Monogenic hypertension: Lessons from the genome
TL;DR: The patient was born in Silesia (Poland), her mother also This patient has severe hypertension and type E brachyhad brachydactyly, as did other members of the family.
About: This article is published in Kidney International.The article was published on 2001-07-01 and is currently open access. It has received 19 citations till now. The article focuses on the topics: Blood pressure & Plasma renin activity.
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TL;DR: An overview of the implications of next generation sequencing for clinical diagnostics and personalised medicine in the cardiology clinic is presented.
Abstract: The fast moving field of genomic medicine is already impacting on clinical care and cardiologists are fortunate to be in a position to benefit early from the transformative advances in genomics. However, the challenges associated with genomics in the clinic in general, and with next generation sequencing technologies in particular, are significant and cardiologists need to be prepared if they wish to surf the wave of genomic opportunity. This paper presents an overview of the implications of next generation sequencing for clinical diagnostics and personalised medicine in the cardiology clinic.
51 citations
Cites background from "Monogenic hypertension: Lessons fro..."
...Treatment may also be targeted to correct a specific molecular defect, as is already the case for rare cardiovascular diseases including monogenic hypertension and monogenic type 2 diabetes.(40) 41...
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TL;DR: The objective of this review is to describe some of the syndromes in which BDE is present, focusing on clinical, biochemical and genetic characteristics as features of differential diagnoses, with the aim of establishing an algorithm for their differential diagnosis.
Abstract: Brachydactyly (BD) refers to the shortening of the hands, feet or both. There are different types of BD; among them, type E (BDE) is a rare type that can present as an isolated feature or as part of more complex syndromes, such as: pseudohypopthyroidism (PHP), hypertension with BD or Bilginturan BD (HTNB), BD with mental retardation (BDMR) or BDE with short stature, PTHLH type. Each syndrome has characteristic patterns of skeletal involvement. However, brachydactyly is not a constant feature and shows a high degree of phenotypic variability. In addition, there are other syndromes that can be misdiagnosed as brachydactyly type E, some of which will also be discussed. The objective of this review is to describe some of the syndromes in which BDE is present, focusing on clinical, biochemical and genetic characteristics as features of differential diagnoses, with the aim of establishing an algorithm for their differential diagnosis. As in our experience many of these patients are recruited at Endocrinology and/or Pediatric Endocrinology Services due to their short stature, we have focused the algorithm in those steps that could mainly help these professionals.
43 citations
Cites background from "Monogenic hypertension: Lessons fro..."
...Summary of the phenotype associated with Bilginturan BD or hypertension with brachydactyly syndrome [54-66]....
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...Subsequently, other authors have also studied this family and its new generations [55-66]....
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TL;DR: The regions of the human genome that correspond to all but 1 of the 14 blood pressure QTL in mice are linked to blood pressure in humans, suggesting that these regions contain causal genes with a conserved role in blood pressure control.
Abstract: The genetic basis of hypertension is well established, yet very few genes that cause common forms of hypertension are known. Quantitative trait locus (QTL) analyses in rodent models can guide the search for human hypertension genes, but the excellent genetic resources for mice have been underused in this regard. To address this issue, we surveyed blood pressure variation in mice from 37 inbred strains and generated 2577 mice in 8 intercross populations to perform QTL analyses of blood pressure. We identified 14 blood pressure QTL in these populations, including > or =7 regions of the mouse genome not linked previously to blood pressure. Many QTL were detected in multiple crosses, either within our study or in studies published previously, which facilitates the use of bioinformatics methods to narrow the QTL and focus the search for candidate genes. The regions of the human genome that correspond to all but 1 of the 14 blood pressure QTL in mice are linked to blood pressure in humans, suggesting that these regions contain causal genes with a conserved role in blood pressure control. These results greatly expand our knowledge of the genomic regions underlying blood pressure regulation in mice and support future studies to identify the causal genes within these QTL intervals.
35 citations
Cites background from "Monogenic hypertension: Lessons fro..."
...Although recent progress has been made in identifying rare mutations that cause Mendelian forms of altered BP control in affected families (15, 16 ), unfortunately, the genetic components of the common form of essential hypertension have proved less tractable....
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TL;DR: Precise diagnosis with specific treatment regimens aimed at the underlying physiologic derangement can restore normotension and prevent the severe sequelae of chronic hypertension.
Abstract: Monogenic or Mendelian forms of hypertension are described as a group of conditions characterized by insults to the normal regulation of blood pressure by the kidney and adrenal gland. These alterations stem from single mutations that lead to maladaptive overabsorption of electrolytes with fluid shift into the vasculature, and consequent hypertension. Knowledge of these various conditions is essential in diagnosing pediatric or early-onset adult hypertension as they directly affect treatment strategies. Precise diagnosis with specific treatment regimens aimed at the underlying physiologic derangement can restore normotension and prevent the severe sequelae of chronic hypertension.
35 citations
TL;DR: In renal patients rigorous blood pressure control is crucial to prevent renal and cardiovascular target organ damage, and it is recommended that therapy should be titrated not only on blood pressure, but also on reduction of proteinuria.
