RESUMO
BACKGROUND: Autosomal dominant hypertension with brachydactyly type E syndrome caused by pathogenic variants in the PDE3A gene was first reported in 2015. To date, there are only a few reports of this kind of syndrome. Other patients still lack a genetic diagnosis. CASE PRESENTATION: Whole-exome sequencing was performed in an 18-year-old female proband with a clinical diagnosis of hypertension with brachydactyly syndrome. Quantitative real-time PCR was used to identify pathogenic copy number variations (CNVs). After bioinformatics analysis and healthy control database filtering, we revealed a heterozygous missense PDE3A variant (c.1346G > A, p.Gly449Asp). The variant was absent in the ExAC database and located in a highly evolutionarily conserved cluster of reported PDE3A pathogenic variants. Importantly, this variant was predicted to affect protein function by both SIFT (score = 0) and PolyPhen-2 (score = 1). After Sanger sequencing, the variant was determined to be absent in the healthy parents of the proband as well as 800 ethnically and geographically matched healthy controls. CONCLUSION: We present a report linking a de novo PDE3A variant to autosomal dominant hypertension with brachydactyly type E syndrome.
Assuntos
Braquidactilia/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Sequenciamento do Exoma , Genes Dominantes , Hipertensão/congênito , Mutação/genética , Adolescente , Braquidactilia/diagnóstico por imagem , Éxons/genética , Feminino , Humanos , Hipertensão/diagnóstico por imagem , Hipertensão/genética , Masculino , Linhagem , SíndromeRESUMO
BACKGROUND: Hypertension and brachydactyly syndrome (HTNB), also called Bilginturan syndrome, is a rare autosomal dominant disorder characterized by severe salt-independent hypertension, a short stature, brachydactyly, and death from stroke before the age of 50 years when untreated. The purpose of the present study was to identify a PDE3A mutation leading to HTNB associated with vertebral artery malformation in a Chinese family. METHODS: Peripheral blood samples were collected from all subjects for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the PDE3A mutation. A comparative overview was performed in the probands with HTNB caused by PDE3A mutations. RESULTS: Genetic analysis identified a missense mutation in PDE3A, c.1346G>A, in the proband with HTNB. This mutation, resulting in p.Gly449Asp, was located in a highly conserved domain and predicted to be damaging by different bioinformatics tools. Cosegregation analyses showed that the proband inherited the identified mutation from her father. Antihypertensive therapy was effective for the proband. Comparative overview of HTNB probands with 9 different PDE3A mutations revealed phenotypic heterogeneity. CONCLUSIONS: Genetic screening can significantly improve the diagnosis of HTNB patients at an early age. Our study not only adds to the spectrum of PDE3A mutations in the Chinese population and extends the phenotype of HTNB patients to include vertebral malformation but also improves the awareness of pathogenesis in HTNB patients. We emphasize the importance of antihypertensive treatment and long-term follow-up to prevent stroke and adverse cardiovascular events.
Assuntos
Pressão Sanguínea/genética , Braquidactilia/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Hipertensão/congênito , Mutação de Sentido Incorreto , Artéria Vertebral/anormalidades , Braquidactilia/diagnóstico , Braquidactilia/fisiopatologia , Braquidactilia/terapia , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos , Hipertensão/diagnóstico , Hipertensão/genética , Hipertensão/fisiopatologia , Hipertensão/terapia , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Artéria Vertebral/diagnóstico por imagem , Adulto JovemRESUMO
Cerebral artery hypoperfusion may provide the basis for linking ischemic stroke with hypertension. Brain hypoperfusion may induce hypertension that may serve as an auto-protective mechanism to prevent ischemic stroke. We hypothesised that hypertension is caused by remodelling of the cerebral arteries, which is triggered by inflammation. We used a congenital rat model of hypertension and examined age-related changes in gene expression of the cerebral arteries using RNA sequencing. Prior to hypertension, we found changes in signalling pathways associated with the immune system and fibrosis. Validation studies using second harmonics generation microscopy revealed upregulation of collagen type I and IV in both tunica externa and media. These changes in the extracellular matrix of cerebral arteries pre-empted hypertension accounting for their increased stiffness and resistance, both potentially conducive to stroke. These data indicate that inflammatory driven cerebral artery remodelling occurs prior to the onset of hypertension and may be a trigger elevating systemic blood pressure in genetically programmed hypertension.
