RCCX is a complex, multiallelic, and tandem copy number variation (CNV) human DNA locus on chromosome 6p21.3, a cluster located in the major histocompatibility complex (MHC) class III region.[1][2] CNVs are segments of DNA that vary in copy number compared to a reference genome and play a significant role in human phenotypic variation and disease development. The RCCX cluster consists of one or more modules each having a series of genes close to each other: serine/threonine kinase 19 (STK19), complement 4 (C4), steroid 21-hydroxylase (CYP21), and tenascin-X (TNX).[3]

Name

The RCCX abbreviation is composed of the names of the genes RP (a former name for STK19 serine/threonine kinase 19),[2][3] C4, CYP21 and TNX).[4] The RCCX abbreviation was first mentioned in a 1994 article published in Immunogenetics, an academic journal, for a study by Dangel et al.[5]

Structure

The number of RCCX segments varies between one and four in a chromosome,[2] with the prevalence of approximately 15% for monomodular, 75% for bimodular (STK19-C4A-CYP21A1P-TNXA-STK19B-C4B-CYP21A2-TNXB),[3][6] and 10% for trimodular in Europeans.[7] The quadrimodular structure of the RCCX unit is very rare.[8][2][7]

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.[2][7] 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),[7] can be of one of two types: C4A and C4B.[9] 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.[10][3]

The RCCX module is the most complex gene cluster in the human genome.[3][9][11] It is part of the major histocompatibility complex (MHC) class III (MHC class III),[12][13] which is the most gene-dense region of the human genome, containing many genes that yet have unknown function or structure.[14][15][16][17] 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.[10][2]

Function

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.[7]

The RP gene (a former name for the STK19 gene) is involved in cell growth and differentiation, but its exact functions remain unclear.[18] 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.[19][20][21]

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.[22]

The CYP21A2 gene encodes the enzyme 21-hydroxylase involved in synthesizing cortisol and aldosterone.[23]

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.[24]

Clinical significance

The RCCX module is related to personality traits such as novelty seeking and impulsivity[25] 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.[3]

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.[3]

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.[26][27][28] 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.[29][30][31]

The presence of multiple RCCX modules is also associated with an increased risk of autoimmune diseases.[3]

Genetic variations in the RCCX module have been linked to many other disorders, including autism spectrum disorder, and drug addiction.[32]

The CYP21 gene is associated with developing congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH),[33][34][35] a genetic disorder that affects the adrenal glands and causes cortisol deficiencies (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).[36]

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[37] and the functional gene TNXB[38] within the RCCX module, resulting in CYP21A2 deletion along with impaired TNXB function, is called CAH-X Syndrome[39][6] and leads to both congenital adrenal hyperplasia (CAH) symptoms and features consistent with EDS.[3] 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.[3]

Society and culture

An "RCCX theory", a hypothesis developed by Sharon Meglathery, a US psychiatrist,[40] an author of a few publications on psychiatry,[41][42] and oncology,[43][44] 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.[45][46] Meglathery encountered obstacles in initiating bench research for her hypothesis such as skepticism from the scientific community.[47]

