RESUMEN
Hypertension (HT) is a major cardiovascular risk factor that affects 10% to 40% of the general population in an age-dependent manner. Detection of secondary forms of HT is particularly important because it allows the targeted management of the underlying disease. Among hypertensive patients, the prevalence of endocrine HT reaches up to 10%. Adrenal diseases are the most frequent cause of endocrine HT and are associated with excess production of mineralocorticoids (mainly primary aldosteronism), glucocorticoids (Cushing syndrome), and catecholamines (pheochromocytoma). In addition, a few rare diseases directly affecting the action of mineralocorticoids and glucocorticoids in the kidney also lead to endocrine HT. Over the past years, genomic and genetic studies have allowed improving our knowledge on the molecular mechanisms of endocrine HT. Those discoveries have opened new opportunities to transfer knowledge to clinical practice for better diagnosis and specific treatment of affected subjects. In this review, we describe the physiology of adrenal hormone biosynthesis and action, the clinical and biochemical characteristics of different forms of endocrine HT, and their underlying genetic defects. We discuss the impact of these discoveries on diagnosis and management of patients, as well as new perspectives related to the use of new biomarkers for improved patient care.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Hiperaldosteronismo , Hipertensión , Humanos , Glucocorticoides , Mineralocorticoides , Hiperaldosteronismo/complicaciones , Hipertensión/etiología , Neoplasias de las Glándulas Suprarrenales/complicaciones , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/terapia , BiomarcadoresRESUMEN
CONTEXT AND OBJECTIVE: Sonic Hedgehog (SHH) and GLI2, an obligatory mediator of SHH signal transduction, are holoprosencephaly (HPE)-associated genes essential in pituitary formation. GLI2 variants have been found in patients with congenital hypopituitarism without complex midline cerebral defects (MCD). However, data on the occurrence of SHH mutations in these patients are limited. We screened for SHH and GLI2 mutations or copy number variations (CNV) in patients with congenital hypopituitarism without MCD or with variable degrees of MCD. PATIENTS AND METHODS: Detailed data on clinical, laboratory and neuroimaging findings of 115 patients presenting with congenital hypopituitarism without MCD, septo-optic dysplasia or HPE were analysed. The SHH and GLI2 genes were directly sequenced, and the presence of gene CNV was analysed by multiplex ligation-dependent probe amplification (MLPA). RESULTS: Anterior pituitary deficiency was found in 74% and 53% of patients with SOD or HPE, respectively. Diabetes insipidus was common in patients with HPE (47%) but infrequent in patients with congenital hypopituitarism or SOD (7% and 8%, respectively). A single heterozygous nonsense SHH mutation (p.Tyr175Ter) was found in a patient presenting with hypopituitarism and alobar HPE. No other SHH mutations or CNV were found. Nine GLI2 variations (8 missense and 1 frameshift) including a homozygous and a compound heterozygous variation were found in patients with congenital hypopituitarism or SOD, but not in HPE patients. No GLI2 CNV were found. CONCLUSION: SHH mutations or copy number variations are not a common cause of congenital hypopituitarism in patients without complex midline cerebral defects. GLI2 variants are found in some patients with congenital hypopituitarism without complex midline cerebral defects or septo-optic dysplasia. However, functional analyses of these variants are needed to strengthen genotype-phenotype relationship.
Asunto(s)
Proteínas Hedgehog/genética , Hipopituitarismo/congénito , Hipopituitarismo/genética , Mutación , Adolescente , Adulto , Encéfalo/fisiopatología , Niño , Preescolar , Femenino , Dosificación de Gen , Estudios de Asociación Genética , Variación Genética , Heterocigoto , Holoprosencefalia/genética , Humanos , Lactante , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Imagen por Resonancia Magnética , Masculino , Mutación Missense , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenotipo , Hipófisis/metabolismo , Transducción de Señal , Adulto Joven , Proteína Gli2 con Dedos de ZincRESUMEN
Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production.