Assuntos
Artérias Cerebrais/fisiopatologia , Hipertensão/genética , Inflamação/genética , Transcriptoma , Animais , Artérias Cerebrais/metabolismo , Circulação Cerebrovascular , Hipertensão/complicações , Hipertensão/congênito , Hipertensão/fisiopatologia , Inflamação/complicações , Inflamação/fisiopatologia , Masculino , Ratos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/fisiopatologia , Ativação TranscricionalRESUMO
Autosomal-dominant hypertension and brachydactyly syndrome (HTNB; Bilginturan syndrome) is known to cause stroke before age 50 when untreated. We report a novel PDE3A gene mutation in a mother and daughter affected with dominant brachydactyly of the hands and feet, a short stature, and hypertension. The hypertension was medically responsive to anti-hypertensive treatment. The 3-bp deletion in the PDE3A gene presented de novo in the mother. Here, we expand the list of PDE3A mutations identified in Bilginturan syndrome and emphasize the importance of standardized genetic testing of HTNB patients to improve diagnostics at an early age. We recommend extended phenotyping in patients with brachydactyly, a short stature or hypertension in clinical practice.
Assuntos
Braquidactilia/diagnóstico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Hipertensão/congênito , Adulto , Braquidactilia/genética , Feminino , Testes Genéticos , Humanos , Hipertensão/diagnóstico , Hipertensão/genética , Recém-Nascido , Mutação , Triagem Neonatal , Linhagem , FenótipoRESUMO
PURPOSE: 11ß-hydroxylase deficiency accounts for 5% of congenital adrenal hyperplasia cases. Diagnosis suspiction is classically based on the association between abnormal virilization, precocious puberty, and hypertension in 46XX or 46XY subjects. We investigated two families with siblings presenting with opposed clinical features, and provided a review of the mechanisms involved in mineralocorticoid-dependent phenotypic heterogeneity. METHODS: The coding region of the CYP11B1 gene of 4 patients was sequenced and familial segregation was confirmed. Clinical characterization and blood steroid profile were performed. RESULTS: Family 1 comprised a female and a male siblings who presented in middle childhood with genital ambiguity (Prader II) and precocious puberty, respectively, associated with hypertension. In the second decade of life, the woman had three full-term pregnancies, and then evolved normotensive with no treatment over a 5-year follow up. On the other hand, her brother had hypertensive end-organ damage at age 24. In family 2, a 2.9 year-old boy presented with precocious puberty and hypertension, whereas his 21 days-old sister had genital ambiguity (Prader III) and salt wasting. A homozygous exon 4 splice site mutation was identified (IVS4ds-1G > A; c.799 G > A) in family 1, while a nonsense mutation in exon 6 (p. Q356X; c.1066 C > T) was found in family 2. CONCLUSION: CYP11B1 mutations were associated with highly variable phenotypes, from mild to severe virilization, and early-onset hypertension or salt wasting. Further analysis of variants in other hypertension-related genes, steroid synthesis and metabolism compensatory pathways, and/or the investigation of chimeric CYP11B genes are needed to clarify the phenotypic heterogeneity in 11ß-hydroxylase deficiency.
