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48-693: The RCCX abbreviation is composed of the names of the genes R P (a former name for STK19 serine/threonine kinase 19), C 4 , C YP21 and TN X ). The RCCX abbreviation was first mentioned in a 1994 article published in Immunogenetics , an academic journal, for a study by Dangel et al. 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. The quadrimodular structure of

96-610: A heme cofactor binding loop. Each subunit in the human enzyme consists of a total of 13 α-helices and 9 β-strands that folds into a triangular prism-like tertiary structure . The iron(III) heme group that defines the active site resides in the center of each subunit. The human enzyme binds one substrate at a time. In contrast, the well-characterized bovine enzyme can bind two substrates. The human and bovine enzyme share 80% amino acid sequence identity, but are structurally different, particularly in loop regions, and also evident in secondary structure elements. Variations of

144-417: 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. The C4 gene encodes

192-717: A certain disease or condition. If the primers are not designed carefully, they may bind to both the CYP21A2 and the CYP21A1P pseudogene, or to different segments of the RCCX cluster, resulting in false-positive or false-negative results. Therefore, PCR for the CYP21A2 requires the use of locus-specific primers that can distinguish between the gene and the pseudogene, and between different RCCX modules. Moreover, PCR may not be able to detect complex variants such as large gene conversions , deletions , or duplications , which are frequent in

240-440: A disturbance in the development of the enzyme, leading to congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Gene conversion events involving the functional gene and the pseudogene account for many cases of steroid 21-hydroxylase deficiency. CAH is an autosomal recessive disorder . There are multiple forms of CAH, defined as classical and nonclassical forms based on the amount of enzyme function still present in

288-483: A hypothesis developed by Sharon Meglathery, a US psychiatrist, an author of a few publications on psychiatry, and oncology, 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

336-536: 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. Due to the high degree of homology between the CYP21A2 gene and the CYP21A1P pseudogene and the complexity of the RCCX locus, it is difficult to perform molecular diagnostics for CYP21A2 . The pseudogene can have single-nucleotide polymorphisms (SNP) that are identical or similar to those in

384-470: A product of a reaction catalyzed by CYP21, as their primary glucocorticoid hormone with mineralocorticoid properties. This suggests the presence of a complex and highly specific corticosteroid signaling pathway that emerged at least half a billion years ago during early vertebrate evolution. In vertebrates, such as fish, amphibians, reptiles, birds, and mammals, Cyp21 participates in the biosynthesis of glucocorticoids and mineralocorticoids, therefore, Cyp21

432-786: 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

480-542: Is a member of the cytochrome P450 family of monooxygenase enzymes, the protein has 494 amino acid residues with a molecular weight of 55,000. This enzyme is at most 28% homologous to other P-450 enzymes that have been studied. Structurally, the protein contains an evolutionarily conserved core of four α-helix bundles (the importance of such genetic conservation is in demonstrating the functional importance of this aspect of this protein's structure). In addition, it has two additional alpha helices, two sets of β-sheets , and

528-432: Is almost exclusively expressed in the adrenal gland. As of 2023, the main subcellular location for the encoded protein in human cells is not known, and is pending cell analysis. The enzyme, steroid 21-hydroxylase hydroxylates steroids at the C21 position. Steroids are a group of naturally occurring and synthetically produced organic compounds, steroids all share a four ring primary structure. The enzyme catalyzes

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576-793: 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 . The CYP21 gene is associated with developing congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH), 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 ). The TNXB gene, also known as tenascin-X,

624-400: Is approximately 1.3 x 10 M s at 37 °C. This makes it the most catalytically efficient P450 enzyme of those reported to date, and catalytically more efficient than the closely related bovine steroid 21-hydroxylase enzyme. C-H bond breaking to create a primary carbon radical is thought to be the rate-limiting step in the hydroxylation. Genetic variants in the CYP21A2 gene cause

672-560: Is associated with mild and clinically silent cortisol impairment, but an excess of androgens post-puberty. Non-classical congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (NCCAH) is a milder and late-onset congenital adrenal hyperplasia. Its prevalence rate in different ethnic groups varies from 1 in 1000 to 1 in 50 . Some people affected by the condition have no relevant signs and symptoms, while others experience symptoms of hyperandrogenism . Women with NCCAH usually have normal female genitalia at birth. In later life,

720-536: 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 and the functional gene TNXB within the RCCX module, resulting in CYP21A2 deletion along with impaired TNXB function, is called CAH-X Syndrome and leads to both congenital adrenal hyperplasia (CAH) symptoms and features consistent with EDS. This impaired function of