Asunto(s)
Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Hiperaldosteronismo , Hipertensión , Humanos , Aldosterona , Citocromo P-450 CYP11B2 , Uniones Comunicantes , Mutación , Molécula 1 de Adhesión CelularRESUMEN
Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease of mineralocorticoid resistance characterized by salt wasting and failure to thrive in infancy. Here we describe the first case of a newborn with severe recessive PHA1 caused by two heterozygous mutations in NR3C2, gene coding for the mineralocorticoid receptor (MR). Independent segregation of the mutations occurred in the family, with p.Ser166X being transmitted from the affected father and p.Trp806X from the asymptomatic mother Whereas the truncated MR(166X) protein was degraded, MR(806X) was expressed both at the mRNA and protein level. Functional studies demonstrated that despite its inability to bind aldosterone, MR(806X) had partial ligand-independent transcriptional activity. Partial nuclear localization of MR(806X) in the absence of hormone was identified as a prerequisite to initiate transcription. This exceptional case broadens the spectrum of clinical phenotypes of PHA1 and demonstrates that minimal residual activity of MR is compatible with life. It also suggests that rare hypomorphic NR3C2 alleles may be more common than expected from the prevalence of detected PHA1 cases. This might prove relevant for patient's care in neonatal salt losing disorders and may affect renal salt handling and blood pressure in the general population.
Asunto(s)
Codón sin Sentido/genética , Insuficiencia de Crecimiento/genética , Hiponatremia/genética , Seudohipoaldosteronismo/genética , Receptores de Mineralocorticoides/genética , Aldosterona/metabolismo , Animales , Células COS , Preescolar , Chlorocebus aethiops , Codón de Terminación/genética , Salud de la Familia , Femenino , Humanos , Recién Nacido , Masculino , Linaje , Unión Proteica/genética , Receptores de Mineralocorticoides/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
Primary aldosteronism is the most common form of secondary arterial hypertension, due to excessive aldosterone production from the adrenal gland. Although somatic mutations have been identified in aldosterone producing adenoma, the exact mechanisms leading to increased cell proliferation and nodule formation remain to be established. One hypothesis is that changes in vascular supply to the adrenal cortex, due to phenomena of atherosclerosis or high blood pressure, may influence the morphology of the adrenal cortex, resulting in a compensatory growth and nodule formation in response to local hypoxia. In this review, we will summarize our knowledge on the mechanisms regulating adrenal cortex development and function, describe adrenal vascularization in normal and pathological conditions and address the mechanisms allowing the cross-talk between the hormonal and vascular components to allow the extreme tissue plasticity of the adrenal cortex in response to endogenous and exogenous stimuli. We will then address recent evidence suggesting a role for alterations in the vascular compartment that could eventually be involved in nodule formation and the development of primary aldosteronism.
Asunto(s)
Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Hiperaldosteronismo , Hipertensión , Humanos , Hiperaldosteronismo/complicaciones , Neoplasias de la Corteza Suprarrenal/patología , Adenoma Corticosuprarrenal/patología , Glándulas Suprarrenales/patología , Aldosterona , Hipertensión/complicacionesRESUMEN
CONTEXT: Aldosterone-producing adenomas (APAs) are a common cause of primary aldosteronism (PA). Despite the discovery of somatic mutations in APA and the characterization of multiple factors regulating adrenal differentiation and function, the sequence of events leading to APA formation remains to be determined. OBJECTIVE: We investigated the role of Wnt/ß-catenin and adrenocorticotropin signaling, as well as elements of paracrine regulation of aldosterone biosynthesis in adrenals with APA and their relationship to intratumoral heterogeneity and mutational status. METHODS: We analyzed the expression of aldosterone-synthase (CYP11B2), CYP17A1, ß-catenin, melanocortin type 2 receptor (MC2R), phosphorlyated cAMP response element-binding protein (pCREB), tryptase, S100, CD34 by multiplex immunofluorescence, and immunohistochemistry-guided reverse transcription-quantitative polymerase chain reaction. Eleven adrenals with APA and 1 with micronodular hyperplasia from patients with PA were analyzed. Main outcome measures included localization of CYP11B2, CYP17A1, ß-catenin, MC2R, pCREB, tryptase, S100, CD34 in APA and aldosterone-producing cell clusters (APCCs). RESULTS: Immunofluorescence revealed abundant mast cells and a dense vascular network in APA, independent of mutational status. Within APA, mast cells were localized in areas expressing CYP11B2 and were rarely colocalized with nerve fibers, suggesting that their degranulation is not controlled by innervation. In these same areas, ß-catenin was activated, suggesting a zona glomerulosa cell identity. In heterogeneous APA with KCNJ5 mutations, MC2R and vascular endothelial growth factor A expression was higher in areas expressing CYP11B2. A similar pattern was observed in APCC, with high expression of CYP11B2, activated ß-catenin, and numerous mast cells. CONCLUSION: Our results suggest that aldosterone-producing structures in adrenals with APA share common molecular characteristics and cellular environment, despite different mutation status, suggesting common developmental mechanisms.
