A5006230926- Ion Transport and Channel Regulation
- Ion channel regulation and function
- Hormonal Regulation and Hypertension
- Cardiac electrophysiology and arrhythmias
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Electrolyte and hormonal disorders
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Renin-Angiotensin System Studies
- Cystic Fibrosis Research Advances
- Neuroscience of respiration and sleep
- Ion Channels and Receptors
- Drug Transport and Resistance Mechanisms
- Metabolism and Genetic Disorders
- Adrenal and Paraganglionic Tumors
- Magnesium in Health and Disease
- Biomedical Research and Pathophysiology
- Neonatal Respiratory Health Research
- ATP Synthase and ATPases Research
- Pharmacogenetics and Drug Metabolism
- Renal and related cancers
- Cellular transport and secretion
- DNA Repair Mechanisms
- Mitochondrial Function and Pathology
- Erythrocyte Function and Pathophysiology
University of Regensburg
2015-2024
Johns Hopkins Medicine
2023
Johns Hopkins University
2023
Richard Wolf (Germany)
2014
Inserm
2001-2014
Paris Cardiovascular Research Center
2011-2014
University of Pavia
2014
Helmholtz Zentrum München
2014
Heidelberg University
1998-2013
Aarhus University
2013
Five children from two consanguineous families presented with epilepsy beginning in infancy and severe ataxia, moderate sensorineural deafness, a renal salt-losing tubulopathy normotensive hypokalemic metabolic alkalosis. We investigated the genetic basis of this autosomal recessive disease, which we call EAST syndrome (the presence epilepsy, tubulopathy).
Mineralocorticoid receptor (MR)-deficient mice were generated by gene targeting. These animals had a normal prenatal development. During the first week of life, MR-deficient (−/−) developed symptoms pseudohypoaldosteronism. They finally lost weight and eventually died at around day 10 after birth from dehydration renal sodium water loss. At 8, −/− showed hyperkalemia, hyponatremia, strong increase in renin, angiotensin II, aldosterone plasma concentrations. Methods established to measure...
The calcium-activated chloride channel anoctamin1 (ANO1; TMEM16A) is fundamental for the function of epithelial organs. Mice lacking ANO1 expression exhibit transport defects and a pathology similar to cystic fibrosis. They also show general defect electrolyte transport. Here we analyzed all ten members (ANO1-ANO10) in broad range murine tissues detected predominant ANO1, 6, 7, 8, 9, 10 tissues, while ANO2, 3, 4, 5 are common neuronal muscle tissues. When expressed Fisher Rat Thyroid (FTR)...
Mutations of the KCNJ10 ( Kir4.1 ) K + channel underlie autosomal recessive epilepsy, ataxia, sensorineural deafness, and (a salt-wasting) renal tubulopathy (EAST) syndrome. We investigated localization homologous KCNJ16 in kidney functional consequences mutations found our patients with EAST Kcnj10 Kcnj16 were basolateral membrane mouse distal convoluted tubules, connecting cortical collecting ducts. In human kidney, staining was additionally observed thick ascending limb Henle's loop. EM...
Primary aldosteronism is the most frequent cause of endocrine hypertension. Three forms familial hyperaldosteronism (FH) have been described, named FH-I to -III. Recently, a mutation KCNJ5 has shown be associated with FH-III, whereas FH-II still unknown. In this study we searched for mutations in 46 patients from 21 families FH, which was excluded. We identified new germline G151E 2 primary aldosteronism–affected subjects an Italian family and 3 somatic aldosterone-producing adenomas, T158A...
Aldosterone-producing adenomas (APAs) cause a sporadic form of primary aldosteronism and somatic mutations in the KCNJ5 gene, which encodes G-protein–activated inward rectifier K + channel 4, GIRK4, account for ≈40% APAs. Additional APA were identified recently 2 other genes, ATP1A1 ATP2B3 , encoding Na /K -ATPase 1 Ca 2+ 3, respectively, at combined prevalence 6.8%. We have screened 112 APAs known hotspots genetic alterations associated with aldosteronism. Somatic present 6.3%, 0.9%, 39.3%...
