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Xianliang Zhou - One of the best experts on this subject based on the ideXlab platform.
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pediatric Liddle Syndrome caused by a novel scnn1g variant in a chinese family and characterized by early onset hypertension
American Journal of Hypertension, 2020Co-Authors: Di Zhang, Linping Wang, Kunqi Yang, Huimin Zhang, Lei Song, Ying Zhang, Tao Tian, Xianliang ZhouAbstract:BACKGROUND: Liddle Syndrome (LS), an autosomal dominant disorder, is a common monogenic hypertension in pediatrics. In this study, we reported a novel SCNN1G variant in a Chinese family with pediatric LS, and conduct a systematic review of ENaC-gene-positive LS cases to conclude the clinical genetic features of LS in childhood. METHODS: Next-generation sequencing and in silico analysis were performed in the proband to discover candidate variants. Sanger sequencing was used to identify the predicted likely pathogenic variant. LS patients in this family were treated with amiloride. The Medline database was searched to summarize clinical features of pediatric LS cases whose age at genetic diagnosis was not more than 18 years. RESULTS: Genetic analysis identified a novel SCNN1G missense variant (c.1874C>T, p.Pro625Leu) in the proband with LS in childhood. In silico analysis revealed this heterozygous variant was highly conserved and deleterious. A total of 38 publications described pediatric LS associated with 25 pathogenic variants in SCNN1B and SCNN1G in 54 children. Despite the phenotypic heterogeneity, early-onset hypertension is the most common feature. All LS patients in this family or the reviewed cases showed significantly improvements in hypertension and hypokalemia after treatment with ENaC inhibitors. CONCLUSIONS: This study identified a novel SCNN1G missense variant in a patient with pediatric LS, expanding the genetic spectrum of SCNN1G and demonstrating the PY motif of gamma-ENaC as a potential mutant region. Early identification and specific management of LS in children and adolescents is important to prevent the development of hypertensive end-organ disease.
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a novel frameshift mutation of scnn1g causing Liddle Syndrome with normokalemia
Journal of Hypertension, 2019Co-Authors: Yu-mo Zhao, Kunqi Yang, Huimin Zhang, Lei Song, Di Zhang, Ying Liao, Tao Tian, Xianliang ZhouAbstract:Objective:Liddle Syndrome (LS) is an autosomal dominant disorder caused by single-gene mutations of the epithelial sodium channel (ENaC). It is characterized by early onset and resistant hypertension, spontaneous hypokalemia and low plasma renin and aldosterone concentrations. In this study, we repo
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truncated epithelial sodium channel β subunit responsible for Liddle Syndrome in a chinese family
Kidney & Blood Pressure Research, 2019Co-Authors: Chaoxia Lu, Kunqi Yang, Haiying Wu, Huimin Zhang, Lei Song, Xue Zhang, Peipei Lu, Xianliang ZhouAbstract:Background/Aims: Liddle Syndrome (LS) is a rare autosomal dominant disease caused by mutations in genes coding for epithelial sodium channel (ENaC) subunits. The aim of this study was to identify the mutation responsible for the LS in an extended Chinese family. Methods: DNA samples from the proband with early-onset, treatment-resistant hypertension, and hypokalemia and 19 additional relatives were all sequenced for mutations in exon 13 of the β-ENaC and γ-ENaC genes, using amplification by polymerase chain reaction and direct DNA sequencing. Results: Genetic testing of exon 13 of SCNN1B revealed duplication of guanine into a string of 3 guanines located at codon 602. This frameshift mutation is predicted to generate a premature stop codon at position 607, resulting in truncated β-ENaC lacking the remaining 34 amino acids, including the crucial PY motif. Among a total of 9 participants with the identical mutation, different phenotypes were identified. Tailored treatment with amiloride was safe and effective in alleviating disease symptoms in LS. No mutation of SCNN1G was identified in any of the examined participants. Conclusions: We report here a family affected by LS harboring a frameshift mutation (c.1806dupG) with a premature stop codon deleting the PY motif of β-ENaC. Our study demonstrates that the earlier LS patients are diagnosed by genetic testing and treated with tailored medication, the greater the likelihood of preventing or minimizing complications in the vasculature and target organs.