Asunto(s)
Adenoma/metabolismo , Neoplasias de la Corteza Suprarrenal/metabolismo , Hormona Adrenocorticotrópica/metabolismo , Hiperaldosteronismo/metabolismo , Vía de Señalización Wnt , Adenoma/complicaciones , Adenoma/genética , Adenoma/cirugía , Corteza Suprarrenal/metabolismo , Corteza Suprarrenal/patología , Corteza Suprarrenal/cirugía , Neoplasias de la Corteza Suprarrenal/complicaciones , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/cirugía , Adrenalectomía , Aldosterona/metabolismo , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Humanos , Hiperaldosteronismo/genética , Hiperaldosteronismo/cirugía , Mutación , Comunicación Paracrina , beta Catenina/metabolismoRESUMEN
Primary aldosteronism affects up to 10% of hypertensive patients and is responsible for treatment resistance and increased cardiovascular risk. Here we perform a genome-wide association study in a discovery cohort of 562 cases and 950 controls and identify three main loci on chromosomes 1, 13 and X; associations on chromosome 1 and 13 are replicated in a second cohort and confirmed by a meta-analysis involving 1162 cases and 3296 controls. The association on chromosome 13 is specific to men and stronger in bilateral adrenal hyperplasia than aldosterone producing adenoma. Candidate genes located within the two loci, CASZ1 and RXFP2, are expressed in human and mouse adrenals in different cell clusters. Their overexpression in adrenocortical cells suppresses mineralocorticoid output under basal and stimulated conditions, without affecting cortisol biosynthesis. Our study identifies the first risk loci for primary aldosteronism and highlights new mechanisms for the development of aldosterone excess.
Asunto(s)
Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Hiperaldosteronismo , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/cirugía , Adrenalectomía , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/cirugía , Aldosterona , Animales , Proteínas de Unión al ADN/genética , Estudio de Asociación del Genoma Completo , Humanos , Hiperaldosteronismo/genética , Masculino , Ratones , Factores de Transcripción/genéticaRESUMEN
OBJECTIVE: Primary aldosteronism (PA) is the most common form of secondary and curable hypertension. Different germline and somatic mutations are found in aldosterone-producing adenoma (APA) and familial forms of the disease, while the causes of bilateral adrenal hyperplasia (BAH) remain largely unknown. Adrenalectomy is the recommended treatment for patients with APA; however, 6% of patients are not cured and show persistent PA after surgery suggesting BAH. The objective of this study was to analyze clinical data of patients with APA without biochemical success after adrenalectomy as well as the histological and genetic characteristics of their adrenal glands. DESIGN AND METHODS: Clinical data of 12 patients with partial and absent biochemical cure were compared to those from 39 PA patients with hormonal cure after surgery. Histological, morphological, and genetic characterization of the adrenals was carried out by CYP11B2 and CYP11B1 immunostaining and by CYP11B2-guided NGS. RESULTS: Patients with absent hormonal cure displayed a longer duration of arterial hypertension and lower lateralization index of aldosterone production. In ten patients, APAs expressing CYP11B2 were identified. No difference in histological and morphological characteristics was observed between patients with or without a hormonal cure. Somatic mutations in APA driver genes were identified in all CYP11B2 positive APAs; CACNA1D mutations were the most frequent genetic abnormality. CONCLUSIONS: Patients with partial and absent biochemical cure were diagnosed later and exhibited a lower lateralization index of aldosterone production, suggesting asymmetric aldosterone production in the context of BAH. Somatic mutations in adrenal glands from those patients indicate common mechanisms underlying BAH and APA.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales/genética , Enfermedades de las Glándulas Suprarrenales/patología , Adrenalectomía , Hiperaldosteronismo/genética , Hiperaldosteronismo/patología , Enfermedades de las Glándulas Suprarrenales/cirugía , Glándulas Suprarrenales/patología , Glándulas Suprarrenales/cirugía , Adulto , Femenino , Humanos , Hiperaldosteronismo/cirugía , Masculino , Persona de Mediana Edad , Mutación , Resultado del TratamientoRESUMEN