Assuntos
Hiperplasia Suprarrenal Congênita/genética , Heterogeneidade Genética , Esteroide 11-beta-Hidroxilase/genética , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/fisiopatologia , Criança , Pré-Escolar , Família , Feminino , Homozigoto , Humanos , Hipertensão/complicações , Hipertensão/congênito , Hipertensão/genética , Hipopotassemia/complicações , Hipopotassemia/congênito , Hipopotassemia/genética , Recém-Nascido , Masculino , Mutação de Sentido Incorreto , Fenótipo , Puberdade Precoce/genéticaRESUMO
Coarctation of aorta (CoA) usually leads to elevation of blood pressure above the site of obstruction and this elevated blood pressure probably gets transferred and is reflected in the retinal arterioles producing certain signs of hypertensive retinopathy. Fundus examination helps in differentiating hypertension due to CoA from other causes of juvenile hypertension, as corkscrewing of retinal arterioles is seen only in CoA but not in other conditions. A 16 year hypertensive male who was on antihypertensive treatment presented for routine checkup. On examination his visual acuity was 6/6 in both eyes. Funduscopy of both eyes revealed a normal optic disc with generalised narrowing of arterioles and broadened light reflex. The arterioles showed corkscrew tortuosity (U shaped arterioles). Based on the fundus findings, CoA was suspected and the patient was referred for cardiac evaluation. Echocardiogram revealed post ductal CoA. In juvenile hypertension, careful examination of the fundus can provide a clue to the systemic diagnosis and this case highlights the importance of ophthalmoscopic examination in diagnosing a potentially fatal systemic disease.
Assuntos
Coartação Aórtica/diagnóstico , Arteríolas/anormalidades , Hipertensão/congênito , Vasos Retinianos/anormalidades , Adolescente , Anti-Hipertensivos/uso terapêutico , Coartação Aórtica/complicações , Humanos , Hipertensão/tratamento farmacológico , MasculinoAssuntos
Pressão Sanguínea , Braquidactilia/diagnóstico , Ossos da Mão/anormalidades , Hipertensão/congênito , Adulto , Pressão Sanguínea/genética , Braquidactilia/genética , Braquidactilia/fisiopatologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Ossos da Mão/diagnóstico por imagem , Humanos , Hipertensão/diagnóstico , Hipertensão/genética , Hipertensão/fisiopatologia , Mutação , FenótipoRESUMO
Autosomal-dominant hypertension with brachydactyly is a salt-independent Mendelian syndrome caused by activating mutations in the gene encoding phosphodiesterase 3A. These mutations increase the protein kinase A-mediated phosphorylation of phosphodiesterase 3A resulting in enhanced cAMP-hydrolytic affinity and accelerated cell proliferation. The phosphorylated vasodilator-stimulated phosphoprotein is diminished, and parathyroid hormone-related peptide is dysregulated, potentially accounting for all phenotypic features. Untreated patients die prematurely of stroke; however, hypertension-induced target-organ damage is otherwise hardly apparent. We conducted clinical studies of vascular function, cardiac functional imaging, platelet function in affected and nonaffected persons, and cell-based assays. Large-vessel and cardiac functions indeed seem to be preserved. The platelet studies showed normal platelet function. Cell-based studies demonstrated that available phosphodiesterase 3A inhibitors suppress the mutant isoforms. However, increasing cGMP to indirectly inhibit the enzyme seemed to have particular use. Our results shed more light on phosphodiesterase 3A activation and could be relevant to the treatment of severe hypertension in the general population.
Assuntos
Braquidactilia/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , DNA/genética , Hipertensão/congênito , Mutação , Adolescente , Adulto , Pressão Sanguínea/fisiologia , Braquidactilia/diagnóstico , Braquidactilia/enzimologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Análise Mutacional de DNA , Ecocardiografia Doppler de Pulso , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/enzimologia , Hipertensão/genética , Immunoblotting , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB). The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated. In vitro analyses of mesenchymal stem cell-derived vascular smooth muscle cells (VSMCs) and chondrocytes provided insights into molecular pathogenesis. The mutations increased protein kinase A-mediated PDE3A phosphorylation and resulted in gain of function, with increased cAMP-hydrolytic activity and enhanced cell proliferation. Levels of phosphorylated VASP were diminished, and PTHrP levels were dysregulated. We suggest that the identified PDE3A mutations cause the syndrome. VSMC-expressed PDE3A deserves scrutiny as a therapeutic target for the treatment of hypertension.
