Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2.

Pascoe, Leigh; Curnow, Kathleen M.; Slutsker, Liliya; Connell, John; Speiser, Phyllis; New, Maria I.; White, Perrin C.

doi:10.1073/pnas.89.17.8327

Cited by 250 publications

(103 citation statements)

References 24 publications

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“…This astounding abundance has, of course, arisen primarily through gene duplication. Tandem duplication arrays are common among CYPs, as are documented cases of inter-paralog recombination (Sinnott et al, 1990;Pascoe et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

A Revised Evolutionary History of the CYP1A Subfamily: Gene Duplication, Gene Conversion, and Positive Selection

Goldstone

Stegeman

2006

J Mol Evol

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Running header: Recombination and selection in tetrapod CYP1AsKey words: Cytochrome P450, gene conversion, gene duplication, chicken, mammalian Abbreviations:Page 1 of 32 JME-2005-00134 ABSTRACTMembers of cytochrome P450 subfamily 1A (CYP1As) are involved in detoxification and bioactivation of common environmental pollutants. Understanding the functional evolution of these genes is essential to predicting and interpreting species differences in sensitivity to toxicity by such chemicals. The CYP1A gene subfamily comprises a single ancestral representative in most fish species and two paralogs in higher vertebrates, including birds and mammals.Phylogenetic analysis of complete coding sequences suggests that mammalian and bird paralog pairs (CYP1A1/2 and CYP1A4/5, respectively) are the result of independent gene duplication events. However, comparison of vertebrate genome sequences revealed that CYP1A genes lie within an extended region of conserved fine-scale synteny, suggesting that avian and mammalian CYP1A paralogs share a common genomic history. Algorithms designed to detect recombination between nucleotide sequences indicate that gene conversion has homogenized most of the length of the chicken CYP1A genes, as well as the 5' end of mammalian CYP1As.Together, these data indicate that avian and mammalian CYP1A paralog pairs resulted from a single gene duplication event and that extensive gene conversion is responsible for the exceptionally high degree of sequence similarity between CYP1A4 and CYP1A5. Elevated nonsynonymous/synonymous substitution ratios within a putatively unconverted stretch of ~250 bp suggests that positive selection may have reduced the effective rate of gene conversion in this region, which contains two substrate recognition sites. This work significantly alters our understanding of functional evolution in the CYP1A subfamily, suggesting that gene conversion and positive selection have been the dominant processes of sequence evolution.

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Section: Discussionmentioning

confidence: 99%

A Revised Evolutionary History of the CYP1A Subfamily: Gene Duplication, Gene Conversion, and Positive Selection

Goldstone

Stegeman

2006

J Mol Evol

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“…prednisone, blocks the production of the abnormal steroids and lowers blood pressure (Sutherland et al 1966). Using the anomalous generation of steroids as an intermediate phenotype in a large pedigree, Lifton and colleagues linked this syndrome to a locus on chromosome 8q (Lifton et al 1992a,b;Pascoe et al 1992a). Two closely related genes for adrenal steroid biosynthesis are confined to this locus in a tandem arrangement, 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) (Fig.…”

Section: Monogenic or Mendelian Forms Of Hypertensionmentioning

confidence: 99%

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

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Human hypertension affects affects more than 20% of the adult population in industrialized countries, and it is implicated in millions of deaths worldwide each year from stroke, heart failure and ischemic heart disease. Available evidence suggests a major genetic impact on blood pressure regulation. Studies in monogenic hypertension revealed that renal salt and volume regulation systems are predominantly involved in the genesis of these disorders. Mutations here affect the synthesis of mineralocorticoids, the function of the mineralocorticoid receptor, epithelial sodium channels and their regulation by a new class of kinases, termed WNK kinases. It has been learned from monogenic hypotension that almost all ion transporters involved in the renal uptake of Na + have a major impact on blood pressure regulation. For essential hypertension as a complex disease, many candidate genes have been analysed. These include components of the reninangiotensin-aldosterone system, adducin, β-adrenoceptors, G protein subunits, regulators of G protein signalling (RGS) proteins, Rho kinases and G protein receptor kinases. At present, the individual impact of common polymorphisms in these genes on the observed blood pressure variation, on risk for stroke and as predictors of antihypertensive responses remains small and clinically irrelevant. Nevertheless, these studies have greatly augmented our knowledge on the regulation of renal functions, cellular signal transduction and the integration of both. Together, this provides the basis for the identification of novel drug targets and, hopefully, innovative antihypertensive drugs.

