal Disorders:
  • Autoimmune & Autoantibody diseases : Lupus, Raynaulds, CADASIL, Hashimoto's, etc.
  • GU/Renal Issues: Fibromuscular Dysplasia, Diabetes Insipidus, Interstitial Cystitis, Vesicoureteral Reflux

The Major Histocompatibility Complex (MHC) region on chromosome 6 is the most gene-dense region in the human genome1,2, containing gene families essential to the immune system.

The RCCX region within chr6 are chimeric genes which are thought to be critical for genome evolution. The number of modules and type of C4 complement genes within the RCCX regions vary between individuals, and gene dosage of C4A and C4B has been associated with various disorders. For instance, lower levels of C4A have been associated with susceptibility to systemic lupus erythematosis33, while lower levels of C4B have been associated with increased rates of acute myocardial infection and stroke

RCCX Theory preposes that co-inheritance of the highly mutable genes of the RCCX module (CYP21A2, TNXB, C4) may confer vulnerability to familial clusters of overlapping syndromes of chronic illness (hyper-mobility, autoimmune disease, CFS/ME, MCAS, POTS, and 80% of Psychiatric and neurodevelopmental disorders).

In many families, a cluster of seemingly unrelated diagnoses will be found and I believe that those families are likely to contain the gene mutations I discuss.

You may see a family with a member, diagnosed with or suspected to have Ehlers-Danlos Syndrome, Hypermobility Type (EDS-HT), postural orthostatic tachycardia syndrome (POTS) and mast cell activation syndrome (MCAS).

Then in the extended family, you may find rare autoimmune diseases, i.e. multiple sclerosis, lupus, CADASIL , Reynaul’s— cutting and eating disorders, Mood disorders, late-onset type 1 diabetes and Crohn’s.  

Along with gender fluidity, a highly successful and innovative genius, someone with chronic fatigue syndrome (CFS) or fibromyalgia (FM), someone with severe post-traumatic stress disorder (PTSD) and someone else with bouts of psychosis.

The children who are more scrutinized in this day and age, may be diagnosed with attention deficit disorder (ADHD), sensory processing issues, Autism & Asperger’s Disorder. And the kicker, these issues may be found on both sides of the family because I believe that we are attracted to each-others psychological profile. There is a characteristic psychological profile which goes with this: hyper-sensitive, emotional, often gifted abstract thinkers, artists, or problem solvers.
“Giftedness may even be linked with physiological conditions such as food allergies, asthma and autoimmune diseases, which sometimes go hand-in-hand with “sensory processing disorder”. — The Economist
The degree of hypermobility ranges from noneto severe in this family and correlates with the degree of musculoskeletal involvement and orthostasis/dysautonomia. But not with the other ‘sick’ symptoms which tend to develop later in life — but not always — mostly women or males who were sick in their youth. Many will react strongly to stress. If this sounds like your family (albeit a dramatic version), I am writing this for you.
EDS-HT is increasing being diagnosed and often progresses, especially in women in the presence of prolonged stress, hormonal changes and/or an infection (progesterone and pesticides which cause childhood-asthma are common triggers — although some RCCX’ers benefit greatly from progesterone)

This spirals into a disabling complex multi-system condition which is not well-recognised within the medical community. Leading oftenly to POTS/EDS/MCAS in varying severity from some mild hypersensitivity (bloating, itching, flush, sensory) to full blown chronic conditions.

RCCX Theory

Predisposition to chronic psychiatric illness via:

  • CYP21A2 gene mutations create a hormone milieu which could affect the developing brain, making it a “brain wired for danger” by age 5, also known as CAPS (CYP21A2 Mutation Associated Psychiatric Spectrum). CAPS likely predisposes to 4/5 of the major psychiatric illnesses (anxiety disorders, mood disorders, attentional disorders, autism spectrum) due to exaggerated stress response, low basal arousal and resultant harm-avoidance and threat circuits (except Schizophrenia which can be co-inherited via C4 mutation)

​Predisposition to medical illness (CFS/ME, POTS, MCAS, FM, etc) due to:

  • CYP21A2 gene mutations could confer a stress vulnerability for the development of chronic medical illness (EDS-HT, CFS/ME, FM, POTS, MCAS, etc.) via “21hydroxylase overwhelm” and via PTSD-wiring from CAPS (CYP21A2 Mutation Associated Neuropsychiatric Spectrum) plus negative events.

