RCCX

The RCCX abbreviation is composed of the names of the genes RP (a former name for STK19 serine/threonine kinase 19), C4, CYP21 and TNX).{{cite journal | vauthors = Sweeten TL, Odell DW, Odell JD, Torres AR | title = C4B null alleles are not associated with genetic polymorphisms in the adjacent gene CYP21A2 in autism | journal = BMC Medical Genetics | volume = 9 | page = 1 | date = January 2008 | pmid = 18179706 | pmc = 2265260 | doi = 10.1186/1471-2350-9-1 | doi-access = free }} The RCCX abbreviation was first mentioned in a 1994 article published in Immunogenetics, an academic journal, for a study by Dangel et al.{{cite journal |vauthors=Dangel AW, Mendoza AR, Baker BJ, Daniel CM, Carroll MC, Wu LC, Yu CY |title=The dichotomous size variation of human complement C4 genes is mediated by a novel family of endogenous retroviruses, which also establishes species-specific genomic patterns among Old World primates |journal=Immunogenetics |volume=40 |issue=6 |pages=425–436 |date=1994 |pmid=7545960 |doi=10.1007/BF00177825 |s2cid=19796359}}

The number of RCCX segments varies between one and four in a chromosome, with the prevalence of approximately 15% for monomodular, 75% for bimodular (STK19-C4A-CYP21A1P-TNXA-STK19B-C4B-CYP21A2-TNXB), and 10% for trimodular in Europeans.{{cite journal |vauthors=Bánlaki Z, Szabó JA, Szilágyi Á, Patócs A, Prohászka Z, Füst G, Doleschall M |title=Intraspecific evolution of human RCCX copy number variation traced by haplotypes of the CYP21A2 gene |journal=Genome Biol Evol |volume=5 |issue=1 |pages=98–112 |date=2013 |pmid=23241443 |pmc=3595039 |doi=10.1093/gbe/evs121}} The quadrimodular structure of the RCCX unit is very rare.{{cite journal |vauthors=Tsai LP, Lee HH |title=Analysis of CYP21A1P and the duplicated CYP21A2 genes |journal=Gene |volume=506 |issue=1 |pages=261–262 |date=September 2012 |pmid=22771554 |doi=10.1016/j.gene.2012.06.045}}

In a monomodular structure, all of the genes are functional i.e. protein-coding, but if a module count is two or more, there is only one copy of each functional gene rest being non-coding pseudogenes with the exception of the C4 gene which always has active copies. Each copy of the C4 gene, due to five adjacent nucleotide substitutions cause four amino acid changes and immunological subfunctionalization (different functions related to the immune system), can be of one of two types: C4A and C4B. Each C4 gene contains 41 exons and has a dichotomous size variation (existence of two distinct sizes) between approximately 22 kb and 16 kb, with the longer variant being the result of the integration of the endogenous retrovirus HERV-K(C4) into intron 9.{{cite journal |vauthors=Zhou D, Rudnicki M, Chua GT, Lawrance SK, Zhou B, Drew JL, Barbar-Smiley F, Armstrong TK, Hilt ME, Birmingham DJ, Passler W, Auletta JJ, Bowden SA, Hoffman RP, Wu YL, Jarjour WN, Mok CC, Ardoin SP, Lau YL, Yu CY |title=Human Complement C4B Allotypes and Deficiencies in Selected Cases With Autoimmune Diseases |journal=Front Immunol |volume=12 |issue= |at=739430 |date=2021 |pmid=34764957 |pmc=8577214 |doi=10.3389/fimmu.2021.739430 |doi-access=free }}