768-422: Is essential for the biosynthesis of cortisol and aldosterone . Steroid 21-hydroxylase is a cytochrome P450 enzyme that is notable for its substrate specificity and relatively high catalytic efficiency . Like other cytochrome P450 enzymes, steroid 21-hydroxylase participates in the cytochrome P450 catalytic cycle and engages in one-electron transfer with NADPH - P450 reductase . Steroid 21-hydroxylase

816-453: Is essential for the regulation of stress response, electrolyte balance and blood pressure, immune system, and metabolism in vertebrates. Cyp21 is relatively conserved among mammals, and shows some variations in its structure, expression, and regulation. Rhesus macaques and orangutans possess two copies of Cyp21 , while chimpanzees have three, still, a pseudogene ( CYP21A1P ) is only present in humans among primates. Steroid 21-hydroxylase

864-410: Is highly specific for hydroxylation of progesterone and 17-hydroxyprogesterone. This is in marked contrast to the evolutionarily and functionally related P450 enzyme 17-hydroxylase , which has a broad range of substrates. The chemical reaction in which steroid 21-hydroxylase catalyzes the addition of hydroxyl (-OH) to the C21 position of progesterone , 17α-hydroxyprogesterone and 21-desoxycortisone

912-417: 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. The RCCX module

960-478: Is localized in microsomes of endoplasmic reticulum membranes within adrenal cortex . It is one of three microsomal steroidogenic cytochrome P450 enzymes, the others being steroid 17-hydroxylase and aromatase . Unlike other enzymes of the cytochrome P450 superfamily of enzymes that are expressed in multiple tissues, with most abundant expression in the liver, in adult humans steroid 21-hydroxylase, along with steroid 11β-hydroxylase and aldosterone synthase ,

1008-437: Is part of the major histocompatibility complex (MHC) class III ( MHC class III ), which is the most gene-dense region of the human genome, containing many genes that yet have unknown function or structure. 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

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1056-656: Is related to personality traits such as novelty seeking and impulsivity 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 :

1104-452: Is the most complex gene cluster in the human genome. 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. The quadrimodular structure of the RCCX unit is very rare. In a monomodular structure, all of the genes are functional i.e. protein-coding , but if

1152-442: Is unable to detect the junction sites of chimeras. The CYP21A2 gene is prone to mismatch and rearrangement, producing different types of complex variations that include copy number variants , large gene conversions , small insertions / deletions , and single-nucleotide (SNP) variants. Southern blotting is not capable of detecting all these types of variants simultaneously. Besides that, southern blotting requires genetic analysis of

1200-530: The STK19 gene) is involved in cell growth and differentiation , but its exact functions remain unclear. 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

1248-810: 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 . 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 . The presence of multiple RCCX modules

1296-663: 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",

1344-574: The Tenascin X gene TNXB and STK19 . MHC class III is the most gene-dense region of the human genome, containing many genes that have, as of 2023 - unknown functions or structures. Inside the MHC class III , CYP21A2 is located within the RCCX cluster (an abbreviation composed of the names of the genes RP (a former name for STK19 serine/threonine kinase 19), C4 , CYP21 and TNX ), which

1392-424: The chemical reaction in which the hydroxyl group (-OH) is added at the C21 position of the steroid biomolecule . This location is on a side chain of the D ring. The enzyme is a member of the cytochrome P450 superfamily of monooxygenase enzymes. The cytochrome P450 enzymes catalyze many reactions involved in drug metabolism and synthesis of cholesterol , steroids and other lipids . Steroid 21-hydroxylase

1440-453: 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. The CYP21A2 gene encodes the enzyme 21-hydroxylase involved in synthesizing cortisol and aldosterone . The TNXB gene encodes the Tenascin X , an extracellular matrix glycoprotein. Tenascin X

1488-597: The mouse genome , the Cyp21a2 is a pseudogene and the Cyp21a1 is a functional gene. In the chicken and quail , there is only a single Cyp21 gene, which locus is located between complement component C4 and TNX gene, along with Cenpa . CYP21A2 in humans is located in chromosome 6 , in the major histocompatibility complex III (MHC class III) close to the Complement component 4 genes C4A and C4B ,

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1536-476: The RCCX unit is very rare. 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

1584-589: 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

1632-496: The case of the CYP21A2 . Southern blotting , a method used for detecting and quantifying a specific DNA sequence in DNA samples, also has limitations in analyzing CYP21A2 . This method is time-consuming and requires a large amount of good-quality DNA, which makes it less applicable in routine diagnostic settings. This method comes with a radioactive biohazard, which poses safety concerns and makes it labor-intensive. Southern blotting

1680-560: The enzyme may cause congenital adrenal hyperplasia . Steroid 21-hydroxylase is a member of the cytochrome P450 family of monooxygenase enzymes that use an iron-containing heme cofactor to oxidize substrates. In humans, the enzyme is localized in endoplasmic reticulum membranes of cells in adrenal cortex , and is encoded by the CYP21A2 gene which is located near the CYP21A1P pseudogene that has high degree of sequence similarity. This similarity makes it difficult to analyze