Both “21hydroxylase overwhelm” and PTSD wiring associated with CAPS could likely result in stress-induced mitochondrial shutdown (as described by Naviaux MD PhD).

To date, no gene has been found to explain the prevalence of EDS-HT in the general population. Nor why these individuals become so ill with such a wide range of not easily explainable symptoms, including: white matter lesions; hormone disruptions; autoimmune diseases; and MCAS, psychiatric issues and why some individuals with hypermobile relatives develop these same conditions without hypermobility.

However, RCCX has been implicated in disease from the start.

Modular Variations of the Human Major Histocompatibility Complex Class III Genes for Serine/Threonine Kinase RP, Complement Component C4, Steroid 21-Hydroxylase CYP21, and Tenascin TNX (the RCCX Module) (1999)

The RCCX modular variations appear to be a root cause for the acquisition of deleterious mutations from pseudogenes or gene segments in the RCCX to their corresponding functional genes.

The burdens are the accompanying genetic or autoimmune diseases such as CAH, systemic lupus erythematosus, and possibly EDS, caused by unequal crossovers and incorporations of deleterious mutations in the constituents of the RCCX. 

CYP21A2 mutations may be the diathesis in the stress diathesis model of disease — conferring the vulnerability to stress with resulting neurological and immunological issues in patients with and without  hypermobility.

A staggering amount of developments support this hypothesis.

Metabolic features and regulation of the healing cycle — A new model for chronic disease pathogenesis and treatment (2019)

Interruptions in the molecular stages of the healing cycle may be at the root of many complex, chronic illnesses. Three stages of the cell danger response(CDR1, 2, and 3) comprise the healing cycle. These stages are triggered by stress or injury and controlled by changes in mitochondrial function and metabolism. A small clinical trialof the antipurinergic drug suraminin autism spectrum disorder (ASD) has shown promise for this approach (Naviaux, 2017; Naviaux et al., 2017).Metabolic addiction to the chemistry produced by different stages of the CDR can occur. When this happens, it can create a life-long risk of relapse or slow return to chronic illness if diet and lifestyle interventions are not maintained. 

Immune, Autonomic, and Endocrine Dysregulation in Autism and Ehlers-Danlos Syndrome/Hypermobility Spectrum Disorders Versus Unaffected Controls (2019)

These data suggest that EDS/HSD and autism share aspects of immune/autonomic/endocrine dysregulation, pain, and some tissue fragility, This overlap, as well as documented comorbidity, suggests some forms of autism may be hereditary connective tissue disorders (HCTD). —[source]

Hypermobility and autonomic hyperacitivty (2019)

It is likely that the importance of hypermobility and autonomic dysfunction to the generation and maintenance of psychopathology in neurodevelopmental disorders is poorly appreciated. This mechanism might explain increased vulnerability to stress sensitive and developmental neuropsychiatric conditions. — [source]

Rationale for Dietary Antioxidant Treatment of ADHD (2018)

The potential involvement of the immune system in ADHD has long been suspected due to the increased prevalence of allergic diseases including atopic dermatitis, asthma and rhinitis in patients with ADHD [69].

ADHD might thus be a (non) allergic hypersensitivity disorder caused by an environmental trigger. — [source]

Application of immunotherapy for neurological manifestations in hypermobile Ehlers–Danlos syndrome (2018)

It has recently been proposed that the diverse clinical features of EDS, including neurological and immunological manifestations,can be attributed to mast cell activation.9,10Roles of mast cells have also been indicated in the pathogenesis ofautoimmune diseases, MS, and rheumatoid arthritis. These case reports and case series suggest that the pathogenesis of hEDS can be partly associated with an autoimmune mechanism. While the underlying mechanisms of hEDS remain unclear, autoimmunity and mast cell activation may play key roles. 