Abstract: In renal patients rigorous blood pressure control is crucial to prevent renal and cardiovascular target organ damage. For renoprotection target blood pressure depends on the severity of proteinuria before treatment. For proteinuria of 1--3g/day a mean arterial pressure of 98 mmHg provides additional benefit, whereas the target should be as low as 92 mmHg if proteinuria exceeds 3g/day. The antiproteinuric effect of antihypertensive intervention predicts renoprotection; it is therefore recommended that therapy should be titrated not only on blood pressure, but also on reduction of proteinuria. All currently available classes of antihypertensives can be used to reduce blood pressure in renal patients. Interventions based on blockade of the renin-angiotensin-aldosterone system have additional antiproteinuric, and thus renoprotective, potential. Large individual differences in therapeutic benefit are common, even for interventions of proven efficacy at group level. Studies applying different classes of drugs in the same patient (rotation schedules) demonstrate that individual factors are main determinants of therapy response. Exploration of the mechanisms underlying these patient factors is important to improve treatment outcome. Analysis of genetic determinants of therapy response has great potential in this respect. However, therapy response is a complex phenotype. Thus, careful study of gene-gene and gene-environment interactions will be needed in order to turn this type of knowledge into benefit for the patient.
22 citations
References
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TL;DR: It is demonstrated that Liddle's syndrome is caused by mutations in the beta subunit of the epithelial sodium channel and have implications for the regulation of this epithelial ion channel as well as blood pressure homeostasis.
1,174 citations
TL;DR: Analysis of earlier developmental stages revealed that disturbance in cartilage growth preceded abnormal endochondral bone formation, and direct evidence implicating PTHrP in normal skeletal development is provided to emphasize its potential involvement in human osteochondrodysplasias.
Abstract: The parathyroid hormone-related peptide (PTHrP) gene was disrupted in murine embryonic stem cells by homologous recombination, and the null allele was introduced into the mouse germ line. Mice homozygous for the PTHrP null mutation died postnatally, probably from asphyxia, and exhibited widespread abnormalities of endochondral bone development. Histological examination revealed a diminution of chondrocyte proliferation, associated with premature maturation of chondrocytes and accelerated bone formation. Analysis of earlier developmental stages revealed that disturbance in cartilage growth preceded abnormal endochondral bone formation. There were no morphological abnormalities apparent in other tissues. These results provide direct evidence implicating PTHrP in normal skeletal development and serve to emphasize its potential involvement in human osteochondrodysplasias.
1,110 citations
"Monogenic hypertension: Lessons fro..." refers background in this paper
...For instance, we were able to exclude the gene for parathyroid-hormone-related peptide (PTHrP), which we had considered a highly attractive candidate, as the PTHrP homozygous gene-disrupted mouse has skeletal anomalie...
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TL;DR: This work demonstrates complete linkage of GRA in a large kindred to a gene duplication arising from unequal crossing over, fusing the 5' regulatory region of 11β-hydroxylase to the coding sequences of aldosterone synthase.
Abstract: Glucocorticoid-remediable aldosteronism (GRA), an autosomal dominant disorder, is characterized by hypertension with variable hyperaldosteronism and by high levels of the abnormal adrenal steroids 18-oxocortisol and 18-hydroxycortisol, which are all under control of adrenocorticotropic hormone and suppressible by glucocorticoids. These abnormalities could result from ectopic expression of aldosterone synthase, which is normally expressed only in adrenal glomerulosa, in the adrenal fasciculata. Genes encoding aldosterone synthase and steroid 11 beta-hydroxylase (expressed in both adrenal fasciculata and glomerulosa), which are 95% identical and lie on chromosome 8q (refs 7, 10), are therefore candidate genes for GRA. Here we demonstrate complete linkage of GRA in a large kindred to a gene duplication arising from unequal crossing over, fusing the 5' regulatory region of 11 beta-hydroxylase to the coding sequences of aldosterone synthase (maximum lod score 5.23 for complete linkage, odds ratio of 170,000:1). This mutation can account for all the physiological abnormalities of GRA. Our result represents the demonstration of a mutation causing hypertension in otherwise phenotypically normal animals or humans.
1,064 citations
TL;DR: In the treatment of patients with hypertension and renal-artery stenosis, angioplasty has little advantage over antihypertensive-drug therapy.
Abstract: Background Patients with hypertension and renal-artery stenosis are often treated with percutaneous transluminal renal angioplasty. However, the long-term effects of this procedure on blood pressure are not well understood. Methods We randomly assigned 106 patients with hypertension who had atherosclerotic renal-artery stenosis (defined as a decrease in luminal diameter of 50 percent or more) and a serum creatinine concentration of 2.3 mg per deciliter (200 μmol per liter) or less to undergo percutaneous transluminal renal angioplasty or to receive drug therapy. To be included, patients also had to have a diastolic blood pressure of 95 mm Hg or higher despite treatment with two antihypertensive drugs or an increase of at least 0.2 mg per deciliter (20 μmol per liter) in the serum creatinine concentration during treatment with an angiotensin-converting–enzyme inhibitor. Blood pressure, doses of antihypertensive drugs, and renal function were assessed at 3 and 12 months, and patency of the renal artery was ...
826 citations
TL;DR: Genetic heterogeneity of Liddle's syndrome is demonstrated, independent roles of β and γ subunits in the negative regulation of channel activity are indicated, and a new gene in which mutation causes a salt–sensitive form of human hypertension is identified.
Abstract: Sensitivity of blood pressure to dietary salt is a common feature in subjects with hypertension. These features are exemplified by the mendelian disorder, Liddle's syndrome, previously shown to arise from constitutive activation of the renal epithelial sodium channel due to mutation in the β subunit of this channel. We now demonstrate that this disease can also result from a mutation truncating the carboxy terminus of the γ subunit of this channel; this truncated subunit also activates channel activity. These findings demonstrate genetic heterogeneity of Liddle's syndrome, indicate independent roles of β and γ subunits in the negative regulation of channel activity, and identify a new gene in which mutation causes a salt–sensitive form of human hypertension.
749 citations
"Monogenic hypertension: Lessons fro..." refers background in this paper
...Subsequently a mutation in the g-subunit of ENaC has been found that also can cause Liddle's syndrom...
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