Assuntos
Braquidactilia/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Hipertensão/congênito , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Sequência de Bases , Estudos de Casos e Controles , Diferenciação Celular , Criança , Feminino , Estudos de Associação Genética , Células HeLa , Humanos , Hipertensão/genética , Cinética , Masculino , Células-Tronco Mesenquimais/fisiologia , Camundongos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Miócitos de Músculo Liso/fisiologia , LinhagemRESUMO
Mother-child cohort studies have established that both pre-pregnancy body mass index (BMI) and gestational weight gain are independently associated with cardio-metabolic risk factors in young adult offspring, including systolic and diastolic blood pressure. Animal models in sheep and non-human primates provide further evidence for the influence of maternal obesity on offspring cardiovascular function, whilst recent studies in rodents suggest that perinatal exposure to the metabolic milieu of maternal obesity may permanently change the central regulatory pathways involved in blood pressure regulation. Leptin plays an important role in the central control of appetite, is also involved in activation of efferent sympathetic pathways to both thermogenic and non-thermogenic tissues, such as the kidney, and is therefore implicated in obesity-related hypertension. Leptin is also thought to have a neurotrophic role in the development of the hypothalamus, and altered neonatal leptin profiles secondary to maternal obesity are associated with permanently altered hypothalamic structure and function. In rodent studies, maternal obesity confers persistent sympathoexcitatory hyper-responsiveness and hypertension acquired in the early stages of development. Experimental neonatal hyperleptinaemia in naive rat pups provides further evidence of heightened sympathetic tone and proof of principle that hyperleptinaemia during a critical window of hypothalamic development may directly lead to adulthood hypertension. Insight from these animal models raises the possibility that early-life exposure to leptin in humans may lead to early onset essential hypertension. Ongoing mother-child cohort and intervention studies in obese pregnant women provide a unique opportunity to address associations between maternal obesity and offspring cardiovascular function. The goal of the review is to highlight the potential importance of leptin in the developmental programming of hypertension in obese pregnancy.
Assuntos
Hipertensão/congênito , Hipertensão/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Feminino , Humanos , Mães , Obesidade/complicações , Obesidade/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologiaRESUMO
There is a growing number of evidence linking fetal intrauterine malnutrition, other adverse events or exposures and arterial hypertension during the following life. After important epidemiological studiesfrom many countries, research now focuses on mechanisms of organ dysfunction and on refining the understanding of the interaction between common elements ofadverse perinatal conditions and normal development. This review focused on advances in comprehension of the influence of intrauterine malnutrition on developmental programming of hypertension. Significant decrease in nephrons number was demonstrated as a result of fetal asymmetrical growth restriction syndrome both in human and experimental animal model. The role of malnutrition and dexametasone induced rennin-angiotensin system inhibition in fetal and newborn nephrogenesis is discussed. Recent studies have revealed important mechanisms of altered vascular function and structure as well as sympathetic regulation of the cardiovascular system in perinatal hypertension models. Some of adverse effects on nephrogenesis and blood pressure regulation could be reversed by special diet and treatment during first two years of life. While the complexity of the interactions between antenatal and postnatal influences on blood pressure is increasingly recognized, the importance of early postnatal life in modulating developmental programming offers the hope of a critical 1000 days window of opportunity to reverse programming and prevent or reduce child hypertension.