Most aldosterone-producing adenomas (APAs) have gain-of-function somatic mutations of ion channels or transporters. However, their frequency in aldosterone-producing cell clusters of normal adrenal gland suggests a requirement for codriver mutations in APAs. Here we identified gain-of-function mutations in both CTNNB1 and GNA11 by whole-exome sequencing of 3/41 APAs. Further sequencing of known CTNNB1-mutant APAs led to a total of 16 of 27 (59%) with a somatic p.Gln209His, p.Gln209Pro or p.Gln209Leu mutation of GNA11 or GNAQ. Solitary GNA11 mutations were found in hyperplastic zona glomerulosa adjacent to double-mutant APAs. Nine of ten patients in our UK/Irish cohort presented in puberty, pregnancy or menopause. Among multiple transcripts upregulated more than tenfold in double-mutant APAs was LHCGR, the receptor for luteinizing or pregnancy hormone (human chorionic gonadotropin). Transfections of adrenocortical cells demonstrated additive effects of GNA11 and CTNNB1 mutations on aldosterone secretion and expression of genes upregulated in double-mutant APAs. In adrenal cortex, GNA11/Q mutations appear clinically silent without a codriver mutation of CTNNB1.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/genética , Adenoma Corticosuprarrenal/genética , Aldosterona/biosíntesis , Subunidades alfa de la Proteína de Unión al GTP/genética , beta Catenina/genética , Adolescente , Neoplasias de la Corteza Suprarrenal/patología , Adenoma Corticosuprarrenal/patología , Adulto , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Humanos , Hiperaldosteronismo/patología , Masculino , Menopausia/metabolismo , Persona de Mediana Edad , Embarazo , Pubertad/metabolismoRESUMEN
Aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia are the main cause of primary aldosteronism (PA), the most frequent form of secondary hypertension. Mutations in ion channels and ATPases have been identified in APA and inherited forms of PA, highlighting the central role of calcium signaling in PA development. Different somatic mutations are also found in aldosterone-producing cell clusters in adrenal glands from healthy individuals and from patients with unilateral and bilateral PA, suggesting additional pathogenic mechanisms. Recent mouse models have also contributed to a better understanding of PA. Application of genetic screening in familial PA, development of surrogate biomarkers for somatic mutations in APA, and use of targeted treatment directed at mutated proteins may allow improved management of patients.
Asunto(s)
Hiperaldosteronismo/genética , Adenoma Corticosuprarrenal/genética , Aldosterona/genética , Animales , Señalización del Calcio/genética , Genética , Genómica/métodos , Humanos , Hiperplasia/genética , Hipertensión/genética , Mutación/genéticaRESUMEN
Early diagnosis and appropriate treatment of primary aldosteronism, the most frequent cause of secondary hypertension, are crucial to prevent deleterious cardiovascular outcomes. In the past decade, the discovery of genetic abnormalities responsible for sporadic and familial forms of primary aldosteronism has improved the knowledge of the pathogenesis of this disorder. Mutations in genes encoding ion channels and pumps lead to increased cytosolic concentrations of calcium in zona glomerulosa cells, which triggers CYP11B2 expression and autonomous aldosterone production. Improved understanding of the mechanisms underlying the disease is key to improving diagnostics and to developing and implementing targeted treatments. This Review provides an update on the genetic abnormalities associated with sporadic and familial forms of primary aldosteronism, their frequency among different populations and the mechanisms explaining excessive aldosterone production and adrenal nodule development. The possible effects and uses of these findings for improving the diagnostics for primary aldosteronism are discussed. Furthermore, current treatment options of primary aldosteronism are reviewed, with particular attention to the latest studies on blood pressure and cardiovascular outcomes following medical or surgical treatment. The new perspectives regarding the use of targeted drug therapy for aldosterone-producing adenomas with specific somatic mutations are also addressed.