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“…Mutações no gene CYP11B1, que codifica a enzima 11OH, causam HCA, ao passo que as mutações no gene CYP11B2, que codifica a enzima CYP11B2, são as causas da deficiência de corticosterona metiloxidase ou deficiência da aldosterona sintase (17). Por outro lado, a síndrome conhecida como hiperaldosteronismo supressível por glicocorticóides é resultado de uma recombinação intergênica, justapondo-se o promotor do CYP11B1 com seqüências codificadoras do CYP11B2 formando um gene híbrido (18,19). Mutações deletérias no gene CYP11B1, entretanto, são encontradas nas análises de DNA de pacientes com deficiência de 11OH e são correlacionadas com alterações em resíduos importantes para a atividade enzimática ou com interrupções da transcrição normal do gene gerando mRNA alterados e, conseqüentemente, proteínas truncadas (12,17,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31).…”

Section: Hiperplasia Congênita De Adrenal Por Deficiência De 11β β-Hiunclassified

Causas raras de pseudo-hermafroditismo feminino: quando suspeitar?

Castro

Elias

2005

Arq Bras Endocrinol Metab

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RESUMONeste artigo discutiremos as causas raras de pseudo-hermafroditismo feminino. Hiperplasia congênita adrenal é a causa mais comum da ambigüidade da genitalia externa no nascimento, em fetos 46,XX, devido principalmente à forma clássica de deficiência de 21-hidroxilase. São apresentadas aqui as deficiências de 11β-hidroxilase e de 3β-hidroxiesteroide desidrogenase, além da resistência familial aos glicocorticóides, caracterizada pela secreção aumentada de cortisol sem evidência clínica de hipercortisolismo, mas com manifestations de excesso de andrógenos e de mineralocorticóides, decorrente de mutações no gene do receptor do glucocorticóide. Também são discutidas a deficiência de aromatase placentária, caracterizada por masculinização do feto feminino, acompanhada de virilização materna durante a gestação, e deve ser considerada na ausência da hiperplasia adrenal fetal e de tumores maternos produtores de andrógenos e a deficiência da P450-oxidorredutase, além das causas maternas e de quadros dismórficos complexos que levam ao pseudo-hermafroditismo feminino. A investigação requer a análise do cariótipo, dosagens séricas iniciais de 17OH progesterona, 11 desoxicortisol, 17-pregnenolone e andrógenos para avaliar o diagnóstico das diferentes causas de hiperplasia adrenal congênita. Após este diagnóstico ser afastado, dados clínicos e laboratoriais devem ser coletados para afastar as causas ainda mais raras de pseudo-hermafroditismo feminino. The congenital adrenal hyperplasia is the commonest cause of ambiguity of the external genitalia at birth, due to classic forms of 21-hydroxylase and 11β-hydroxylase deficiencies. 3β-hydroxysteroid dehydrogenase (3βHSD) is a rare disorder that affects both sexes and female patients may have ambiguous genitalia. Familial glucocorticoid resistance is characterized by increased cortisol secretion without clinical evidence of hypercortisolism, but with manifestations of androgen and mineralocorticoid excess, caused by glucocorticoid receptor gene mutation, and rarely can lead to female pseudohermaphroditism. Placental aromatase deficiency is a rare disease characterized by a masculinized female fetus and a virilized mother, which should be considered in the absence of fetal adrenal hyperplasia and maternal androgen-secreting tumours. Finally, mutations of P450 oxidoreductase causes disordered steroidogenesis with ambiguous genitalia. The investigation of abnormal sexual development requires an initial karyotype analysis and serum 17OH progesterone, 11 deoxycortisol, 17 pregnenolone, and androgen measurements to assess the diagnosis of different forms of congenital adrenal hyperplasia.

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Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2.

Cited by 250 publications

References 24 publications

A Revised Evolutionary History of the CYP1A Subfamily: Gene Duplication, Gene Conversion, and Positive Selection

A Revised Evolutionary History of the CYP1A Subfamily: Gene Duplication, Gene Conversion, and Positive Selection

Genetics of arterial hypertension and hypotension

Causas raras de pseudo-hermafroditismo feminino: quando suspeitar?

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