1728-523: The functional gene, making it difficult to distinguish between them. The pseudogene can also recombine with the functional gene, creating hybrid genes that have features of both. This can result in false-positive or false-negative results when testing for SNPs in the CYP21A2 . The whole genome sequencing technology relies on breaking the DNA into small fragments, sequencing them, and then assembling them back together based on their overlaps. However, because of

1776-456: The gene at the molecular level, and sometimes leads to loss-of-function mutations of the gene due to intergenic exchange of DNA . 4Y8W ,%%s 2GEG 1589 13079 ENSG00000235134 ENSMUSG00000024365 P08686 Q08AG9 P03940 NM_000500 NM_001128590 NM_009995 NP_001122062.3 NP_034125 Steroid 21-hydroxylase in humans is encoded by the CYP21A2 gene that may be accompanied by one or several copies of

1824-532: 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. Meglathery encountered obstacles in initiating bench research for her hypothesis such as skepticism from

1872-429: The high homology and variability of the CYP21A2 and its pseudogene, the fragments cannot be mapped unambiguously to either copy of the gene. This can lead to errors or gaps in the assembly, or missing some variants that are present in the gene. Polymerase chain reaction (PCR) molecular diagnostics uses selective primers to amplify specific segments of the DNA sequence that are relevant for diagnosing or detecting

1920-403: 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. The RCCX module is the most complex gene cluster in the human genome. It

1968-423: The nonfunctional pseudogene CYP21A1P , this pseudogene shares 98% of the exonic informational identity with the actual functional gene. Pseudogenes are common in genomes, and they originate as artifacts during the duplication process. Though often thought of as "junk DNA", research has shown that retaining these faulty copies can have a beneficial role, often providing regulation of their parent genes. In

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2016-444: The nucleus. Its specific function is unknown; it is possible that phosphorylation of this protein is involved in transcriptional regulation. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6 and expresses two transcript variants. This article on a gene on human chromosome 6 is a stub . You can help Misplaced Pages by expanding it . CYP21A2 Steroid 21-hydroxylase

2064-472: The parents, which is not always feasible or practical. Therefore, to analyze the CYP21A2 gene accurately, a more specialized and sensitive method is needed, such as targeted long-read sequencing , which can sequence longer DNA fragments and capture more information about the gene structure and variation. However, this method is not widely available or affordable for clinical use. Steroid 21-hydroxylase,

2112-537: The patient. The classical forms occur in approximately 1 in 10 000 to 1 in 20 000 births globally, and includes both the salt-wasting (excessive excretion of sodium via the urine causing hyponatremia and dehydration) and simple-virilizing forms. Complete loss of enzymatic activity causes the salt-wasting form. Variations in the structure of steroid 21-hydroxylase are related to the clinical severity of congenital adrenal hyperplasia. Cortisol and aldosterone deficits are associated with life-threatening sodium loss, as

2160-460: The scientific community. STK19 8859 54402 ENSG00000234947 ENSMUSG00000061207 P49842 Q9JHN8 NM_004197 NM_032454 NM_019442 NP_004188 NP_115830 NP_062315 Serine/threonine-protein kinase 19 is an enzyme that in humans is encoded by the STK19 gene . This gene encodes a serine/threonine kinase which localizes predominantly to

2208-503: The steroid 21-hydroxylase can be found in all vertebrates . Cyp21 first emerged in chordates before the speciation between basal chordates and vertebrates. The sea lamprey , an early jawless fish species that originated over 500 million years ago, provides valuable insights into the evolution and emergence of Cyp21 . Sea lampreys lack the 11β-hydroxylase enzyme responsible for converting 11-deoxycortisol to cortisol as observed in mammals. Instead, they rely on 11-deoxycortisol,

2256-413: The steroids play roles in regulating sodium homeostasis . Simple-virilizing CAH patients (~1-2% enzyme function) maintain adequate sodium homeostasis, but exhibit other symptoms shared by the salt-wasting form, including accelerated growth in childhood and ambiguous genitalia in female neonates . The nonclassical form is the mildest condition, retaining about 20% to 50% of enzyme function. This form

2304-434: Was first described in 1952. Studies of the human enzyme expressed in yeast initially classified 17-hydroxyprogesterone as the preferred substrate for steroid 21-hydroxylase, however, later analysis of the purified human enzyme found a lower K M and greater catalytic efficiency for progesterone over 17-hydroxyprogesterone. The catalytic efficiency of steroid 21-hydroxylase for conversion of progesterone in humans

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