The RCCX module is the most complex gene cluster in the human genome.{{cite journal |vauthors=Carrozza C, Foca L, De Paolis E, Concolino P |title=Genes and Pseudogenes: Complexity of the RCCX Locus and Disease |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |at=709758 |date=2021 |pmid=34394006 |pmc=8362596 |doi=10.3389/fendo.2021.709758 |doi-access=free }}{{cite journal |vauthors=Doleschall M, Luczay A, Koncz K, Hadzsiev K, Erhardt É, Szilágyi Á, Doleschall Z, Németh K, Török D, Prohászka Z, Gereben B, Fekete G, Gláz E, Igaz P, Korbonits M, Tóth M, Rácz K, Patócs A |title=A unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics |journal=Eur J Hum Genet |volume=25 |issue=6 |pages=702–710 |date=June 2017 |pmid=28401898 |pmc=5477366 |doi=10.1038/ejhg.2017.38}}{{cite journal | vauthors = Milner CM, Campbell RD | title = Genetic organization of the human MHC class III region | journal = Frontiers in Bioscience: A Journal and Virtual Library | volume = 6 | pages = D914–26 | date = August 2001 | pmid = 11487476 | doi = 10.2741/milner | doi-access = free }} It is part of the major histocompatibility complex (MHC) class III (MHC class III),{{cite journal |vauthors=Yu CY |title=Molecular genetics of the human MHC complement gene cluster |journal=Exp Clin Immunogenet |volume=15 |issue=4 |pages=213–230 |date=1998 |pmid=10072631 |doi=10.1159/000019075 |s2cid=25061446}}{{cite journal |vauthors=Yu CY, Chung EK, Yang Y, Blanchong CA, Jacobsen N, Saxena K, Yang Z, Miller W, Varga L, Fust G |title=Dancing with Complement C4 and the RP-C4-CYP21-TNX (RCCX) Modules of the Major Histocompatibility Complex |journal=Prog Nucleic Acid Res Mol Biol |series=Progress in Nucleic Acid Research and Molecular Biology |volume=75 |issue= |pages=217–292 |date=2003 |pmid=14604014 |doi=10.1016/s0079-6603(03)75007-7 |isbn=9780125400756}} which is the most gene-dense region of the human genome, containing many genes that yet have unknown function or structure.{{cite journal | vauthors = Xie T, Rowen L, Aguado B, Ahearn ME, Madan A, Qin S, Campbell RD, Hood L | title = Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse | journal = Genome Research | volume = 13 | issue = 12 | pages = 2621–36 | date = December 2003 | pmid = 14656967 | pmc = 403804 | doi = 10.1101/gr.1736803 }}{{cite journal |vauthors=Rupert KL, Rennebohm RM, Yu CY |title=An unequal crossover between the RCCX modules of the human MHC leading to the presence of a CYP21B gene and a tenascin TNXB/TNXA-RP2 recombinant between C4A and C4B genes in a patient with juvenile rheumatoid arthritis |journal=Exp Clin Immunogenet |volume=16 |issue=2 |pages=81–97 |date=1999 |pmid=10343159 |doi=10.1159/000019099 |s2cid=24623016}}{{cite journal | vauthors = Espinosa Reyes TM, Collazo Mesa T, Lantigua Cruz PA, Agramonte Machado A, Domínguez Alonso E, Falhammar H | title = Molecular diagnosis of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = BMC Endocrine Disorders | volume = 20 | issue = 1 | page = 165 | date = November 2020 | pmid = 33168061 | doi = 10.1186/s12902-020-00643-z| pmc = 7653887 | doi-access = free }}{{cite journal |vauthors=Lee HH |title=Chimeric CYP21P/CYP21 and TNXA/TNXB genes in the RCCX module |journal=Mol Genet Metab |volume=84 |issue=1 |pages=4–8 |date=January 2005 |pmid=15639189 |doi=10.1016/j.ymgme.2004.09.009}} RCCX modules exhibit a high degree of linkage disequilibrium, meaning that genes are inherited together more frequently than would be expected by chance. It indicates that there is a non-random association or correlation between the alleles of different genes within the RCCX modules. The high degree of linkage disequilibrium observed in the RCCX modules suggests that the genes within this module are inherited as a group, rather than independently. This makes the RCCX module well-suited for genetic association studies, especially in the context of autoimmune diseases.

The RCCX module is involved in the synthesis of the steroid hormones cortisol, aldosterone, and androgen precursors, in extracellular matrix glycoprotein synthesis, and in innate immune system.