Asunto(s)
Aldosterona/biosíntesis , Hiperaldosteronismo/genética , Hiperaldosteronismo/terapia , Hipertensión/etiología , Glándulas Suprarrenales/patología , Animales , Humanos , Hiperaldosteronismo/metabolismo , Hiperaldosteronismo/patología , MutaciónRESUMEN
Aldosterone-producing adenoma (APA) cause primary aldosteronism-the most frequent form of secondary hypertension. Somatic mutations in genes coding for ion channels and ATPases are found in APA and in aldosterone-producing cell clusters. We investigated the genetic, cellular, and molecular heterogeneity of different aldosterone-producing structures in adrenals with APA, to get insight into the mechanisms driving their development and to investigate their clinical and biochemical correlates. Genetic analysis of APA, aldosterone-producing cell clusters, and secondary nodules was performed in adrenal tissues from 49 patients by next-generation sequencing following CYP11B2 immunohistochemistry. Results were correlated with clinical and biochemical characteristics of patients, steroid profiles, and histological features of the tumor and adjacent adrenal cortex. Somatic mutations were identified in 93.75% of APAs. Adenoma carrying KCNJ5 mutations had more clear cells and cells expressing CYP11B1, and fewer cells expressing CYP11B2 or activated ß-catenin, compared with other mutational groups. 18-hydroxycortisol and 18-oxocortisol were higher in patients carrying KCNJ5 mutations and correlated with histological features of adenoma; however, mutational status could not be predicted using steroid profiling. Heterogeneous CYP11B2 expression in KCNJ5-mutated adenoma was not associated with genetic heterogeneity. Different mutations were identified in secondary nodules expressing aldosterone synthase and in independent aldosterone-producing cell clusters from adrenals with adenoma; known KCNJ5 mutations were identified in 5 aldosterone-producing cell clusters. Genetic heterogeneity in different aldosterone-producing structures in the same adrenal suggests complex mechanisms underlying APA development.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/metabolismo , Glándulas Suprarrenales/metabolismo , Adenoma Corticosuprarrenal/metabolismo , Aldosterona/metabolismo , Hiperaldosteronismo/metabolismo , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/patología , Glándulas Suprarrenales/patología , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/patología , Adulto , Anciano , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Femenino , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Humanos , Hiperaldosteronismo/genética , Hiperaldosteronismo/patología , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Mutación , Esteroide 11-beta-Hidroxilasa/genética , Esteroide 11-beta-Hidroxilasa/metabolismoRESUMEN
Human primary aldosteronism (PA) can be caused by mutations in several ion channel genes but mouse models replicating this condition are lacking. We now show that almost all known PA-associated CLCN2 mutations markedly increase ClC-2 chloride currents and generate knock-in mice expressing a constitutively open ClC-2 Cl- channel as mouse model for PA. The Clcn2op allele strongly increases the chloride conductance of zona glomerulosa cells, provoking a strong depolarization and increasing cytoplasmic Ca2+ concentration. Clcn2op mice display typical features of human PA, including high serum aldosterone in the presence of low renin activity, marked hypertension and hypokalemia. These symptoms are more pronounced in homozygous Clcn2op/op than in heterozygous Clcn2+/op mice. This difference is attributed to the unexpected finding that only ~50 % of Clcn2+/op zona glomerulosa cells are depolarized. By reproducing essential features of human PA, Clcn2op mice are a valuable model to study the pathological mechanisms underlying this disease.
