RCCX

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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]

Contents

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 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). [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]

Related Research Articles

<span class="mw-page-title-main">Autoimmunity</span> Immune response against an organisms own healthy cells

In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, Henoch–Schönlein purpura, systemic lupus erythematosus, Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, and multiple sclerosis. Autoimmune diseases are very often treated with steroids.

<span class="mw-page-title-main">Congenital adrenal hyperplasia</span> Medical condition

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex. Most of these disorders involve excessive or deficient production of hormones such as glucocorticoids, mineralocorticoids, or sex steroids, and can alter development of primary or secondary sex characteristics in some affected infants, children, or adults. It is one of the most common autosomal recessive disorders in humans.

<span class="mw-page-title-main">Adrenal insufficiency</span> Medical condition

Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids, mineralocorticoids, and androgens. These hormones are important in regulating blood pressure, electrolytes, and metabolism as a whole. Deficiency of these hormones leads to symptoms ranging from abdominal pain, vomiting, muscle weakness and fatigue, low blood pressure, depression, mood and personality changes to organ failure and shock. Adrenal crisis may occur if a person having adrenal insufficiency experiences stresses, such as an accident, injury, surgery, or severe infection; this is a life-threatening medical condition resulting from severe deficiency of cortisol in the body. Death may quickly follow.

<span class="mw-page-title-main">Lipoid congenital adrenal hyperplasia</span> Medical condition

Lipoid congenital adrenal hyperplasia is an endocrine disorder that is an uncommon and potentially lethal form of congenital adrenal hyperplasia (CAH). It arises from defects in the earliest stages of steroid hormone synthesis: the transport of cholesterol into the mitochondria and the conversion of cholesterol to pregnenolone—the first step in the synthesis of all steroid hormones. Lipoid CAH causes mineralocorticoid deficiency in affected infants and children. Male infants are severely undervirilized causing their external genitalia to look feminine. The adrenals are large and filled with lipid globules derived from cholesterol.

<span class="mw-page-title-main">Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency</span> Medical condition

Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency is an uncommon form of congenital adrenal hyperplasia (CAH) resulting from a mutation in the gene for one of the key enzymes in cortisol synthesis by the adrenal gland, 3β-hydroxysteroid dehydrogenase (3β-HSD) type II (HSD3B2). As a result, higher levels of 17α-hydroxypregnenolone appear in the blood with adrenocorticotropic hormone (ACTH) challenge, which stimulates adrenal corticosteroid synthesis.

Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency is an uncommon form of congenital adrenal hyperplasia (CAH) resulting from a mutation in the gene CYP17A1, which produces the enzyme 17α-hydroxylase. It causes decreased synthesis of cortisol and sex hormones, with resulting increase in mineralocorticoid production. Thus, common symptoms include mild cortisol deficiency, ambiguous genitalia in men or amenorrhea at puberty in women, and hypokalemic hypertension. However, partial (incomplete) deficiency often has inconsistent symptoms between patients, and affected women may be asymptomatic except for infertility.

<span class="mw-page-title-main">Congenital adrenal hyperplasia due to 21-hydroxylase deficiency</span> Medical condition

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) is a genetic disorder characterized by impaired production of cortisol in the adrenal glands.

<span class="mw-page-title-main">Classical complement pathway</span> Aspect of the immune system

The classical complement pathway is one of three pathways which activate the complement system, which is part of the immune system. The classical complement pathway is initiated by antigen-antibody complexes with the antibody isotypes IgG and IgM.

<span class="mw-page-title-main">Complement component 2</span> Protein found in humans

Complement C2 is a protein that in humans is encoded by the C2 gene. The protein encoded by this gene is part of the classical pathway of the complement system, acting as a multi-domain serine protease. Deficiency of C2 has been associated with certain autoimmune diseases.

<span class="mw-page-title-main">21-Hydroxylase</span> Human enzyme that hydroxylates steroids

Steroid 21-hydroxylase is a protein that in humans is encoded by the CYP21A2 gene. The protein is an enzyme that hydroxylates steroids at the C21 position on the molecule. Naming conventions for enzymes are based on the substrate acted upon and the chemical process performed. Biochemically, this enzyme is involved in the biosynthesis of the adrenal gland hormones aldosterone and cortisol, which are important in blood pressure regulation, sodium homeostasis and blood sugar control. The enzyme converts progesterone and 17α-hydroxyprogesterone into 11-deoxycorticosterone and 11-deoxycortisol, respectively, within metabolic pathways which in humans ultimately lead to aldosterone and cortisol creation—deficiency in the enzyme may cause congenital adrenal hyperplasia.