The RP gene (a former name for the STK19 gene) is involved in cell growth and differentiation, but its exact functions remain unclear.{{cite journal |vauthors=((Asquith CRM)), Temme L |title=STK19: a new target for NRAS-driven cancer |journal=Nat Rev Drug Discov |volume=19 |issue=9 |page=579 |date=September 2020 |pmid=32587355 |doi=10.1038/d41573-020-00116-x |s2cid=256745367}} Current knowledge suggests that the STK19 gene encodes the protein called nuclear serine/threonine kinase 19. This protein probably plays a role in regulating the activity of neuroblastoma RAS viral oncogene homolog (NRAS), a protein involved in cellular signaling. STK19 phosphorylates NRAS, which means it adds a phosphate functional group to NRAS. This phosphorylation event facilitates interactions between NRAS and its downstream effectors, which are molecules that carry out specific cellular functions. By increasing the activation of the mitogen-activated protein kinase (MAPK) cascade, STK19 ultimately influences cellular processes such as cell growth, proliferation, and differentiation.{{cite journal |vauthors=Yin C, Zhu B, Zhang T, Liu T, Chen S, Liu Y, Li X, Miao X, Li S, Mi X, Zhang J, Li L, Wei G, Xu ZX, Gao X, Huang C, Wei Z, Goding CR, Wang P, Deng X, Cui R |title=Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis |journal=Cell |volume=176 |issue=5 |pages=1113–1127.e16 |date=February 2019 |pmid=30712867 |doi=10.1016/j.cell.2019.01.002 |s2cid=72333604 |url=https://ora.ox.ac.uk/objects/uuid:e8a97267-aec4-495e-9534-e2c4d0d59ed3/files/m189c9d506602cdef4a724d39718c6f0c |doi-access=free |access-date=8 March 2024 |archive-date=8 March 2024 |archive-url=https://web.archive.org/web/20240308022950/https://ora.ox.ac.uk/objects/uuid:e8a97267-aec4-495e-9534-e2c4d0d59ed3/files/m189c9d506602cdef4a724d39718c6f0c |url-status=live }}{{cite journal |vauthors=Rodríguez-Martínez M, Boissiére T, Noe Gonzalez M, Litchfield K, Mitter R, Walker J, Kjœr S, Ismail M, Downward J, Swanton C, Svejstrup JQ |title=Evidence That STK19 Is Not an NRAS-dependent Melanoma Driver |journal=Cell |volume=181 |issue=6 |pages=1395–1405.e11 |date=June 2020 |pmid=32531245 |pmc=7298618 |doi=10.1016/j.cell.2020.04.014 |url=}}{{cite journal |vauthors=Yin C, Zhu B, Li X, Goding CR, Cui R |title=A Reply to "Evidence that STK19 Is Not an NRAS-Dependent Melanoma Driver" |journal=Cell |volume=181 |issue=6 |pages=1406–1409.e2 |date=June 2020 |pmid=32531246 |doi=10.1016/j.cell.2020.04.029 |s2cid=219572289 |url=|doi-access=free }}

The C4 gene encodes the complement component 4, which is involved in the complement system and is an important part of the innate immune system. The gene has two forms: C4A and C4B, encoding form A and B of the complement component 4 protein, respectively.{{cite journal |vauthors=Pereira KM, Faria AG, Liphaus BL, Jesus AA, Silva CA, Carneiro-Sampaio M, Andrade LE |title=Low C4, C4A and C4B gene copy numbers are stronger risk factors for juvenile-onset than for adult-onset systemic lupus erythematosus |journal=Rheumatology (Oxford) |volume=55 |issue=5 |pages=869–73 |date=May 2016 |pmid=26800705 |doi=10.1093/rheumatology/kev436 |url=|doi-access=free }}

The CYP21A2 gene encodes the enzyme 21-hydroxylase involved in synthesizing cortisol and aldosterone.{{cite journal |vauthors=Marino R, Moresco A, Perez Garrido N, Ramirez P, Belgorosky A |title=Congenital Adrenal Hyperplasia and Ehlers-Danlos Syndrome |journal=Front Endocrinol (Lausanne) |volume=13 |issue= |pages=803226 |date=2022 |pmid=35282436 |pmc=8913572 |doi=10.3389/fendo.2022.803226 |url= |doi-access=free }}

The TNXB gene encodes the Tenascin X, an extracellular matrix glycoprotein. Tenascin X is involved in the formation and maintenance of the extracellular matrix, which provides structural support and regulates cell behavior. It is also involved in tissue repair and regeneration and musculoskeletal development. Tenascin X interacts with other extracellular matrix proteins such as fibrillin-1 and collagen and is thought to play a role in regulating their organization and function.{{cite journal |vauthors=Morissette R, Chen W, Perritt AF, Dreiling JL, Arai AE, Sachdev V, Hannoush H, Mallappa A, Xu Z, McDonnell NB, Quezado M, Merke DP |title=Broadening the Spectrum of Ehlers Danlos Syndrome in Patients With Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=100 |issue=8 |pages=E1143–52 |date=August 2015 |pmid=26075496 |pmc=4525000 |doi=10.1210/jc.2015-2232 |url=}}

The RCCX module is related to personality traits such as novelty seeking and impulsivity{{cite book |doi=10.1007/978-3-319-66362-3_12-1 |isbn=978-3-319-66362-3|title=Endocrinology and Systemic Diseases |publisher=Springer Cham |s2cid=164396406 |editor=Piero Portincasa |editor2=Gema Frühbeck |editor3=Hendrik M. Nathoe |chapter=Endocrine Disorders and Psychiatric Manifestations |date=2019 |pages=1–35 }} as major histocompatibility complex (MHC), where the RCCX module is located, may affect these traits through its role in immune function and neurodevelopment, still, the exact mechanisms are not fully understood.