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Liddle Syndrome misdiagnosed as primary aldosteronism resulting from a novel frameshift mutation of scnn1b
Endocrine connections, 2018Co-Authors: Chaoxia Lu, Kunqi Yang, Huimin Zhang, Lei Song, Ying Zhang, Xu Meng, Xue Zhang, Di Zhang, Peipei Lu, Xianliang ZhouAbstract:Liddle Syndrome (LS), a monogenetic autosomal dominant disorder, is mainly characterized by early-onset hypertension and hypokalemia. Clinically, misdiagnosis or missing diagnosis is common, since clinical phenotypes of LS are variable and nonspecific. We report a family with misdiagnosis of primary aldosteronism (PA), but identify as LS with a pathogenic frameshift mutation of the epithelial sodium channel (ENaC) β subunit. DNA samples were collected from a 32-year-old proband and 31 other relatives in the same family. A designed panel including 41 genes associated with monogenic hypertension was screened using next-generation sequencing. The best candidate disease-causing variants were verified by Sanger sequencing. Genetic analysis of the proband revealed a novel frameshift mutation c.1838delC (p.Pro613Glnfs*675) in exon 13 of SCNN1B. This heterozygous mutation involved the deletion of a cytosine from a string of three consecutive cytosines located at codons 612 to 613 and resulted in deletion of the crucial PY motif and elongation of the β-ENaC protein. The identical mutation was also found in 12 affected family members. Amiloride was effective in alleviating LS for patients. There were no SCNN1A or SCNN1G mutations in this family. Our study emphasizes the importance of considering LS in the differential diagnosis of early-onset hypertension. The identification of a novel frameshift mutation of SCNN1B enriches the genetic spectrum of LS and has allowed treatment of this affected family to prevent severe complications.
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genetic screening of scnn1b and scnn1g genes in early onset hypertensive patients helps to identify Liddle Syndrome
Clinical and Experimental Hypertension, 2018Co-Authors: Kunqi Yang, Haiying Wu, Huimin Zhang, Chaoxia Lu, Ying Zhang, Xu Meng, Xueqi Dong, Xue Zhang, Xianliang ZhouAbstract:ABSTRACTBackground: Liddle Syndrome is an autosomal dominant form of monogenic hypertension. Phenotypic variability makes it difficult to identify patients with Liddle Syndrome, resulting in misdiagnosis and severe complications at early age. Objectives: To identify mutation in SCNN1B and SCNN1G genes in an adolescent with suspicious Liddle Syndrome and his family members and to explore the screening target subjects of Liddle Syndrome. Methods: Genetic analysis of the C-terminus of SCNN1B and SCNN1G genes was conducted in an adolescent, with treatment-resistant hypertension and hypokalemia, who was suspected of having Liddle Syndrome, and his family members. A Medline research of the reported cases with Liddle Syndrome was also performed. Results: A recurrent SCNN1B mutation, c.1853C>A (p.P618H), was detected in the 19-year-old male patient, and family screening identified five additional members who were heterozygous for the mutation. The diagnosis of Liddle Syndrome was made in all affected individuals....
Kunqi Yang - One of the best experts on this subject based on the ideXlab platform.
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pediatric Liddle Syndrome caused by a novel scnn1g variant in a chinese family and characterized by early onset hypertension
American Journal of Hypertension, 2020Co-Authors: Di Zhang, Linping Wang, Kunqi Yang, Huimin Zhang, Lei Song, Ying Zhang, Tao Tian, Xianliang ZhouAbstract:BACKGROUND: Liddle Syndrome (LS), an autosomal dominant disorder, is a common monogenic hypertension in pediatrics. In this study, we reported a novel SCNN1G variant in a Chinese family with pediatric LS, and conduct a systematic review of ENaC-gene-positive LS cases to conclude the clinical genetic features of LS in childhood. METHODS: Next-generation sequencing and in silico analysis were performed in the proband to discover candidate variants. Sanger sequencing was used to identify the predicted likely pathogenic variant. LS patients in this family were treated with amiloride. The Medline database was searched to summarize clinical features of pediatric LS cases whose age at genetic diagnosis was not more than 18 years. RESULTS: Genetic analysis identified a novel SCNN1G missense variant (c.1874C>T, p.Pro625Leu) in the proband with LS in childhood. In silico analysis revealed this heterozygous variant was highly conserved and deleterious. A total of 38 publications described pediatric LS associated with 25 pathogenic variants in SCNN1B and SCNN1G in 54 children. Despite the phenotypic heterogeneity, early-onset hypertension is the most common feature. All LS patients in this family or the reviewed cases showed significantly improvements in hypertension and hypokalemia after treatment with ENaC inhibitors. CONCLUSIONS: This study identified a novel SCNN1G missense variant in a patient with pediatric LS, expanding the genetic spectrum of SCNN1G and demonstrating the PY motif of gamma-ENaC as a potential mutant region. Early identification and specific management of LS in children and adolescents is important to prevent the development of hypertensive end-organ disease.