References

  1. ↑ Chang SF, Lee HH (2011). "Analysis of the CYP21A2 gene with intergenic recombination and multiple gene deletions in the RCCX module". Genet Test Mol Biomarkers. 15 (1–2): 35–42. doi:10.1089/gtmb.2010.0080. PMID 21117955.
  2. 1 2 3 4 5 6 Bánlaki Z, Doleschall M, Rajczy K, Fust G, Szilágyi A (October 2012). "Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes". Genes Immun. 13 (7): 530–535. doi:10.1038/gene.2012.29. PMID 22785613. S2CID 36582994.
  3. 1 2 3 4 5 6 7 8 9 10 Carrozza C, Foca L, De Paolis E, Concolino P (2021). "Genes and Pseudogenes: Complexity of the RCCX Locus and Disease". Front Endocrinol (Lausanne). 12. 709758. doi:10.3389/fendo.2021.709758. PMC 8362596. PMID 34394006.
  4. ↑ Sweeten TL, Odell DW, Odell JD, Torres AR (January 2008). "C4B null alleles are not associated with genetic polymorphisms in the adjacent gene CYP21A2 in autism". BMC Medical Genetics. 9: 1. doi:10.1186/1471-2350-9-1. PMC 2265260. PMID 18179706.
  5. ↑ Dangel AW, Mendoza AR, Baker BJ, Daniel CM, Carroll MC, Wu LC, Yu CY (1994). "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". Immunogenetics. 40 (6): 425–436. doi:10.1007/BF00177825. PMID 7545960. S2CID 19796359.
  6. 1 2 Kim JH, Kim GH, Yoo HW, Choi JH (June 2023). "Molecular basis and genetic testing strategies for diagnosing 21-hydroxylase deficiency, including CAH-X syndrome". Ann Pediatr Endocrinol Metab. 28 (2): 77–86. doi:10.6065/apem.2346108.054. PMC 10329939. PMID 37401054.
  7. 1 2 3 4 5 Bánlaki Z, Szabó JA, Szilágyi Á, Patócs A, Prohászka Z, Füst G, Doleschall M (2013). "Intraspecific evolution of human RCCX copy number variation traced by haplotypes of the CYP21A2 gene". Genome Biol Evol. 5 (1): 98–112. doi:10.1093/gbe/evs121. PMC 3595039. PMID 23241443.
  8. ↑ Tsai LP, Lee HH (September 2012). "Analysis of CYP21A1P and the duplicated CYP21A2 genes". Gene. 506 (1): 261–262. doi:10.1016/j.gene.2012.06.045. PMID 22771554.
  9. 1 2 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 (June 2017). "A unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics". Eur J Hum Genet. 25 (6): 702–710. doi:10.1038/ejhg.2017.38. PMC 5477366. PMID 28401898.
  10. 1 2 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 (2021). "Human Complement C4B Allotypes and Deficiencies in Selected Cases With Autoimmune Diseases". Front Immunol. 12. 739430. doi:10.3389/fimmu.2021.739430. PMC 8577214. PMID 34764957.
  11. ↑ Milner CM, Campbell RD (August 2001). "Genetic organization of the human MHC class III region". Frontiers in Bioscience: A Journal and Virtual Library. 6: D914–26. doi:10.2741/milner. PMID 11487476.
  12. ↑ Yu CY (1998). "Molecular genetics of the human MHC complement gene cluster". Exp Clin Immunogenet. 15 (4): 213–230. doi:10.1159/000019075. PMID 10072631. S2CID 25061446.
  13. ↑ Yu CY, Chung EK, Yang Y, Blanchong CA, Jacobsen N, Saxena K, Yang Z, Miller W, Varga L, Fust G (2003). "Dancing with Complement C4 and the RP-C4-CYP21-TNX (RCCX) Modules of the Major Histocompatibility Complex". Prog Nucleic Acid Res Mol Biol. Progress in Nucleic Acid Research and Molecular Biology. 75: 217–292. doi:10.1016/s0079-6603(03)75007-7. ISBN 9780125400756. PMID 14604014.
  14. ↑ Xie T, Rowen L, Aguado B, Ahearn ME, Madan A, Qin S, Campbell RD, Hood L (December 2003). "Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse". Genome Research. 13 (12): 2621–36. doi:10.1101/gr.1736803. PMC 403804. PMID 14656967.
  15. ↑ Rupert KL, Rennebohm RM, Yu CY (1999). "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". Exp Clin Immunogenet. 16 (2): 81–97. doi:10.1159/000019099. PMID 10343159. S2CID 24623016.