Variations in complement component C4 genes within the RCCX module have been associated with psychiatric disorders such as schizophrenia and neurodegenerative diseases such as Alzheimer's disease.

The RCCX module may be involved in developing autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis: the C4A gene may be associated with an increased risk of systemic lupus erythematosus, while the C4B gene may be associated with an increased risk of rheumatoid arthritis.{{cite journal |vauthors=Wu Z, Zhang S, Li P, Zhang F, Li Y |title=Association between complement 4 copy number variation and systemic lupus erythematosus: a meta-analysis |journal=Clin Exp Med |volume=20 |issue=4 |pages=627–634 |date=November 2020 |pmid=32691186 |doi=10.1007/s10238-020-00640-5 |s2cid=220638363}}{{cite journal |vauthors=((Pereira KMC)), Perazzio S, ((Faria AGA)), Moreira ES, Santos VC, Grecco M, da Silva NP, ((Andrade LEC)) |title=Impact of C4, C4A and C4B gene copy number variation in the susceptibility, phenotype and progression of systemic lupus erythematosus |journal=Adv Rheumatol |volume=59 |issue=1 |page=36 |date=August 2019 |pmid=31387635 |doi=10.1186/s42358-019-0076-6 |doi-access=free }}{{cite web|url=https://acrabstracts.org/abstract/low-gene-copy-number-for-c4-c4a-and-c4b-is-a-strong-risk-factor-for-developing-systemic-lupus-erythematosus-in-childhood/|title=Low Gene Copy Number for C4, C4A and C4B Is a Strong Risk Factor for Developing Systemic Lupus Erythematosus in Childhood|access-date=25 October 2023|archive-date=25 October 2023|archive-url=https://web.archive.org/web/20231025224003/https://acrabstracts.org/abstract/low-gene-copy-number-for-c4-c4a-and-c4b-is-a-strong-risk-factor-for-developing-systemic-lupus-erythematosus-in-childhood/|url-status=live}} The HERV-K retrovirus within the C4 gene has also been associated with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, probably because retrovirus may activate the C4 gene, leading to increased production of C4 proteins, which can contribute to autoimmune responses, and can probably lead to neuroinflammation, and increased risk of developing diseases such as schizophrenia and bipolar disorder.{{cite journal |vauthors=Mason MJ, Speake C, Gersuk VH, Nguyen QA, O'Brien KK, Odegard JM, Buckner JH, Greenbaum CJ, Chaussabel D, Nepom GT |title=Low HERV-K(C4) copy number is associated with type 1 diabetes |journal=Diabetes |volume=63 |issue=5 |pages=1789–95 |date=May 2014 |pmid=24430436 |doi=10.2337/db13-1382 |s2cid=11775986|doi-access=free }}{{cite journal |vauthors=((Tsang-A-Sjoe MWP)), ((Bultink IEM)), Korswagen LA, van der Horst A, Rensink I, de Boer M, Hamann D, Voskuyl AE, Wouters D |title=Comprehensive approach to study complement C4 in systemic lupus erythematosus: Gene polymorphisms, protein levels and functional activity |journal=Mol Immunol |volume=92 |issue= |pages=125–131 |date=December 2017 |pmid=29080553 |s2cid=10363726 |doi=10.1016/j.molimm.2017.10.004}}{{cite journal |vauthors=Mack M, Bender K, Schneider PM |title=Detection of retroviral antisense transcripts and promoter activity of the HERV-K(C4) insertion in the MHC class III region |journal=Immunogenetics |volume=56 |issue=5 |pages=321–332 |date=August 2004 |pmid=15309346 |s2cid=7128183 |doi=10.1007/s00251-004-0705-y}}

The presence of multiple RCCX modules is also associated with an increased risk of autoimmune diseases.

