RCCX is a multi-allelic copy number variation locus that is known for being one of the longest in humans, and named after the genes STK19, formerly RP, C4 (complement component 4), CYP21 (steroid 21-hydroxylase) and TNX (tenascin-X). The RCCX complex or module, is located in the human leucocyte antigen (HLA) major histocompatibility complex (MHC) on chromosome 6p21.3. It spans 3.2-Mb in distance in an important area of the genome for the immune system.
Variations in the RCCX module notably contributes to disease susceptibility. Mutations in the CYP21 gene encodes 21-hydroxylase, the deficient enzyme in congenital adrenal hyperplasia (CAH). It is one of the commonest genetic disorders in nature with a disease frequency of 0.1% in the general population, and carrier rates of 5%. Individuals with CAH have deficient synthesis of cortisol, which signals the hypothalamus and pituitary to release more cortisol hormone releasing factors. Over time, the adrenal glands become hyperplastic, producing excess circulating sex hormones that causes virilization in women. About three-quarters of affected individuals fail to synthesize aldosterone necessary for sodium balance resulting in hyponatremia and dehydration.
Haplo-insufficiency of TNXB is associated with a phenotype of joint hypermobility similar to Ehlers-Danlos syndrome (EDS), but differs from the latter most often due to mutations in COL3A1 in the absence of vascular and skin complications.Individuals with deficient TNX levels show hypermobile joints associated with subluxation and chronic musculoskeletal pain.
Deficient production of the complement proteins C4A and C4B has other consequences. C4A takes part in removing immune complexes, whereas C4B has an important role in the defense against infectious intruders. One endogenous retroviral sequence, HERV-K associated with C4, confers protection against exogenous retroviral attacks. Moreover, low circulating levels of C4A confer a higher susceptibility to autoimmune disorders.
With its high number of MHC-related immune system genes that allow for enhanced coordination of expression, RCCX has rapidly diversified by recombination and sequence exchanges rendering it a highly evolutionarily adaptable, and therefore highly conserved genetic locus.
Epigenetic changes, which refers to the ability to regulate or modify the underlying DNA sequence by external environmental factors without altering the DNA code itself, has likely been important in the RCCX module and in conferring highly divergent haplotypes, polymorphisms and phenotypes across human populations.
Practically speaking however, recognizing one disorder in the RCCX module in a given individual enables the clinician to postulate the existence or propensity for one of the other genetically encoded or highly associated disorders such as postural orthostatic tachycardia syndrome, mast cell activation syndrome, chronic fatigue and neuropsychiatric illness, often in association with joint hypermobility/EDS. And as many of the associated illness are chronic in nature, RCCX has become synonymous with the propensity for chronic disease.