Asunto(s)
Canales de Cloruro/genética , Modelos Animales de Enfermedad , Hiperaldosteronismo/genética , Hipertensión/genética , Ratones , Zona Glomerular/metabolismo , Animales , Canales de Cloruro CLC-2 , Técnicas de Sustitución del Gen , Heterocigoto , Homocigoto , Hiperaldosteronismo/complicaciones , Hipertensión/etiología , Hipopotasemia/etiología , Hipopotasemia/genética , MutaciónRESUMEN
Primary aldosteronism (PA) is the most frequent form of secondary arterial hypertension. Mutations in different genes increase aldosterone production in PA, but additional mechanisms may contribute to increased cell proliferation and aldosterone producing adenoma (APA) development. We performed transcriptome analysis in APA and identified retinoic acid receptor alpha (RARα) signaling as a central molecular network involved in nodule formation. To understand how RARα modulates adrenal structure and function, we explored the adrenal phenotype of male and female Rarα knockout mice. Inactivation of Rarα in mice led to significant structural disorganization of the adrenal cortex in both sexes, with increased adrenal cortex size in female mice and increased cell proliferation in males. Abnormalities of vessel architecture and extracellular matrix were due to decreased Vegfa expression and modifications in extracellular matrix components. On the molecular level, Rarα inactivation leads to inhibition of non-canonical Wnt signaling, without affecting the canonical Wnt pathway nor PKA signaling. Our study suggests that Rarα contributes to the maintenance of normal adrenal cortex structure and cell proliferation, by modulating Wnt signaling. Dysregulation of this interaction may contribute to abnormal cell proliferation, creating a propitious environment for the emergence of specific driver mutations in PA.
Asunto(s)
Hiperaldosteronismo/genética , Hipertensión/genética , Receptor alfa de Ácido Retinoico/genética , Factor A de Crecimiento Endotelial Vascular/genética , Corteza Suprarrenal/metabolismo , Corteza Suprarrenal/patología , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/patología , Animales , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patología , Proliferación Celular/genética , Matriz Extracelular/genética , Humanos , Hiperaldosteronismo/patología , Hipertensión/patología , Ratones , Ratones Noqueados , Mutación/genética , Vía de Señalización Wnt/genéticaRESUMEN
PURPOSE OF REVIEW: Primary aldosteronism is the most common form of secondary hypertension. Early diagnosis and treatment are key to cure of hypertension and prevention of cardiovascular complications. Recent genetic discoveries have improved our understanding on the pathophysiology of aldosterone production and triggered the development of new diagnostic procedures and targeted treatments for primary aldosteronism. RECENT FINDINGS: Different inherited genetic abnormalities distinguish specific forms of familial hyperaldosteronism. Somatic mutations are found not only in aldosterone-producing adenoma (APA), leading to primary aldosteronism, but also in aldosterone producing cell clusters of normal and micronodules from image-negative adrenal glands. Genetic knowledge has allowed the discovery of surrogate biomarkers and specific pharmacological inhibitors. Ageing appears to be associated with dysregulated and relatively autonomous aldosterone production. SUMMARY: New biochemical markers and pharmacological approaches may allow preoperative identification of somatic mutation carriers and use of targeted treatments.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/genética , Adenoma Corticosuprarrenal/genética , Aldosterona/biosíntesis , Aldosterona/genética , Hiperaldosteronismo/genética , Neoplasias de la Corteza Suprarrenal/metabolismo , Glándulas Suprarrenales/metabolismo , Adenoma Corticosuprarrenal/metabolismo , Factores de Edad , Envejecimiento , Aldosterona/fisiología , Citocromo P-450 CYP11B2/genética , Femenino , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/terapia , Hipertensión/etiología , Masculino , Mutación , Factores Sexuales , SíndromeRESUMEN
Primary aldosteronism is the most common and curable form of secondary arterial hypertension. We performed whole-exome sequencing in patients with early-onset primary aldosteronism and identified a de novo heterozygous c.71G>A/p.Gly24Asp mutation in the CLCN2 gene, encoding the voltage-gated ClC-2 chloride channel 1 , in a patient diagnosed at 9 years of age. Patch-clamp analysis of glomerulosa cells of mouse adrenal gland slices showed hyperpolarization-activated Cl- currents that were abolished in Clcn2-/- mice. The p.Gly24Asp variant, located in a well-conserved 'inactivation domain'2,3, abolished the voltage- and time-dependent gating of ClC-2 and strongly increased Cl- conductance at resting potentials. Expression of ClC-2Asp24 in adrenocortical cells increased expression of aldosterone synthase and aldosterone production. Our data indicate that CLCN2 mutations cause primary aldosteronism. They highlight the important role of chloride in aldosterone biosynthesis and identify ClC-2 as the foremost chloride conductor of resting glomerulosa cells.