Genetic variations in the RCCX module have been linked to many other disorders, including autism spectrum disorder, and drug addiction.{{cite journal |vauthors=Trowsdale J, Knight JC |title=Major histocompatibility complex genomics and human disease |journal=Annu Rev Genomics Hum Genet |volume=14 |issue= |pages=301–323 |date=2013 |pmid=23875801 |pmc=4426292 |doi=10.1146/annurev-genom-091212-153455}}

The CYP21 gene is associated with developing congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH),{{cite journal |vauthors=Fanis P, Skordis N, Phylactou LA, Neocleous V |title=Salt-wasting congenital adrenal hyperplasia phenotype as a result of the TNXA/TNXB chimera 1 (CAH-X CH-1) and the pathogenic IVS2-13A/C > G in CYP21A2 gene |journal=Hormones (Athens) |volume=22 |issue=1 |pages=71–77 |date=March 2023 |pmid=36264454 |pmc=10011304 |doi=10.1007/s42000-022-00410-w}}{{cite journal |vauthors=Fanis P, Skordis N, Toumba M, Picolos M, Tanteles GA, Neocleous V, Phylactou LA |title=The pathogenic p.Gln319Ter variant is not causing congenital adrenal hyperplasia when inherited in one of the duplicated CYP21A2 genes |journal=Front Endocrinol (Lausanne) |volume=14 |issue= |at=1156616 |date=2023 |pmid=37324257 |pmc=10266209 |doi=10.3389/fendo.2023.1156616 |doi-access=free }}{{cite journal |vauthors=Lao Q, Burkardt DD, Kollender S, Faucz FR, Merke DP |title=Congenital adrenal hyperplasia due to two rare CYP21A2 variant alleles, including a novel attenuated CYP21A1P/CYP21A2 chimera |journal=Mol Genet Genomic Med |volume=11 |issue=7 |at=e2195 |date=July 2023 |pmid=37157918 |pmc=10337281 |doi=10.1002/mgg3.2195}} a genetic disorder that affects the adrenal glands and causes cortisol deficiencies and excessive androgen biosynthesis (that may lead to virilization of female infants) and in severe cases also aldosterone deficiencies (that may lead to salt wasting - large amounts of sodium in urine that causes such life-threatening consequences as hypotension, hyponatremia, and hyperkalemic metabolic acidosis).{{cite journal |veditors=Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A |vauthors=Nimkarn S, Gangishetti PK, Yau M, New MI |title=21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia |date=4 February 2016 |orig-date=26 February 2002 |journal=GeneReviews |pmid=20301350 |id=NBK1171 |url=https://www.ncbi.nlm.nih.gov/books/NBK1171/pdf/Bookshelf_NBK1171.pdf |access-date=8 March 2024 |archive-date=6 November 2022 |archive-url=https://web.archive.org/web/20221106053315/https://ncbi.nlm.nih.gov/books/NBK1171/pdf/Bookshelf_NBK1171.pdf |url-status=live }}

The TNXB gene, also known as tenascin-X, is associated with such disorders of connective tissue, such as Ehlers-Danlos syndrome (EDS), characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Another disorder, when recombination events occur between a pseudogene TNXA{{NCBI RefSeq|url=https://www.ncbi.nlm.nih.gov/gene/7146|title=TNXA tenascin XA (pseudogene) [ Homo sapiens (human) ]}} and the functional gene TNXB{{NCBI RefSeq|url=https://www.ncbi.nlm.nih.gov/gene/7148|title=TNXB tenascin XB [ Homo sapiens (human)}} within the RCCX module, resulting in CYP21A2 deletion along with impaired TNXB function, is called CAH-X Syndrome{{cite journal |vauthors=Paragliola RM, Perrucci A, Foca L, Urbani A, Concolino P |title=Prevalence of CAH-X Syndrome in Italian Patients with Congenital Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency |journal=J Clin Med |volume=11 |issue=13 |date=July 2022 |page=3818 |pmid=35807105 |pmc=9267771 |doi=10.3390/jcm11133818 |doi-access=free }}{{cite journal |vauthors=Kim JH, Kim GH, Yoo HW, Choi JH |title=Molecular basis and genetic testing strategies for diagnosing 21-hydroxylase deficiency, including CAH-X syndrome |journal=Ann Pediatr Endocrinol Metab |volume=28 |issue=2 |pages=77–86 |date=June 2023 |pmid=37401054 |pmc=10329939 |doi=10.6065/apem.2346108.054}} and leads to both congenital adrenal hyperplasia (CAH) symptoms and features consistent with EDS. This impaired function of the TNXB gene refers to the decreased production or abnormal structure of the tenascin-X protein due to genetic changes within the TNXB gene. The exact molecular mechanisms through which alterations or deficiencies in the TNXB gene or its impaired function lead to these conditions (the EDS and the CAH-X syndrome) are not fully understood yet but are believed to be related to defects in extracellular matrix organization and cell adhesion processes mediated by tenascin-X protein.