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a novel frameshift mutation of scnn1g causing Liddle Syndrome with normokalemia
Journal of Hypertension, 2019Co-Authors: Yu-mo Zhao, Kunqi Yang, Huimin Zhang, Lei Song, Di Zhang, Ying Liao, Tao Tian, Xianliang ZhouAbstract:Objective:Liddle Syndrome (LS) is an autosomal dominant disorder caused by single-gene mutations of the epithelial sodium channel (ENaC). It is characterized by early onset and resistant hypertension, spontaneous hypokalemia and low plasma renin and aldosterone concentrations. In this study, we repo
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A Novel Frameshift Mutation of SCNN1G Causing Liddle Syndrome with Normokalemia
American Journal of Hypertension, 2019Co-Authors: Yu-mo Zhao, Kunqi Yang, Di Zhang, Ying Liao, Tao Tian, Wenjun Ma, Huimin ZhangAbstract:Liddle Syndrome (LS) is an autosomal dominant disorder caused by single-gene mutations of the epithelial sodium channel (ENaC). It is characterized by early-onset hypertension, spontaneous hypokalemia and low plasma renin and aldosterone concentrations. In this study, we reported an LS pedigree with normokalemia resulting from a novel SCNN1G frameshift mutation. Peripheral blood samples were collected from the proband and eight family members for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the SCNN1G mutation. Clinical examinations were used to comprehensively evaluate the phenotypes of two patients. Genetic analysis identified a novel SCNN1G frameshift mutation, p.Arg586Valfs*598, in the proband with LS. This heterozygous frameshift mutation generated a premature stop codon and deleted the vital PY motif of ENaC. The same mutation was present in his elder brother with LS, and his mother without any LS symptoms. Biochemical examination showed normokalemia in the three mutation carriers. The mutation identified was not found in any other family members, 100 hypertensives, or 100 healthy controls. Our study identified a novel SCNN1G frameshift mutation in a Chinese family with LS, expanding the genetic spectrum of SCNN1G. Genetic testing helped us identify LS with a pathogenic mutation when the genotypes and phenotype were not completely consistent because of the hypokalemia. This case emphasizes that once a proband is diagnosed with LS by genetic testing, family genetic sequencing is necessary for early diagnosis and intervention for other family members, to protect against severe cardiovascular complications. © The Author(s) 2019. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.
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truncated epithelial sodium channel β subunit responsible for Liddle Syndrome in a chinese family
Kidney & Blood Pressure Research, 2019Co-Authors: Chaoxia Lu, Kunqi Yang, Haiying Wu, Huimin Zhang, Lei Song, Xue Zhang, Peipei Lu, Xianliang ZhouAbstract:Background/Aims: Liddle Syndrome (LS) is a rare autosomal dominant disease caused by mutations in genes coding for epithelial sodium channel (ENaC) subunits. The aim of this study was to identify the mutation responsible for the LS in an extended Chinese family. Methods: DNA samples from the proband with early-onset, treatment-resistant hypertension, and hypokalemia and 19 additional relatives were all sequenced for mutations in exon 13 of the β-ENaC and γ-ENaC genes, using amplification by polymerase chain reaction and direct DNA sequencing. Results: Genetic testing of exon 13 of SCNN1B revealed duplication of guanine into a string of 3 guanines located at codon 602. This frameshift mutation is predicted to generate a premature stop codon at position 607, resulting in truncated β-ENaC lacking the remaining 34 amino acids, including the crucial PY motif. Among a total of 9 participants with the identical mutation, different phenotypes were identified. Tailored treatment with amiloride was safe and effective in alleviating disease symptoms in LS. No mutation of SCNN1G was identified in any of the examined participants. Conclusions: We report here a family affected by LS harboring a frameshift mutation (c.1806dupG) with a premature stop codon deleting the PY motif of β-ENaC. Our study demonstrates that the earlier LS patients are diagnosed by genetic testing and treated with tailored medication, the greater the likelihood of preventing or minimizing complications in the vasculature and target organs.
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Liddle Syndrome misdiagnosed as primary aldosteronism resulting from a novel frameshift mutation of scnn1b
Endocrine connections, 2018Co-Authors: Chaoxia Lu, Kunqi Yang, Huimin Zhang, Lei Song, Ying Zhang, Xu Meng, Xue Zhang, Di Zhang, Peipei Lu, Xianliang ZhouAbstract:Liddle Syndrome (LS), a monogenetic autosomal dominant disorder, is mainly characterized by early-onset hypertension and hypokalemia. Clinically, misdiagnosis or missing diagnosis is common, since clinical phenotypes of LS are variable and nonspecific. We report a family with misdiagnosis of primary aldosteronism (PA), but identify as LS with a pathogenic frameshift mutation of the epithelial sodium channel (ENaC) β subunit. DNA samples were collected from a 32-year-old proband and 31 other relatives in the same family. A designed panel including 41 genes associated with monogenic hypertension was screened using next-generation sequencing. The best candidate disease-causing variants were verified by Sanger sequencing. Genetic analysis of the proband revealed a novel frameshift mutation c.1838delC (p.Pro613Glnfs*675) in exon 13 of SCNN1B. This heterozygous mutation involved the deletion of a cytosine from a string of three consecutive cytosines located at codons 612 to 613 and resulted in deletion of the crucial PY motif and elongation of the β-ENaC protein. The identical mutation was also found in 12 affected family members. Amiloride was effective in alleviating LS for patients. There were no SCNN1A or SCNN1G mutations in this family. Our study emphasizes the importance of considering LS in the differential diagnosis of early-onset hypertension. The identification of a novel frameshift mutation of SCNN1B enriches the genetic spectrum of LS and has allowed treatment of this affected family to prevent severe complications.