  16. ↑ Espinosa Reyes TM, Collazo Mesa T, Lantigua Cruz PA, Agramonte Machado A, Domínguez Alonso E, Falhammar H (November 2020). "Molecular diagnosis of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency". BMC Endocrine Disorders. 20 (1): 165. doi:10.1186/s12902-020-00643-z. PMC 7653887. PMID 33168061.
  17. ↑ Lee HH (January 2005). "Chimeric CYP21P/CYP21 and TNXA/TNXB genes in the RCCX module". Mol Genet Metab. 84 (1): 4–8. doi:10.1016/j.ymgme.2004.09.009. PMID 15639189.
  18. ↑ Asquith CRM, Temme L (September 2020). "STK19: a new target for NRAS-driven cancer". Nat Rev Drug Discov. 19 (9): 579. doi:10.1038/d41573-020-00116-x. PMID 32587355. S2CID 256745367.
  19. ↑ 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 (February 2019). "Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis". Cell. 176 (5): 1113–1127.e16. doi:10.1016/j.cell.2019.01.002. PMID 30712867. S2CID 72333604.
  20. ↑ Rodríguez-Martínez M, Boissiére T, Noe Gonzalez M, Litchfield K, Mitter R, Walker J, Kjœr S, Ismail M, Downward J, Swanton C, Svejstrup JQ (June 2020). "Evidence That STK19 Is Not an NRAS-dependent Melanoma Driver". Cell. 181 (6): 1395–1405.e11. doi:10.1016/j.cell.2020.04.014. PMC 7298618. PMID 32531245.
  21. ↑ Yin C, Zhu B, Li X, Goding CR, Cui R (June 2020). "A Reply to "Evidence that STK19 Is Not an NRAS-Dependent Melanoma Driver"". Cell. 181 (6): 1406–1409.e2. doi:10.1016/j.cell.2020.04.029. PMID 32531246. S2CID 219572289.
  22. ↑ Pereira KM, Faria AG, Liphaus BL, Jesus AA, Silva CA, Carneiro-Sampaio M, Andrade LE (May 2016). "Low C4, C4A and C4B gene copy numbers are stronger risk factors for juvenile-onset than for adult-onset systemic lupus erythematosus". Rheumatology (Oxford). 55 (5): 869–73. doi:10.1093/rheumatology/kev436. PMID 26800705.
  23. ↑ Marino R, Moresco A, Perez Garrido N, Ramirez P, Belgorosky A (2022). "Congenital Adrenal Hyperplasia and Ehlers-Danlos Syndrome". Front Endocrinol (Lausanne). 13: 803226. doi:10.3389/fendo.2022.803226. PMC 8913572. PMID 35282436.
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  25. ↑ Piero Portincasa, Gema Frühbeck, Hendrik M. Nathoe, eds. (2019). "Endocrine Disorders and Psychiatric Manifestations". Endocrinology and Systemic Diseases. Springer Cham. pp. 1–35. doi:10.1007/978-3-319-66362-3_12-1. ISBN 978-3-319-66362-3. S2CID 164396406.
  26. ↑ Wu Z, Zhang S, Li P, Zhang F, Li Y (November 2020). "Association between complement 4 copy number variation and systemic lupus erythematosus: a meta-analysis". Clin Exp Med. 20 (4): 627–634. doi:10.1007/s10238-020-00640-5. PMID 32691186. S2CID 220638363.
  27. ↑ Pereira KMC, Perazzio S, Faria AGA, Moreira ES, Santos VC, Grecco M, da Silva NP, Andrade LEC (August 2019). "Impact of C4, C4A and C4B gene copy number variation in the susceptibility, phenotype and progression of systemic lupus erythematosus". Adv Rheumatol. 59 (1): 36. doi:10.1186/s42358-019-0076-6. PMID 31387635.
  28. ↑ "Low Gene Copy Number for C4, C4A and C4B Is a Strong Risk Factor for Developing Systemic Lupus Erythematosus in Childhood".
  29. ↑ Mason MJ, Speake C, Gersuk VH, Nguyen QA, O'Brien KK, Odegard JM, Buckner JH, Greenbaum CJ, Chaussabel D, Nepom GT (May 2014). "Low HERV-K(C4) copy number is associated with type 1 diabetes". Diabetes. 63 (5): 1789–95. doi:10.2337/db13-1382. PMID 24430436. S2CID 11775986.
  30. ↑ Tsang-A-Sjoe MWP, Bultink IEM, Korswagen LA, van der Horst A, Rensink I, de Boer M, Hamann D, Voskuyl AE, Wouters D (December 2017). "Comprehensive approach to study complement C4 in systemic lupus erythematosus: Gene polymorphisms, protein levels and functional activity". Mol Immunol. 92: 125–131. doi:10.1016/j.molimm.2017.10.004. PMID 29080553. S2CID 10363726.
