Variants of the CYP21A2 and CYP21A1P genes in congenital adrenal hyperplasia

Lee, Hsien-Hsiung

doi:10.1016/j.cca.2012.12.030

Cited by 10 publications

(7 citation statements)

References 68 publications

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“…Some P450 SNPs are exceedingly rare, occurring in less than 1% of the population. These rare mutations are linked to congenital defects, including glaucoma (CYP1B1; Stoilov et al, 1998;Tanwar et al, 2009;Sheikh et al, 2014), 17-a hydroxylase deficiency (CYP17A1; Yamaguchi et al, 1998;Costa-Santos et al, 2004;Hwang et al, 2011;Qiao et al, 2011), congenital adrenal hyperplasia (CYP21A2; Robins et al, 2006;Lee, 2013;Szabó et al, 2013;Sharaf et al, 2015), spina bifida (CYP26A1; Rat et al, 2006), focal facial dermal dysplasia (CYP26C1; Slavotinek et al, 2013), and cerebrotendinous xanthomatosis (CYP27A1; Garuti et al, 1996;Verrips et al, 1997;Chen et al, 1998;Tian and Zhang, 2011). Other P450 polymorphisms that alter splicing are associated with neurologic and metabolic diseases, including Parkinson's disease (CYP2D6, Denson et al, 2005;CYP2J2, Searles Nielsen et al, 2013), hypertension (CYP4A11, Zhang et al, 2013;CYP17A1, Wang et al, 2011), breast cancer (CYP2D6, Huang et al, 1996;CYP19A1, Kristensen et al, 2000;) colon cancer (CYP2W1, Stenstedt et al, 2012), and lung cancer (CYP2D6, Huang et al, 1997;CYP2F1, Tournel et al, 2007).…”

Section: Snp-sensitive Alternative Splicing In the Cytochrome P450 Sumentioning

confidence: 99%

Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism

2017

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The human genome encodes 57 cytochrome P450 genes, whose enzyme products metabolize hundreds of drugs, thousands of xenobiotics, and unknown numbers of endogenous compounds, including steroids, retinoids, and eicosanoids. Indeed, P450 genes are the first line of defense against daily environmental chemical challenges in a manner that parallels the immune system. Several National Institutes of Health databases, including PubMed, AceView, and Ensembl, were queried to establish a comprehensive analysis of the full human P450 transcriptome. This review describes a remarkable diversification of the 57 human P450 genes, which may be alternatively processed into nearly 1000 distinct mRNA transcripts to shape an individual's P450 proteome. Important P450 splice variants from families 1A, 1B, 2C, 2D, 3A, 4F, 19A, and 24A have now been documented, with some displaying alternative subcellular distribution or catalytic function directly linked to a disease pathology. The expansion of P450 transcript diversity involves tissue-specific splicing factors, transformation-sensitive alternate splicing, -splicing between gene transcripts, single-nucleotide polymorphisms, and epigenetic regulation of alternate splicing. Homeostatic regulation of variant P450 expression is influenced also by nuclear receptor signaling, suppression of nonsense-mediated decay or premature termination codons, mitochondrial dysfunction, or host infection. This review focuses on emergent aspects of the adaptive gene-splicing process, which when viewed through the lens of P450-nuclear receptor gene interactions, resembles a primitive immune-like system that can rapidly monitor, respond, and diversify to acclimate to fluctuations in endo-xenobiotic exposure. Insights gained from this review should aid future drug discovery and improve therapeutic management of personalized drug regimens.