Bernard C Rossier - One of the best experts on this subject based on the ideXlab platform.
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Liddle s Syndrome pseudoaldosteronism
Genetic Diseases of the Kidney, 2009Co-Authors: Laurent Schild, Bernard C RossierAbstract:Publisher Summary This chapter sheds light on the genetic, physiological, and biochemical studies of Liddle’s Syndrome (pseudoaldosteronism) providing a new understanding of the cellular and molecular basis of the regulation of blood pressure and volume by the kidney. Morphological and functional studies on rodent and human kidneys indicate that at least three successive portions of the distal nephron, i.e., the late portion of the distal convoluted tubule (DCT), the connecting tubule (CNT), and the collecting duct (CD), contribute to the ASDN. Although these segments have distinct structural and functional features, they have in common the expression of the epithelial sodium channel (ENaC), the mineralocorticoid receptor (MR), and the 11-βhydroxysteroid dehydrogenase type II (11-βHSD2) proteins. Analysis of the β ENaC gene of subject with Liddle’s Syndrome showed different types of mutations, all located in the cytosolic C-terminus end of the β or γ ENaC subunit (exon XIII of SCNN1B and SCNN1G). These mutations include premature stop codons, frameshift or missense mutations that delete or change a conserved proline-rich sequence. Liddle’s Syndrome also arises from mutations in the γ ENaC subunit at corresponding positions in the cytosolic C-terminus of the subunit (exon XIII). All the mutations associated with Liddle Syndrome delete or modify the sequence of a conserved proline-rich motif xPPxY (x being any amino acid, P proline, and Y tyrosine) in the C-terminus of the β and γ ENaC subunits. In addition to Liddle’s Syndrome, hereditary renal disorders associated with elevated blood pressure, expansion of the extracellular fluid volume due to excessive distal Na+ absorption include the apparent mineralocorticoid excess (AME), the hypertension exacerbated in pregnancy, or the pseudohypoaldosteronism type II.
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dysfunction of the epithelial sodium channel expressed in the kidney of a mouse model for Liddle Syndrome
Journal of The American Society of Nephrology, 2003Co-Authors: Sylvain Pradervand, Ivan Gautschi, Laurent Schild, Alain Vandewalle, Marcelle Bens, Johannes Loffing, Edith Hummler, Bernard C RossierAbstract:ABSTRACT. The Liddle Syndrome is a dominant form of salt-sensitive hypertension resulting from mutations in the β or γ subunit of ENaC. A previous study established a mouse model carrying a premature Stop codon corresponding to the R 566stop mutation (L) found in the original pedigree that recapitulates to a large extent the human disease. This study investigated the renal Na + transport in vivo , ex vivo (intact perfused tubules), and in vitro (primary cultured cortical collecting ducts [CCD]). In vivo , upon 6 to 12 h of salt repletion, after 1 week of low-salt diet, the L/L mice showed a delayed urinary sodium excretion, despite a lower aldosterone secretion as compared with controls. After 6 h salt of repletion, ENaC γ subunit is rapidly removed from the apical plasma membrane in wild-type mice, whereas it is retained at the apical membrane in L/L mice. Ex vivo , isolated perfused CCD from L/L mice exhibited higher transepithelial potential differences than perfused CCD isolated from +/+ mice. In vitro , confluent primary cultures of CCD microdissected from L/L kidneys grown on permeable filters exhibited significant lower transepithelial electrical resistance and higher negative potential differences than their cultured L/+ and +/+ CCD counterparts. The equivalent short-circuit current (I eq ) and the amiloride-sensitive I eq was approximately twofold higher in cultured L/L CCD than in +/+ CCD. Aldosterone (5 × 10 −7 M for 3 h) further increased I eq from cultured L/L CCD. Thus, this study brings three independent lines of evidence for the constitutive hyperactivity of ENaC in CCD from mice harboring the Liddle mutation. e-mail: Bernard.Rossier@ipharm.unil.ch
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mutations causing Liddle Syndrome reduce sodium dependent downregulation of the epithelial sodium channel in the xenopus oocyte expression system
Journal of Clinical Investigation, 1998Co-Authors: Stephan Kellenberger, Ivan Gautschi, Bernard C Rossier, Laurent SchildAbstract:Liddle Syndrome is an autosomal dominant form of hypertension resulting from deletion or missense mutations of a PPPxY motif in the cytoplasmic COOH terminus of either the beta or gamma subunit of the epithelial Na channel (ENaC). These mutations lead to increased channel activity. In this study we show that wild-type ENaC is downregulated by intracellular Na+, and that Liddle mutants decrease the channel sensitivity to inhibition by intracellular Na+. This event results at high intracellular Na+ activity in 1.2-2.4-fold higher cell surface expression, and 2.8-3.5-fold higher average current per channel in Liddle mutants compared with the wild type. In addition, we show that a rapid increase in the intracellular Na+ activity induced downregulation of the activity of wild-type ENaC, but not Liddle mutants, on a time scale of minutes, which was directly correlated to the magnitude of the Na+ influx into the oocytes. Feedback inhibition of ENaC by intracellular Na+ likely represents an important cellular mechanism for controlling Na+ reabsorption in the distal nephron that has important implications for the pathogenesis of hypertension.