Task2 K(+) channel expression in the central nervous system is surprisingly restricted to a few brainstem nuclei, including retrotrapezoid (RTN) region. All Task2-positive RTN neurons were lost mice bearing Phox2b mutation that causes human congenital hypoventilation syndrome. In plethysmography, Task2(-/-) showed disturbed chemosensory function with hypersensitivity low CO(2) concentrations, leading hyperventilation. probably needed stabilize membrane potential of chemoreceptive cells....
In renal Fanconi's syndrome, dysfunction in proximal tubular cells leads to losses of water, electrolytes, and low-molecular-weight nutrients. For most types isolated the genetic cause underlying defect remain unknown.We clinically genetically characterized members a five-generation black family with autosomal dominant syndrome. We performed genomewide linkage analysis, gene sequencing, biochemical cell-biologic investigations cells, studies knockout mice, functional evaluations...
Significance Statement A novel disease phenotype comprises a tubulopathy with severe hypokalemia, renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness associated variants in KCNJ16 (K ir 5.1). In the kidney, inwardly rectifying potassium channel subunit forms functional heteromers KCNJ10 distal nephron KCNJ15 proximal tubule. Functional studies of mutant Xenopus oocytes demonstrate function complexes both KCNJ15. Individuals may present metabolic acidosis or...
The mineralocorticoid hormone aldosterone controls sodium reabsorption and BP largely by regulating the cell-surface expression function of epithelial channel (ENaC) in target kidney tubules. Part stimulatory effect on ENaC is mediated induction serum- glucocorticoid-regulated kinase 1 (Sgk1), a that interferes with ubiquitylation ubiquitin-protein ligase Nedd4-2. In vivo early aldosterone-regulated mRNA now has been identified microselected mouse distal nephron microarray. From 22 displayed...
The acid- and volume-sensitive TASK2 K + channel is strongly expressed in renal proximal tubules papillary collecting ducts. This study was aimed at investigating the role of bicarbonate reabsorption by using task2 –/– mouse as a model. After backcross to C57BL6, mice showed an increased perinatal mortality and, adulthood, reduced body weight arterial blood pressure. Patch-clamp experiments on tubular cells indicated that activated during \documentclass[12pt]{minimal} \usepackage{amsmath}...
In the adult kidney, renin-producing cells are typically located in walls of afferent arterioles at transition into glomerular capillary network. The mechanisms that responsible for restricting renin expression to juxtaglomerular position largely unknown. This study showed mice lack connexin 40 (Cx40), predominant cells, renin-positive absent vessel and instead found extraglomerular mesangium, tuft, periglomerular interstitium. Blocking macula densa transport function by acute administration...
Context:Primary aldosteronism is a heterogeneous group of disorders comprising both sporadic and familial forms. Mutations in the KCNJ5 gene, which encodes inward rectifier K+ channel 4 (G protein-activated 4, Kir3.4), cause hyperaldosteronism type III (FH-III) are involved pathogenesis aldosterone-producing adenomas.
The KCNE3 beta-subunit constitutively opens outwardly rectifying KCNQ1 (Kv7.1) K(+) channels by abolishing their voltage-dependent gating. resulting KCNQ1/KCNE3 heteromers display enhanced sensitivity to channel inhibitors like chromanol 293B. was also suggested modify biophysical properties of several other channels, and a mutation in proposed underlie forms human periodic paralysis. To investigate physiological roles KCNE3, we now disrupted its gene mice. kcne3(-/-) mice were viable...
TWIK1 belongs to the family of background K + channels with two pore domains. In native and transfected cells, is detected mainly in recycling endosomes. principal cells kidney, gene inactivation leads loss a nonselective cationic conductance, an unexpected effect that was attributed adaptive regulation other channels. Here, we show ion selectivity modulated by extracellular pH. Although selective at neutral pH, it becomes permeable Na acidic pH found Selectivity recovery slow after...