Assuntos
Pressão Sanguínea/fisiologia , Doenças Fetais/fisiopatologia , Hipertensão/congênito , Feminino , Humanos , Hipertensão/fisiopatologia , Recém-Nascido , Gravidez , Fatores de RiscoRESUMO
Mid-aortic syndrome is characterized by narrowing of the abdominal aorta, usually with the involvement of renal arteries and other visceral branches. The combination of the presence of an abdominal bruit, diminished or absent pulsations of the lower extremities, and a blood pressure discrepancy between upper and lower extremities is the classic triad associated with mid-aortic syndrome. However, it has a wide variety of clinical symptoms, and awareness of the variable presentation can lead to early diagnosis of the vascular anomaly. We report three cases presenting at three different stages of this disease, such as hydrops fetalis, refractory hypertension, and intracerebral bleeding. In conclusion, these cases highlight the importance of blood pressure measurements in all patients and accurate physical examination for early recognition of a mid-aortic syndrome.
Assuntos
Doenças da Aorta/diagnóstico , Hipertensão/diagnóstico , Malformações Vasculares/diagnóstico , Adolescente , Aorta Abdominal/anormalidades , Doenças da Aorta/congênito , Criança , Pré-Escolar , Evolução Fatal , Feminino , Humanos , Hipertensão/congênito , Recém-Nascido , Masculino , SíndromeRESUMO
A previously reported blood pressure (BP) quantitative trait locus on rat Chromosome 1 was isolated in a short congenic segment spanning 804.6 kb. The 804.6 kb region contained only two genes, LOC306664 and LOC306665. LOC306664 is predicted to translate into A Disintegrin-like and Metalloproteinase with Thrombospondin Motifs-16 (Adamts16). LOC306665 is a novel gene. All predicted exons of both LOC306664 and LOC306665 were sequenced. Non-synonymous variants were identified in only one of these genes, LOC306664. These variants were naturally existing polymorphisms among inbred, outbred and wild rats. The full-length rat transcript of Adamts16 was detected in multiple tissues. Similar to ADAMTS16 in humans, expression of Adamts16 was prominent in the kidney. Renal transcriptome analysis suggested that a network of genes related to BP was differential between congenic and S rats. These genes were also differentially expressed between kidney cell lines with or without knock-down of Adamts16. Adamts16 is conserved between rats and humans. It is a candidate gene within the homologous region on human Chromosome 5, which is linked to systolic and diastolic BP in the Quebec Family Study. Multiple variants, including an Ala to Pro variant in codon 90 (rs2086310) of human ADAMTS16, were associated with human resting systolic BP (SBP). Replication study in GenNet confirmed the association of two variants of ADAMTS16 with SBP, including rs2086310. Overall, our report represents a high resolution positional cloning and translational study for Adamts16 as a candidate gene controlling BP.
Assuntos
Proteínas ADAM/genética , Variação Genética , Hipertensão/congênito , Hipertensão/genética , Proteínas ADAMTS , Proteína ADAMTS1 , Animais , Pressão Sanguínea , Mapeamento Cromossômico , Feminino , Ligação Genética , Humanos , Hipertensão/fisiopatologia , Masculino , Locos de Características Quantitativas , RatosAssuntos
Hormônios/sangue , Hipertensão/sangue , Hipertensão/epidemiologia , Doenças do Recém-Nascido/epidemiologia , Dor/sangue , Dor/epidemiologia , Medição de Risco/métodos , Estresse Psicológico/sangue , Feminino , Humanos , Hipertensão/congênito , Incidência , Recém-Nascido , Mães , Gravidez , Estresse Psicológico/epidemiologiaRESUMO
BACKGROUND: Various studies have shown an association between low birth weight and the prevalence of elevated blood pressure later in life. However, a relationship between birth weight and blood pressure in the neonatal period has not been investigated yet. OBJECTIVE: To study the relationship between birth weight and blood pressure during the first week of life. METHODS: Systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MBP) were measured every 8 h during days 1, 2, 3, 4 and 7 in 44 small for gestational age (SGA) infants and compared with those of infants born with a birth weight appropriate for gestational age (AGA). The infants were matched for gestational age and gender. RESULTS: Meanbirth weight (range) in the SGA group was 778 (460-1,400) g versus 1,524 (960-2,730) g in the AGA group, and mean (range) gestational age of both groups was 30.5 (27.3-35.5) weeks. In the first week of life, SGA and AGA infants had similar SBP, DBP and MBP. Also, after adjustment for confounders (maternal medication, smoking), SBP, DBP and MBP rose equally in SGA and AGA infants during the first week of life. AGA infants showed a positive correlation between birth weight and blood pressure, but SGA infants showed an inverse correlation. CONCLUSIONS: Although differences in blood pressure were found between SGA and AGA infants in the first week of life, the inverse relationship between birth weight and blood pressure in SGA infants warrants follow-up studies to investigate a possible link with late cardiovascular disease.