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cell surface expression of the epithelial na channel and a mutant causing Liddle Syndrome a quantitative approach
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Dmitri Firsov, Ivan Gautschi, Laurent Schild, Annemarie Merillat, Estelle Schneeberger, Bernard C RossierAbstract:The epithelial amiloride-sensitive sodium channel (ENaC) controls transepithelial Na+ movement in Na+-transporting epithelia and is associated with Liddle Syndrome, an autosomal dominant form of salt-sensitive hypertension. Detailed analysis of ENaC channel properties and the functional consequences of mutations causing Liddle Syndrome has been, so far, limited by lack of a method allowing specific and quantitative detection of cell-surface-expressed ENaC. We have developed a quantitative assay based on the binding of 125I-labeled M2 anti-FLAG monoclonal antibody (M2Ab*) directed against a FLAG reporter epitope introduced in the extracellular loop of each of the α, β, and γ ENaC subunits. Insertion of the FLAG epitope into ENaC sequences did not change its functional and pharmacological properties. The binding specificity and affinity (Kd = 3 nM) allowed us to correlate in individual Xenopus oocytes the macroscopic amiloride-sensitive sodium current (INa) with the number of ENaC wild-type and mutant subunits expressed at the cell surface. These experiments demonstrate that: (i) only heteromultimeric channels made of α, β, and γ ENaC subunits are maximally and efficiently expressed at the cell surface; (ii) the overall ENaC open probability is one order of magnitude lower than previously observed in single-channel recordings; (iii) the mutation causing Liddle Syndrome (β R564stop) enhances channel activity by two mechanisms, i.e., by increasing ENaC cell surface expression and by changing channel open probability. This quantitative approach provides new insights on the molecular mechanisms underlying one form of salt-sensitive hypertension.
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identification of a py motif in the epithelial na channel subunits as a target sequence for mutations causing channel activation found in Liddle Syndrome
The EMBO Journal, 1996Co-Authors: Laurent Schild, Ivan Gautschi, Estelle Schneeberger, Yin Lu, Richard P Lifton, Bernard C RossierAbstract:Abstract Liddle Syndrome is an autosomal dominant form of hypertension, resulting from mutations in the cytoplasmic C-terminus of either the beta or gamma subunits of the amiloride-sensitive epithelial Na channel (ENaC) which lead to constitutively increased channel activity. Most mutations reported to date result in the elimination of 45-75 normal amino acids from these segments, leaving open the question of the identity of the precise amino acids in which mutation can lead to an enhanced channel activity. To address this question, we have performed a systematic mutagenesis study of the C-termini of the alpha, beta and gamma ENaC subunits of the rat channel and have analyzed their function by expression in Xenopus oocytes. The results demonstrate that a short proline-rich segment present in the cytoplasmic C-terminus of each subunit is required for the normal regulation of channel activity. Missense mutations altering a consensus PPPXY sequence of the alpha, beta or gamma subunits reproduced the increase in channel activity found in mutants in which the entire cytoplasmic C-termini are deleted. This proline-rich sequence, referred to as the PY motif, is known to be a site of binding by proteins bearing a WW domain. These findings show that the three PY motifs in the C-termini of ENaC are involved in the regulation of channel activity, probably via protein-protein interactions. This new regulatory mechanism of channel function is critical for the maintenance of normal Na reabsorption in the kidney and of Na+ balance and blood pressure.
Laurent Schild - One of the best experts on this subject based on the ideXlab platform.
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a missense mutation in the extracellular domain of αenac causes Liddle Syndrome
Journal of The American Society of Nephrology, 2017Co-Authors: Mahdi Salih, Ivan Gautschi, Miguel X Van Bemmelen, Michael Di Benedetto, Alice S Brooks, Dorien Lugtenberg, Laurent Schild, Ewout J HoornAbstract:Liddle Syndrome is an autosomal dominant form of hypokalemic hypertension due to mutations in the β - or γ -subunit of the epithelial sodium channel (ENaC). Here, we describe a family with Liddle Syndrome due to a mutation in α ENaC. The proband was referred because of resistant hypokalemic hypertension, suppressed renin and aldosterone, and no mutations in the genes encoding β - or γ ENaC. Exome sequencing revealed a heterozygous, nonconservative T>C single-nucleotide mutation in α ENaC that substituted Cys479 with Arg (C479R). C479 is a highly conserved residue in the extracellular domain of ENaC and likely involved in a disulfide bridge with the partner cysteine C394. In oocytes, the C479R and C394S mutations resulted in similar twofold increases in amiloride-sensitive ENaC current. Quantification of mature cleaved α ENaC in membrane fractions showed that the number of channels did not increase with these mutations. Trypsin, which increases open probability of the channel by proteolytic cleavage, resulted in significantly higher currents in the wild type than in C479R or C394S mutants. In summary, a mutation in the extracellular domain of α ENaC causes Liddle Syndrome by increasing intrinsic channel activity. This mechanism differs from that of the β - and γ -mutations, which result in an increase in channel density at the cell surface. This mutation may explain other cases of patients with resistant hypertension and also provides novel insight into ENaC activation, which is relevant for kidney sodium reabsorption and salt-sensitive hypertension.