Complement component 4 (C4), in humans, is a protein involved in the intricate complement system, originating from the human leukocyte antigen (HLA) system. It serves a number of critical functions in immunity, tolerance, and autoimmunity with the other numerous components. Furthermore, it is a crucial factor in connecting the recognition pathways of the overall system instigated by antibody-antigen (Ab-Ag) complexes to the other effector proteins of the innate immune response. For example, the severity of a dysfunctional complement system can lead to fatal diseases and infections. Complex variations of it can also lead to schizophrenia. The C4 protein was thought to derive from a simple two-locus allelic model, which however has been replaced by a much more sophisticated multimodular RCCX gene complex model which contain long and short forms of the C4A or C4B genes usually in tandem RCCX cassettes with copy number variation, that somewhat parallels variation in the levels of their respective proteins within a population along with CYP21 in some cases depending on the number of cassettes and whether it contains the functional gene instead of pseudogenes or fragments. Originally defined in the context of the Chido/Rodgers blood group system, the C4A-C4B genetic model is under investigation for its possible role in schizophrenia risk and development.

<span class="mw-page-title-main">Tenascin X</span> Protein-coding gene in the species Homo sapiens

Tenascin X (TN-X), also known as flexillin or hexabrachion-like protein, is a 450kDa glycoprotein, a member of the tenascin family, that is expressed in connective tissues. In humans it is encoded by the TNXB gene.

<span class="mw-page-title-main">C4A</span> Protein-coding gene in the species Homo sapiens

Complement C4-A is a kind of the Complement component 4 protein that in humans is encoded by the C4A gene.

<span class="mw-page-title-main">STK19</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase 19 is an enzyme that in humans is encoded by the STK19 gene.

HLA A1-B8-DR3-DQ2 haplotype is a multigene haplotype that covers a majority of the human major histocompatibility complex on chromosome 6. A multigene haplotype is set of inherited alleles covering several genes, or gene-alleles; common multigene haplotypes are generally the result of descent by common ancestry. Chromosomal recombination fragments multigene haplotypes as the distance to that ancestor increases in number of generations.

<span class="mw-page-title-main">Lupus</span> Human autoimmune disease

Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common symptoms include painful and swollen joints, fever, chest pain, hair loss, mouth ulcers, swollen lymph nodes, feeling tired, and a red rash which is most commonly on the face. Often there are periods of illness, called flares, and periods of remission during which there are few symptoms.

<span class="mw-page-title-main">Complement component 4B</span> Protein-coding gene in the species Homo sapiens

Complement component 4B (Chido blood group) is a kind of the Complement component 4 protein that in humans is encoded by the C4B gene.

Maria Iandolo New is a professor of Pediatrics, Genomics and Genetics at Icahn School of Medicine at Mount Sinai in New York City. She is an expert in congenital adrenal hyperplasia (CAH), a genetic condition affecting the adrenal gland that can affect sexual development.

Walter L. Miller is an American endocrinologist and professor emeritus of pediatrics at the University of California, San Francisco (UCSF). Miller is expert in the field of human steroid biosynthesis and disorders of steroid metabolism. Over the past 40 years Miller's group at UCSF has described molecular basis of several metabolic disorders including, congenital adrenal hyperplasia, pseudo vitamin D dependent rickets, severe, recessive form of Ehlers-Danlos syndrome, 17,20 lyase deficiency caused by CYP17A1 defects, P450scc deficiency caused by CYP11A1 defects, P450 oxidoreductase deficiency.

Late onset congenital adrenal hyperplasia (LOCAH), also known as nonclassic congenital adrenal hyperplasia, is a milder form of congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol synthesis that leads to variable degrees of postnatal androgen excess.

References

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  37. ↑ PD-icon.svg This article incorporates public domain material from "TNXA tenascin XA (pseudogene) [ Homo sapiens (human) ]". Reference Sequence collection . National Center for Biotechnology Information.
  38. ↑ PD-icon.svg This article incorporates public domain material from "TNXB tenascin XB [ Homo sapiens (human)". Reference Sequence collection . National Center for Biotechnology Information.
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