Asunto(s)
Canales de Cloruro/genética , Mutación con Ganancia de Función , Hiperaldosteronismo/genética , Adulto , Animales , Canales de Cloruro CLC-2 , Niño , Canales de Cloruro/metabolismo , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Mutación de Línea Germinal , Humanos , Hiperaldosteronismo/patología , Ratones , Ratones Noqueados , Persona de Mediana Edad , Linaje , Secuenciación del Exoma , Adulto Joven , Zona Glomerular/metabolismo , Zona Glomerular/patologíaRESUMEN
Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease characterized by neonatal renal salt wasting, vomiting, dehydration and failure to thrive. Affected patients present hyponatremia, hyperkalemia, associated with high levels of plasma renin and aldosterone resulting from a renal or systemic resistance to aldosterone. The systemic form of PHA1 results in a severe phenotype, and high doses of salt supplementation are necessary. The symptoms are life-long recurrent. This form is associated with autosomal recessive transmission. Homozygous or compound heterozygous loss of function mutations in the genes coding for the epithelial sodium channel (ENaC) subunities are responsible for this disease. The renal form of PHA1 results in a mild phenotype. Low doses of salt supplementation are required and usually the symptoms remit at the end of the first year of life. Heterozygous loss-of-function mutations in the mineralocorticoid receptor (MR) gene are associated with the renal form of PHA1 in the majority of the affected families but sporadic cases have been reported. In this review the mechanisms of aldosterone action and its effects are discussed. Additionally, clinical and molecular findings of a Brazilian family with the renal form of PHA1 caused by a nonsense mutation (R947X) in the MR gene are presented.
Asunto(s)
Aldosterona/sangre , Seudohipoaldosteronismo/genética , Receptores de Mineralocorticoides/genética , Aldosterona/fisiología , Canales Epiteliales de Sodio/genética , Humanos , Recién Nacido , Masculino , Mutación , Linaje , Seudohipoaldosteronismo/metabolismo , Seudohipoaldosteronismo/fisiopatología , Receptores de Mineralocorticoides/metabolismo , Transcripción GenéticaRESUMEN
BACKGROUND: The renal form of pseudohypoaldosteronism type 1 (PHA1) is a rare disease characterized by congenital mineralocorticoid resistance of the kidney. Twenty-two different loss-of-function mutations in the mineralocorticoid receptor gene have been described in families with PHA1. These mutations were not recurrent and resulted in a large phenotypic variability. OBJECTIVE: The objective of this study is to analyze the recurrence of an inactivating mutation in the mineralocorticoid receptor gene in unrelated families with autosomal dominant PHA1. PATIENTS: Seventeen members from three unrelated families with autosomal dominant PHA1 were studied, including 11 affected patients with variable clinical manifestations. Fifty healthy subjects were used as controls. METHODS: Genomic DNA was extracted, and the entire coding region of the mineralocorticoid receptor gene was submitted to automatic sequencing. Four dinucleotide microsatellite markers spanning a region of 3.2 cM in the human mineralocorticoid receptor gene locus, and two intragenic polymorphisms were used for haplotype analysis. RESULTS: A heterozygous point mutation at codon 947 (c.2839C>T) changing arginine to stop codon (R947X) was found in the three families. Different haplotypes segregated with the R947X mutation in each family, demonstrating the absence of a founder effect for this mutation. CONCLUSION: Codon 947 of the mineralocorticoid receptor is the first mutational hot spot for autosomal dominant PHA1.