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Liddle s Syndrome pseudoaldosteronism
Genetic Diseases of the Kidney, 2009Co-Authors: Laurent Schild, Bernard C RossierAbstract:Publisher Summary This chapter sheds light on the genetic, physiological, and biochemical studies of Liddle’s Syndrome (pseudoaldosteronism) providing a new understanding of the cellular and molecular basis of the regulation of blood pressure and volume by the kidney. Morphological and functional studies on rodent and human kidneys indicate that at least three successive portions of the distal nephron, i.e., the late portion of the distal convoluted tubule (DCT), the connecting tubule (CNT), and the collecting duct (CD), contribute to the ASDN. Although these segments have distinct structural and functional features, they have in common the expression of the epithelial sodium channel (ENaC), the mineralocorticoid receptor (MR), and the 11-βhydroxysteroid dehydrogenase type II (11-βHSD2) proteins. Analysis of the β ENaC gene of subject with Liddle’s Syndrome showed different types of mutations, all located in the cytosolic C-terminus end of the β or γ ENaC subunit (exon XIII of SCNN1B and SCNN1G). These mutations include premature stop codons, frameshift or missense mutations that delete or change a conserved proline-rich sequence. Liddle’s Syndrome also arises from mutations in the γ ENaC subunit at corresponding positions in the cytosolic C-terminus of the subunit (exon XIII). All the mutations associated with Liddle Syndrome delete or modify the sequence of a conserved proline-rich motif xPPxY (x being any amino acid, P proline, and Y tyrosine) in the C-terminus of the β and γ ENaC subunits. In addition to Liddle’s Syndrome, hereditary renal disorders associated with elevated blood pressure, expansion of the extracellular fluid volume due to excessive distal Na+ absorption include the apparent mineralocorticoid excess (AME), the hypertension exacerbated in pregnancy, or the pseudohypoaldosteronism type II.
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dysfunction of the epithelial sodium channel expressed in the kidney of a mouse model for Liddle Syndrome
Journal of The American Society of Nephrology, 2003Co-Authors: Sylvain Pradervand, Ivan Gautschi, Laurent Schild, Alain Vandewalle, Marcelle Bens, Johannes Loffing, Edith Hummler, Bernard C RossierAbstract:ABSTRACT. The Liddle Syndrome is a dominant form of salt-sensitive hypertension resulting from mutations in the β or γ subunit of ENaC. A previous study established a mouse model carrying a premature Stop codon corresponding to the R 566stop mutation (L) found in the original pedigree that recapitulates to a large extent the human disease. This study investigated the renal Na + transport in vivo , ex vivo (intact perfused tubules), and in vitro (primary cultured cortical collecting ducts [CCD]). In vivo , upon 6 to 12 h of salt repletion, after 1 week of low-salt diet, the L/L mice showed a delayed urinary sodium excretion, despite a lower aldosterone secretion as compared with controls. After 6 h salt of repletion, ENaC γ subunit is rapidly removed from the apical plasma membrane in wild-type mice, whereas it is retained at the apical membrane in L/L mice. Ex vivo , isolated perfused CCD from L/L mice exhibited higher transepithelial potential differences than perfused CCD isolated from +/+ mice. In vitro , confluent primary cultures of CCD microdissected from L/L kidneys grown on permeable filters exhibited significant lower transepithelial electrical resistance and higher negative potential differences than their cultured L/+ and +/+ CCD counterparts. The equivalent short-circuit current (I eq ) and the amiloride-sensitive I eq was approximately twofold higher in cultured L/L CCD than in +/+ CCD. Aldosterone (5 × 10 −7 M for 3 h) further increased I eq from cultured L/L CCD. Thus, this study brings three independent lines of evidence for the constitutive hyperactivity of ENaC in CCD from mice harboring the Liddle mutation. e-mail: Bernard.Rossier@ipharm.unil.ch
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mutations causing Liddle Syndrome reduce sodium dependent downregulation of the epithelial sodium channel in the xenopus oocyte expression system
Journal of Clinical Investigation, 1998Co-Authors: Stephan Kellenberger, Ivan Gautschi, Bernard C Rossier, Laurent SchildAbstract:Liddle Syndrome is an autosomal dominant form of hypertension resulting from deletion or missense mutations of a PPPxY motif in the cytoplasmic COOH terminus of either the beta or gamma subunit of the epithelial Na channel (ENaC). These mutations lead to increased channel activity. In this study we show that wild-type ENaC is downregulated by intracellular Na+, and that Liddle mutants decrease the channel sensitivity to inhibition by intracellular Na+. This event results at high intracellular Na+ activity in 1.2-2.4-fold higher cell surface expression, and 2.8-3.5-fold higher average current per channel in Liddle mutants compared with the wild type. In addition, we show that a rapid increase in the intracellular Na+ activity induced downregulation of the activity of wild-type ENaC, but not Liddle mutants, on a time scale of minutes, which was directly correlated to the magnitude of the Na+ influx into the oocytes. Feedback inhibition of ENaC by intracellular Na+ likely represents an important cellular mechanism for controlling Na+ reabsorption in the distal nephron that has important implications for the pathogenesis of hypertension.