An "RCCX theory", a hypothesis developed by Sharon Meglathery, a US psychiatrist,{{Cite web |url=https://health.usnews.com/doctors/sharon-meglathery-420774 |title=Dr. Sharon B. Meglathery MD | quote=Dr. Sharon B. Meglathery is a psychiatrist in Tucson, Arizona. She received her medical degree from Oregon Health and Science University School of Medicine |access-date=8 March 2024 |archive-date=15 November 2023 |archive-url=https://web.archive.org/web/20231115013521/https://health.usnews.com/doctors/sharon-meglathery-420774 |url-status=live }} an author of a few publications on psychiatry,{{cite journal |vauthors=Ener RA, Meglathery SB, Van Decker WA, Gallagher RM |title=Serotonin syndrome and other serotonergic disorders |journal=Pain Med |volume=4 |issue=1 |pages=63–74 |date=March 2003 |pmid=12873279 |doi=10.1046/j.1526-4637.2003.03005.x |url=|doi-access=free }}{{cite journal |vauthors=Denicoff KD, Meglathery SB, Post RM, Tandeciarz SI |title=Efficacy of carbamazepine compared with other agents: a clinical practice survey |journal=J Clin Psychiatry |volume=55 |issue=2 |pages=70–6 |date=February 1994 |pmid=8077157 |doi= |url=}} and oncology,{{cite journal |vauthors=Ener RA, Meglathery SB, Styler M |title=Extravasation of systemic hemato-oncological therapies |journal=Ann Oncol |volume=15 |issue=6 |pages=858–62 |date=June 2004 |pmid=15151940 |doi=10.1093/annonc/mdh214 |url=}}{{cite journal |vauthors=Ener RA, Meglathery SB, Cuhaci B, Topolsky D, Styler MJ, Crilley P, Brodsky I, Kahn SB, King RS |title=Use of granulocyte colony-stimulating factor after high-dose chemotherapy and autologous peripheral blood stem cell transplantation: what is the optimal timing? |journal=Am J Clin Oncol |volume=24 |issue=1 |pages=19–25 |date=February 2001 |pmid=11232944 |doi=10.1097/00000421-200102000-00003 |url=|doi-access=free }} highlights the links between certain autoimmune and psychiatric disorders due to variations in the RCCX cluster. According to the hypothesis, these variations contribute to the development of autoimmune disorders, such as lupus and rheumatoid arthritis, as well as psychiatric conditions, such as anxiety and depression. The hypothesis provides insights into the genetic basis of these disorders. It highlights the importance of considering both immunological and psychological factors in their diagnosis and treatment, suggesting shared genetic underpinnings of these disorders and aiming to bridge the gap between immunology and psychiatry, ultimately paving the way for more comprehensive approaches to diagnosis and treatment strategies for patients suffering from these conditions.{{cite web | url=https://www.integrativepractitioner.com/whole-systems-medicine/2020-09-18-the-rccx-theory-of-chronic-illness | title=The RCCX theory of chronic illness | access-date=8 March 2024 | archive-date=10 December 2023 | archive-url=https://web.archive.org/web/20231210175830/https://www.integrativepractitioner.com/whole-systems-medicine/2020-09-18-the-rccx-theory-of-chronic-illness | url-status=live }}{{cite AV media|url=https://www.audible.com/pd/TNP210-RCCX-Theory-of-Complex-Illness-Podcast/B0CJ5NQKSF|title=TNP210 RCCX Theory of Complex Illness|via=www.audible.com|access-date=8 March 2024|archive-date=14 November 2023|archive-url=https://web.archive.org/web/20231114221117/https://www.audible.com/pd/TNP210-RCCX-Theory-of-Complex-Illness-Podcast/B0CJ5NQKSF|url-status=live}} Meglathery encountered obstacles in initiating bench research for her hypothesis such as skepticism from the scientific community.{{cite web | url=https://www.courtneysnydermd.com/blog/hypermobility-rccx-theory-and-one-journey-from-illness-towards-wholeness | title=Hypermobility, RCCX Theory and One Journey from Illness Towards Wholeness | access-date=8 March 2024 | archive-date=14 December 2023 | archive-url=https://web.archive.org/web/20231214130413/https://www.courtneysnydermd.com/blog/hypermobility-rccx-theory-and-one-journey-from-illness-towards-wholeness | url-status=live }}

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Category:Chromosomes (human)

Category:Genetic anomalies