  31. ↑ Mack M, Bender K, Schneider PM (August 2004). "Detection of retroviral antisense transcripts and promoter activity of the HERV-K(C4) insertion in the MHC class III region". Immunogenetics. 56 (5): 321–332. doi:10.1007/s00251-004-0705-y. PMID 15309346. S2CID 7128183.
  32. ↑ Trowsdale J, Knight JC (2013). "Major histocompatibility complex genomics and human disease". Annu Rev Genomics Hum Genet. 14: 301–323. doi:10.1146/annurev-genom-091212-153455. PMC 4426292. PMID 23875801.
  33. ↑ Fanis P, Skordis N, Phylactou LA, Neocleous V (March 2023). "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". Hormones (Athens). 22 (1): 71–77. doi:10.1007/s42000-022-00410-w. PMC 10011304. PMID 36264454.
  34. ↑ Fanis P, Skordis N, Toumba M, Picolos M, Tanteles GA, Neocleous V, Phylactou LA (2023). "The pathogenic p.Gln319Ter variant is not causing congenital adrenal hyperplasia when inherited in one of the duplicated CYP21A2 genes". Front Endocrinol (Lausanne). 14. 1156616. doi:10.3389/fendo.2023.1156616. PMC 10266209. PMID 37324257.
  35. ↑ Lao Q, Burkardt DD, Kollender S, Faucz FR, Merke DP (July 2023). "Congenital adrenal hyperplasia due to two rare CYP21A2 variant alleles, including a novel attenuated CYP21A1P/CYP21A2 chimera". Mol Genet Genomic Med. 11 (7). e2195. doi:10.1002/mgg3.2195. PMC 10337281. PMID 37157918.
  36. ↑ Nimkarn S, Gangishetti PK, Yau M, New MI (4 February 2016) [26 February 2002]. Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A (eds.). "21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia" (PDF). GeneReviews. PMID 20301350. NBK1171.
  37. ↑ Public Domain This article incorporates public domain material from "TNXA tenascin XA (pseudogene) [ Homo sapiens (human) ]". Reference Sequence collection. National Center for Biotechnology Information.
  38. ↑ Public Domain This article incorporates public domain material from "TNXB tenascin XB [ Homo sapiens (human)". Reference Sequence collection. National Center for Biotechnology Information.
  39. ↑ Paragliola RM, Perrucci A, Foca L, Urbani A, Concolino P (July 2022). "Prevalence of CAH-X Syndrome in Italian Patients with Congenital Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency". J Clin Med. 11 (13): 3818. doi:10.3390/jcm11133818. PMC 9267771. PMID 35807105.
  40. ↑ https://health.usnews.com/doctors/sharon-meglathery-420774
  41. ↑ Ener RA, Meglathery SB, Van Decker WA, Gallagher RM (March 2003). "Serotonin syndrome and other serotonergic disorders". Pain Med. 4 (1): 63–74. doi:10.1046/j.1526-4637.2003.03005.x. PMID 12873279.
  42. ↑ Denicoff KD, Meglathery SB, Post RM, Tandeciarz SI (February 1994). "Efficacy of carbamazepine compared with other agents: a clinical practice survey". J Clin Psychiatry. 55 (2): 70–6. PMID 8077157.
  43. ↑ Ener RA, Meglathery SB, Styler M (June 2004). "Extravasation of systemic hemato-oncological therapies". Ann Oncol. 15 (6): 858–62. doi:10.1093/annonc/mdh214. PMID 15151940.
  44. ↑ Ener RA, Meglathery SB, Cuhaci B, Topolsky D, Styler MJ, Crilley P, Brodsky I, Kahn SB, King RS (February 2001). "Use of granulocyte colony-stimulating factor after high-dose chemotherapy and autologous peripheral blood stem cell transplantation: what is the optimal timing?". Am J Clin Oncol. 24 (1): 19–25. doi:10.1097/00000421-200102000-00003. PMID 11232944.
  45. ↑ "The RCCX theory of chronic illness".
  46. ↑ TNP210 RCCX Theory of Complex Illness – via www.audible.com.
  47. ↑ "Hypermobility, RCCX Theory and One Journey from Illness Towards Wholeness".
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