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cell surface expression of the epithelial na channel and a mutant causing Liddle Syndrome a quantitative approach
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Dmitri Firsov, Ivan Gautschi, Laurent Schild, Annemarie Merillat, Estelle Schneeberger, Bernard C RossierAbstract:The epithelial amiloride-sensitive sodium channel (ENaC) controls transepithelial Na+ movement in Na+-transporting epithelia and is associated with Liddle Syndrome, an autosomal dominant form of salt-sensitive hypertension. Detailed analysis of ENaC channel properties and the functional consequences of mutations causing Liddle Syndrome has been, so far, limited by lack of a method allowing specific and quantitative detection of cell-surface-expressed ENaC. We have developed a quantitative assay based on the binding of 125I-labeled M2 anti-FLAG monoclonal antibody (M2Ab*) directed against a FLAG reporter epitope introduced in the extracellular loop of each of the α, β, and γ ENaC subunits. Insertion of the FLAG epitope into ENaC sequences did not change its functional and pharmacological properties. The binding specificity and affinity (Kd = 3 nM) allowed us to correlate in individual Xenopus oocytes the macroscopic amiloride-sensitive sodium current (INa) with the number of ENaC wild-type and mutant subunits expressed at the cell surface. These experiments demonstrate that: (i) only heteromultimeric channels made of α, β, and γ ENaC subunits are maximally and efficiently expressed at the cell surface; (ii) the overall ENaC open probability is one order of magnitude lower than previously observed in single-channel recordings; (iii) the mutation causing Liddle Syndrome (β R564stop) enhances channel activity by two mechanisms, i.e., by increasing ENaC cell surface expression and by changing channel open probability. This quantitative approach provides new insights on the molecular mechanisms underlying one form of salt-sensitive hypertension.
Huimin Zhang - One of the best experts on this subject based on the ideXlab platform.
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pediatric Liddle Syndrome caused by a novel scnn1g variant in a chinese family and characterized by early onset hypertension
American Journal of Hypertension, 2020Co-Authors: Di Zhang, Linping Wang, Kunqi Yang, Huimin Zhang, Lei Song, Ying Zhang, Tao Tian, Xianliang ZhouAbstract:BACKGROUND: Liddle Syndrome (LS), an autosomal dominant disorder, is a common monogenic hypertension in pediatrics. In this study, we reported a novel SCNN1G variant in a Chinese family with pediatric LS, and conduct a systematic review of ENaC-gene-positive LS cases to conclude the clinical genetic features of LS in childhood. METHODS: Next-generation sequencing and in silico analysis were performed in the proband to discover candidate variants. Sanger sequencing was used to identify the predicted likely pathogenic variant. LS patients in this family were treated with amiloride. The Medline database was searched to summarize clinical features of pediatric LS cases whose age at genetic diagnosis was not more than 18 years. RESULTS: Genetic analysis identified a novel SCNN1G missense variant (c.1874C>T, p.Pro625Leu) in the proband with LS in childhood. In silico analysis revealed this heterozygous variant was highly conserved and deleterious. A total of 38 publications described pediatric LS associated with 25 pathogenic variants in SCNN1B and SCNN1G in 54 children. Despite the phenotypic heterogeneity, early-onset hypertension is the most common feature. All LS patients in this family or the reviewed cases showed significantly improvements in hypertension and hypokalemia after treatment with ENaC inhibitors. CONCLUSIONS: This study identified a novel SCNN1G missense variant in a patient with pediatric LS, expanding the genetic spectrum of SCNN1G and demonstrating the PY motif of gamma-ENaC as a potential mutant region. Early identification and specific management of LS in children and adolescents is important to prevent the development of hypertensive end-organ disease.
