Mutations in the RCCX gene may be the ultimate predisposing factor for illness, both physical and psychiatric, and the diathesis in the stress diathesis model of disease. John Waters Follow Jul 6, 2019 · 9 min read

The hypermobile brain.

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The human Major Histocompatibility Complex (MHC) region on chromosome 6p21.3 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 none to 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)

A MECHANISM FOR GENE DELETIONS AND DISEASE ASSOCIATIONS 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. — [source]

CYP21A2 mutations may be the ultimate predisposing factor for stress-related illness, medical and psychiatric, and thus could be the diathesis in the stress diathesis model of disease — conferring the vulnerability to stress with resulting CFS/FM/MCAS/MCAS/POTS/ along with neurological and immunological issues in patients with and without the hypermobility. A staggering amount of developments support this hypothesis. Click here to read more.

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 trial of the antipurinergic drug suramin in 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. — [source]

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.9,10 Roles of mast cells have also been indicated in the pathogenesis of autoimmune 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. — [source]

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. Also as an aside, those with a CAH1 mutation who are treated early enough with steroids will NOT develop a CAPS Personality type as the brain development will differ. — 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”. In fact, this complex is completely ignored in the standard genetic testing done by companies like 23andme, which helps explain why these common gene mutations (up to 20% of the population) have escaped detection up until now.

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:

R = RP1 (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.

= RP1 (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. C = C4 (complement 4) — a gene involved in the complement system and implicated in schizophrenia, CVID, MS, lupus and other autoimmune diseases.

= C4 (complement 4) — a gene involved in the complement system and implicated in schizophrenia, CVID, MS, lupus and other autoimmune diseases. C = CYP21A2 (steroid 21-hydroxylase) — which codes for a crucial enzyme involved in the acute stress response (21-hydroxylase); mutations are associated with an exaggerated stress response in the setting of low basal cortisol, congenital adrenal hyperplasia (2 copies of currently characterized mutations which are likely to be more severe in nature)

= CYP21A2 (steroid 21-hydroxylase) — which codes for a crucial enzyme involved in the acute stress response (21-hydroxylase); mutations are associated with an exaggerated stress response in the setting of low basal cortisol, congenital adrenal hyperplasia (2 copies of currently characterized mutations which are likely to be more severe in nature) X = TNXB (tenascin-X)- The TNXB gene (linked to Ehlers-Danlos) 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). In particular, studies suggest that it helps to regulate the production and assembly of certain types of collagen. Collagens are a family of proteins that strengthen and support connective tissues throughout the body. Tenascin-X is also involved in regulating the structure and stability of elastic fibers, which provide flexibility and stretchiness (elasticity) to connective tissues.

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.

Phenotypes

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 of TNXB, CYP21 and C4, all with 5 distinct clinical profiles. There is a high amount of variance in these profiles with someone co-inheriting copies of CAH1 from both parents effectively doubling their risk — and someone with CAH1-TXNB1-C4(1) could live an asymptomatic life depending on slight variances in genetics and stress encountered.

TNXB1: (TNXB mutation)

normal brain, no CAPS Personality. Moderate vulnerability to anxiety/insomnia/over-arousal due to orthostasis with SNS activation. EDS-HT phenotype. May range from no to high hypermobility. low to no vulnerability for EDS plus/CFS/FM/MCAS/POTS.

CAH1: (CYP21A2 mutation)

CAPS Personality. moderate vulnerability for CFS/FM/MCAS/POTS. co-inheritance of CYP21A2 (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)

CAH1-TNXB1:

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

CAH1-C4(1):

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

CAH1-TNXB1-C4(1):

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

RCCX mutations are extremely common in 10–20% of the population, CAH1 (heterozygosity for a CYP21A2 mutation) may be the genetic diathesis for the stress-diathesis model of physical and psychiatric disease and that CAPS 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.

made in conjunction with Karen Herbst PHD MD

rccixandillness.com — Summary for Scientists

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