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Section: Snp-sensitive Alternative Splicing In the Cytochrome P450 Sumentioning

confidence: 99%

Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism

2017

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“…Nevertheless, the potential for altered protein exists through gene conversion or other processes that combine sequence from multiple instances of the gene. The primary autoantigen in Addison's disease is encoded by CYP21A2 (Table 1), which resides within a segmentally duplicated region and is a known locus of germ-line gene conversion [156].…”

Section: Discussionmentioning

confidence: 99%

Coherent Somatic Mutation in Autoimmune Disease

Ross

2014

PLoS ONE

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BackgroundMany aspects of autoimmune disease are not well understood, including the specificities of autoimmune targets, and patterns of co-morbidity and cross-heritability across diseases. Prior work has provided evidence that somatic mutation caused by gene conversion and deletion at segmentally duplicated loci is relevant to several diseases. Simple tandem repeat (STR) sequence is highly mutable, both somatically and in the germ-line, and somatic STR mutations are observed under inflammation.ResultsProtein-coding genes spanning STRs having markers of mutability, including germ-line variability, high total length, repeat count and/or repeat similarity, are evaluated in the context of autoimmunity. For the initiation of autoimmune disease, antigens whose autoantibodies are the first observed in a disease, termed primary autoantigens, are informative. Three primary autoantigens, thyroid peroxidase (TPO), phogrin (PTPRN2) and filaggrin (FLG), include STRs that are among the eleven longest STRs spanned by protein-coding genes. This association of primary autoantigens with long STR sequence is highly significant (). Long STRs occur within twenty genes that are associated with sixteen common autoimmune diseases and atherosclerosis. The repeat within the TTC34 gene is an outlier in terms of length and a link with systemic lupus erythematosus is proposed.ConclusionsThe results support the hypothesis that many autoimmune diseases are triggered by immune responses to proteins whose DNA sequence mutates somatically in a coherent, consistent fashion. Other autoimmune diseases may be caused by coherent somatic mutations in immune cells. The coherent somatic mutation hypothesis has the potential to be a comprehensive explanation for the initiation of many autoimmune diseases.

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“…Throughout evolution, the inactive CYP21A1P pseudogene has acquired multiple pathogenic variants, as well as small insertions or deletions and point pathogenic variants that prevent the synthesis of a normal functional protein. The high degree of homology between the gene and the pseudogene enables the occurrence of unequal pairing during meiosis between homologous chromosomes and sister chromatids [41]. Approximately 95% of pathogenic variants in the CYP21A2 gene result from meiotic recombination events between the gene and the pseudogene [8], with approximately 75% of pathogenic variants resulting from conversion events of large sequences from the pseudogene to the gene or punctual conversion of single alterations (microconversion).…”

Section: -Oh Cah Deficiency Is Mainly Caused By Pathogenic Variants I...mentioning

confidence: 99%

Congenital Adrenal Hyperplasia – The Main Effect of 21-Hydroxylase Deficiency

Carvalho¹,

Carvalho²,

Carvalho³

2024

Adrenal Glands - The Current Stage and New Perspectives of Diseases and Treatment

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Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders resulting from enzymatic defects in steroidogenesis. More than 95% of CAH cases result from a deficiency of the 21-hydroxylase enzyme, which leads to cortisol deficiency, with or without aldosterone insufficiency, and also an excess of androgen. The clinical spectrum varies from milder symptoms to severe cases settled by the functional impairment of the corresponding pathogenic variant in the CYP21A2 gene. The two major forms of CAH caused by 21-hydroxylase deficiency are the classical form and the non-classic, or late onset form. There are two subtypes of the classic form: salt wasting and simple virilized. Diagnosis is clinically confirmed by 17OH-progesterone measurements, although genotyping is now progressively assuming an essential role for characterising patients. Genotyping is sometimes challenging, due to the existence of the highly homologous CYP21A1P pseudogene. The 21-hydroxylase enzyme is encoded by the CYP21A2 gene, where most of the pathogenic variants defects are due to meiotic recombination phenomena events between the CYP21A2 and CYP21A1P. Complete gene analysis is recommended to obtain a correct diagnosis and a better understanding of the underlying mechanisms of the disease in patients with CAH, and is relevant for prognosis and for prescribing the appropriate type of genetic counselling.

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Variants of the CYP21A2 and CYP21A1P genes in congenital adrenal hyperplasia

Cited by 10 publications

References 68 publications

Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism

Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism

Coherent Somatic Mutation in Autoimmune Disease

Congenital Adrenal Hyperplasia – The Main Effect of 21-Hydroxylase Deficiency

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