Assuntos
Peso ao Nascer/fisiologia , Pressão Sanguínea/fisiologia , Retardo do Crescimento Fetal/epidemiologia , Hipertensão/epidemiologia , Recém-Nascido Pequeno para a Idade Gestacional/fisiologia , Adolescente , Adulto , Feminino , Retardo do Crescimento Fetal/etiologia , Idade Gestacional , Humanos , Hipertensão/congênito , Recém-Nascido , Masculino , Idade Materna , Países Baixos/epidemiologia , Gravidez , Estudos Retrospectivos , Adulto JovemRESUMO
Among the causes of secondary hypertension are a group of disorders with a Mendelian inheritance pattern. Recent advances in molecular biology have unveiled the pathogenesis of hypertension in many of these conditions. Remarkably, the mechanism in every case has proved to be upregulation of sodium (Na) reabsorption in the distal nephron, with accompanying expansion of extracellular volume. In one group, the mutations involve the Na-transport machinery in distal tubule cells themselves: the distal convoluted tubule (DCT) cell and the principal cell of the collecting duct. Examples include Liddle's syndrome, with an activating mutation of epithelial Na channel (ENaC); two types of Gordon's syndrome, with mutations in two regulatory kinases [with no lysine (K) serine/threonine protein kinases (WNK)1 or WNK4]; and apparent mineralocorticoid excess (AME), with an inactivating mutation in the glucocorticoid-metabolizing 11beta-hydroxysteroid dehydrogenase type 2 enzyme (11HD2). In another group, abnormal adrenal steroid production leads to inappropriate stimulation of the mineralocorticoid receptor (MR) in the distal nephron. The pathophysiology may involve inappropriate production of aldosterone [in glucocorticoid-remediable aldosteronism (GRA) and familial hyperaldosteronism type II (FH II)], of cortisol (in familial glucocorticoid resistance), or of other steroid metabolites (in congenital adrenal hyperplasia and GRA). In contrast to earlier beliefs, hypertension in many of the inherited disorders may be mild, and electrolyte and acid-base abnormalities are often not present. Monogenic hypertension should therefore enter the differential diagnosis of any child or adolescent with hypertension. Plasma renin activity (PRA) is the appropriate screening tool for all types of inherited hypertension.
Assuntos
Hipertensão/congênito , Hipertensão/genética , Hipertensão/fisiopatologia , Doenças do Córtex Suprarrenal/complicações , Doenças do Córtex Suprarrenal/metabolismo , Doenças do Córtex Suprarrenal/fisiopatologia , Criança , Humanos , Nefropatias/complicações , Nefropatias/metabolismo , Nefropatias/fisiopatologia , Sódio/metabolismoRESUMO
Severe arterial hypertension rarely occurs in the neonatal period but may have life-threatening consequences. It is most often caused by renal parenchymal or vascular abnormality, which, to be accurately diagnosed, may require a combination of imaging modalities. We report on a case of neonatal hypertension presenting as cardiac failure. Initial imaging suggested unilateral renal artery stenosis, but this was not corroborated by magnetic resonance angiography. Surgical nephrectomy was curative for the hypertension and also allowed diagnosis of renal tubular dysgenesis. Unilateral congenital tubular dysgenesis without renal infarction has not been previously reported. We speculate that the condition was secondary to a period of localised hypoperfusion during early foetal life.