Psychological vulnerability to stress in carriers of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (2017)

"This is important to understand. This one shows what I’ve observed to be true with CYP21A2 carriers." – Meglathery
Conclusions: Carriers of 21-OHD may be predisposed to the development of anxiety disorders. — [source]

The RCCX Gene

RCCX is not your typical genetic “SNP”. The RCCX Gene is a Chimeric gene, littered with psuedogenes. This recent study from July 2019 illustrates the diffculty in sequencing it correctly.

The genes comprising the RCCX cluster code for enzymes and proteins which substantially influence responses to stressors and cell danger signaling. They also affect innate immune responses as well as synaptic and dendritic pruning in the brain, sex hormone levels, fluid and salt balance, and the integrity of the extracellular matrix (ECM).

The genes that make up the RCCX cluster are as follows:

  • RP (also known as STK19) — This gene encodes a serine/threonine kinase which localizes predominantly to the nucleus. Its specific function is unknown; it is possible that phosphorylation of this protein is involved in transcriptional regulation.
  • C4 (complement 4) — a gene involved in the complement system and implicated in schizophrenia, CVID, MS, lupus and other autoimmune diseases.
  • CYP21A2 (steroid 21-hydroxylase) — Mutations are associated with an exaggerated stress response in the setting of low basal cortisol.
  • TNXB (tenascin-X)-  provides instructions for making a protein called tenascin-X. This matrix protein plays an important role in organizing and maintaining the structure of tissues that support the body’s muscles, joints, organs, and skin (connective tissues). Tenascin-X is also involved in regulating the structure and stability of elastic fibers, which provide flexibility and stretchiness (elasticity) to connective tissues(linked to Ehlers-Danlos).

These genes make multiple copies of themselves, which are called copy number variations. They often behave as one unit with the genes deleted and duplicated together, instead of as four separate units. RCCX is the only place in the human genome where genes travel together in this way. Because of this, people can inherit two (or more) rare diseases simultaneously at a much higher rate than would be expected by chance.


The unique quality of the RCCX module would allow for the creation of several phenotypes resulting from co-segregation of various permutations of contiguous, overlapping and spontaneous mutations with 5 distinct clinical profiles. There is a huge amount of variance in these profiles with varying levels of symptoms. Identifying these symptoms and treating the underlying conditions is your greatest tool.

TNXB1: (TNXB mutation)

No CAPS Personality. EDS-HT phenotype (hypermobile brain)
low to no vulnerability for EDS plus/CFS/FM/MCAS/POTS.

Moderate vulnerability to anxiety/insomnia/over-arousal due to orthostasis with SNS activation.

May range from no to high hypermobility.

CAH1: (CYP21A2 mutation)

CAPS Personality.
moderate vulnerability for CFS/FM/MCAS/POTS.
co-inheritance of CAH1 mutations from both parents can cause; Potential for EDS+/ME-CFS/FM and Probable risk for autoimmune due to gut inflammation/permeability/inflammatory cascade downstream effects (Reynauld’s, CADASIL, Crohn’s/IBS)


CAPS Personality / EDS-HT phenotype.
very high vulnerability for EDS plus/CFS/FM/MCAS/POTS
possibly TGF beta issues (scarring and inflammation).


CAPS Personality.
moderate to high vulnerability for EDS/CFS/FM/MCAS/POTS,
higher vulnerability for autoanitbody diseases. (Graves’/Lupus/Hashimoto’s)


CAPS Personality.
EDS-HT phenotype,
high vulnerability for EDS+/CFS/FM/MCAS/POTS;
possible TGF beta issues (scarring and inflammation),
higher vulnerability for autoanitbody diseases.(Graves’/Lupus/Hashimoto’s)

RCCX mutations are extremely common, present in approximately 14–30% of the population, CAH1 may be the genetic diathesis for the stress-diathesis model of physical and psychiatric disease and that CAPS Personality may represent the spectrum disorder which links all 5 of the major psychiatric disorders (Anxiety, ADD, schizophrenia, Mood Disorders, Autism) and vulnerability to the development downstream complications including: POTS, MCAS, EDS, neurological and immunological disorders all with enhanced vulnerability in women, and clustering in families.

Meglathery MD in conjunction with Herbst MD
Developments / Research / Resources — Summary for Scientists

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