Asunto(s)
Mutación Puntual , Seudohipoaldosteronismo/genética , Receptores de Mineralocorticoides/genética , 17-alfa-Hidroxiprogesterona/sangre , Aldosterona/sangre , ADN/química , ADN/genética , Femenino , Humanos , Hidrocortisona/sangre , Lactante , Recién Nacido , Masculino , Repeticiones de Microsatélite , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Seudohipoaldosteronismo/sangre , Seudohipoaldosteronismo/patología , Renina/sangreRESUMEN
Primary aldosteronism (PA) is the most common form of secondary hypertension. Mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D are found in aldosterone producing adenoma (APA) and familial hyperaldosteronism (FH). A recurrent mutation in CACNA1H (coding for Cav3.2) was identified in a familial form of early onset PA. Here we performed whole exome sequencing (WES) in patients with different types of PA to identify new susceptibility genes. Four different heterozygous germline CACNA1H variants were identified. A de novo Cav3.2 p.Met1549Ile variant was found in early onset PA and multiplex developmental disorder. Cav3.2 p.Ser196Leu and p.Pro2083Leu were found in two patients with FH, and p.Val1951Glu was identified in one patient with APA. Electrophysiological analysis of mutant Cav3.2 channels revealed significant changes in the Ca2+ current properties for all mutants, suggesting a gain of function phenotype. Transfections of mutant Cav3.2 in H295R-S2 cells led to increased aldosterone production and/or expression of genes coding for steroidogenic enzymes after K+ stimulation. Identification of CACNA1H mutations associated with early onset PA, FH, and APA suggests that CACNA1H might be a susceptibility gene predisposing to PA with different phenotypic presentations, opening new perspectives for genetic diagnosis and management of patients with PA.
Asunto(s)
Canales de Calcio Tipo T/genética , Estudios de Asociación Genética , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/genética , Mutación , Potenciales de Acción , Adenoma/metabolismo , Adolescente , Adulto , Aldosterona/biosíntesis , Alelos , Biomarcadores , Canales de Calcio Tipo T/metabolismo , Línea Celular , Niño , Preescolar , Análisis Mutacional de ADN , Exoma , Femenino , Expresión Génica , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hiperaldosteronismo/sangre , Lactante , Masculino , Persona de Mediana Edad , Linaje , ARN Mensajero/genética , Adulto JovenRESUMEN
CONTEXT: The GHR polymorphisms contribution to the interindividual variability in prenatal and postnatal growth as well as to metabolic traits is controversial. OBJECTIVE: The aim of this study is to analyze the association of the GHRfl/d3 polymorphism with prenatal and postnatal growth and metabolic outcomes in adult life and to compare the genotype distribution in different populations. DESIGN: 385 community healthy subjects followed from birth to adult life (23-25years old) were grouped according to birth size: small-SGA (n=130, 62 males), appropriate-AGA (n=162, 75 males) and large for gestational age-LGA (n=93, 48 males). GHRfl/d3 genotype distribution and its potential association with anthropometric (at birth, childhood and adult life) and metabolic features (in adult life) were analyzed and compared with data obtained from a systematic review of GHRfl/d3 association studies (31 articles). RESULTS: The frequency of the GHR d3/d3 genotype was lower in the LGA (χ2 p=0.01); SGA and AGA subjects exhibited an increased chance of the d3/d3 genotype (OR=3.58; 95%CI: 1.55; 8.24) and (OR=2.39; 95%CI: 1.02; 5.62), respectively. Despite the different prevalence among different birth size groups, in adults, GHRfl/d3 genotype was not associated with height, plasma IGF1 levels or metabolic phenotype and cardiovascular risk. GHRfl/d3 genotype distributions in AGA, SGA and LGA groups were comparable with those found in subjects of European origin but not with those of Asian ancestry. CONCLUSIONS: The GHRd3 genotype was negatively associated with birth size but it was not associated with adult height or weight, plasma IGF1, metabolic phenotype or any marker of increased cardiovascular risk in young adults.