Assuntos
Hipertensão/congênito , Túbulos Renais Proximais/anormalidades , Diagnóstico Diferencial , Feminino , Insuficiência Cardíaca/diagnóstico , Humanos , Hipertensão/fisiopatologia , Hipertensão/cirurgia , Recém-Nascido , Nefrectomia , Resultado do TratamentoRESUMO
Mutations in mitochondrial DNA have been associated with cardiovascular disease. We report here the clinical, genetic, and molecular characterization of one three-generation Han Chinese family with maternally transmitted hypertension. All matrilineal relatives in this family exhibited the variable degree of hypertension at the age at onset of 36 to 56 years old. Sequence analysis of the complete mitochondrial DNA in this pedigree revealed the presence of the known hypertension-associated tRNA(Ile) A4295G mutation and 33 other variants, belonging to the Asian haplogroup D4j. The A4295G mutation, which is extraordinarily conserved from bacteria to human mitochondria, is located at immediately 3' end to the anticodon, corresponding to conventional position 37 of tRNA(Ile). The occurrence of the A4295G mutation in several genetically unrelated pedigrees affected by cardiovascular disease but the absence of 242 Chinese controls strongly indicates that this mutation is involved in the pathogenesis of cardiovascular disease. Of other variants, the tRNA(Glu) A14693G and ND1 G11696A mutations were implicated to be associated with other mitochondrial disorders. The A14693G mutation, which is a highly conserved nucleoside at the TpsiC-loop of tRNA(Glu), has been implicated to be important for tRNA structure and function. Furthermore, the ND4 G11696A mutation was associated with Leber's hereditary optic neuropathy. Therefore, the combination of the A4295G mutation in the tRNA(Ile) gene with the ND4 G11696A mutation and tRNA(Glu) A14693G mutation may contribute to the high penetrance of hypertension in this Chinese family.
Assuntos
Hipertensão/congênito , Hipertensão/genética , Mitocôndrias/genética , Doenças Mitocondriais/congênito , Doenças Mitocondriais/genética , RNA de Transferência/genética , Adulto , China , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mães , Linhagem , PenetrânciaRESUMO
More than 30% of the US population has high blood pressure (BP), and less than a third of people treated for hypertension have it controlled. In addition, the etiology of most high BP is not known. Having a better understanding of the mechanisms underlying hypertension could potentially increase the effectiveness of treatment. Because G(q) signaling mediates vasoconstriction and vascular function can cause BP abnormalities, we were interested in determining the role of vascular smooth muscle (VSM) G(q) signaling in two divergent models of hypertension: a renovascular model of hypertension through renal artery stenosis and a genetic model of hypertension using mice with VSM-derived high BP. Inhibition of VSM G(q) signaling attenuated BP increases induced by renal artery stenosis to a similar extent as losartan, an ANG II receptor blocker and current antihypertensive therapy. Inhibition of G(q) signaling also attenuated high BP in our genetic VSM-derived hypertensive model. In contrast, BP remained elevated 25% following treatment with losartan, and prazosin, an alpha(1)-adrenergic receptor antagonist, only decreased BP by 35%. Inhibition of G(q) signaling attenuated VSM reactivity to ANG II and resulted in a 2.4-fold rightward shift in EC(50). We also determined that inhibition of G(q) signaling was able to reverse VSM hypertrophy in the genetic VSM-derived hypertensive model. These results suggest that G(q) signaling is an important signaling pathway in two divergent models of hypertension and, perhaps, optimization of antihypertensive therapy could occur with the identification of particular G(q)-coupled receptors involved.