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a novel frameshift mutation of scnn1g causing Liddle Syndrome with normokalemia
Journal of Hypertension, 2019Co-Authors: Yu-mo Zhao, Kunqi Yang, Huimin Zhang, Lei Song, Di Zhang, Ying Liao, Tao Tian, Xianliang ZhouAbstract:Objective:Liddle Syndrome (LS) is an autosomal dominant disorder caused by single-gene mutations of the epithelial sodium channel (ENaC). It is characterized by early onset and resistant hypertension, spontaneous hypokalemia and low plasma renin and aldosterone concentrations. In this study, we repo
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A Novel Frameshift Mutation of SCNN1G Causing Liddle Syndrome with Normokalemia
American Journal of Hypertension, 2019Co-Authors: Yu-mo Zhao, Kunqi Yang, Di Zhang, Ying Liao, Tao Tian, Wenjun Ma, Huimin ZhangAbstract:Liddle Syndrome (LS) is an autosomal dominant disorder caused by single-gene mutations of the epithelial sodium channel (ENaC). It is characterized by early-onset hypertension, spontaneous hypokalemia and low plasma renin and aldosterone concentrations. In this study, we reported an LS pedigree with normokalemia resulting from a novel SCNN1G frameshift mutation. Peripheral blood samples were collected from the proband and eight family members for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the SCNN1G mutation. Clinical examinations were used to comprehensively evaluate the phenotypes of two patients. Genetic analysis identified a novel SCNN1G frameshift mutation, p.Arg586Valfs*598, in the proband with LS. This heterozygous frameshift mutation generated a premature stop codon and deleted the vital PY motif of ENaC. The same mutation was present in his elder brother with LS, and his mother without any LS symptoms. Biochemical examination showed normokalemia in the three mutation carriers. The mutation identified was not found in any other family members, 100 hypertensives, or 100 healthy controls. Our study identified a novel SCNN1G frameshift mutation in a Chinese family with LS, expanding the genetic spectrum of SCNN1G. Genetic testing helped us identify LS with a pathogenic mutation when the genotypes and phenotype were not completely consistent because of the hypokalemia. This case emphasizes that once a proband is diagnosed with LS by genetic testing, family genetic sequencing is necessary for early diagnosis and intervention for other family members, to protect against severe cardiovascular complications. © The Author(s) 2019. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.
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truncated epithelial sodium channel β subunit responsible for Liddle Syndrome in a chinese family
Kidney & Blood Pressure Research, 2019Co-Authors: Chaoxia Lu, Kunqi Yang, Haiying Wu, Huimin Zhang, Lei Song, Xue Zhang, Peipei Lu, Xianliang ZhouAbstract:Background/Aims: Liddle Syndrome (LS) is a rare autosomal dominant disease caused by mutations in genes coding for epithelial sodium channel (ENaC) subunits. The aim of this study was to identify the mutation responsible for the LS in an extended Chinese family. Methods: DNA samples from the proband with early-onset, treatment-resistant hypertension, and hypokalemia and 19 additional relatives were all sequenced for mutations in exon 13 of the β-ENaC and γ-ENaC genes, using amplification by polymerase chain reaction and direct DNA sequencing. Results: Genetic testing of exon 13 of SCNN1B revealed duplication of guanine into a string of 3 guanines located at codon 602. This frameshift mutation is predicted to generate a premature stop codon at position 607, resulting in truncated β-ENaC lacking the remaining 34 amino acids, including the crucial PY motif. Among a total of 9 participants with the identical mutation, different phenotypes were identified. Tailored treatment with amiloride was safe and effective in alleviating disease symptoms in LS. No mutation of SCNN1G was identified in any of the examined participants. Conclusions: We report here a family affected by LS harboring a frameshift mutation (c.1806dupG) with a premature stop codon deleting the PY motif of β-ENaC. Our study demonstrates that the earlier LS patients are diagnosed by genetic testing and treated with tailored medication, the greater the likelihood of preventing or minimizing complications in the vasculature and target organs.
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Liddle Syndrome misdiagnosed as primary aldosteronism resulting from a novel frameshift mutation of scnn1b
Endocrine connections, 2018Co-Authors: Chaoxia Lu, Kunqi Yang, Huimin Zhang, Lei Song, Ying Zhang, Xu Meng, Xue Zhang, Di Zhang, Peipei Lu, Xianliang ZhouAbstract:Liddle Syndrome (LS), a monogenetic autosomal dominant disorder, is mainly characterized by early-onset hypertension and hypokalemia. Clinically, misdiagnosis or missing diagnosis is common, since clinical phenotypes of LS are variable and nonspecific. We report a family with misdiagnosis of primary aldosteronism (PA), but identify as LS with a pathogenic frameshift mutation of the epithelial sodium channel (ENaC) β subunit. DNA samples were collected from a 32-year-old proband and 31 other relatives in the same family. A designed panel including 41 genes associated with monogenic hypertension was screened using next-generation sequencing. The best candidate disease-causing variants were verified by Sanger sequencing. Genetic analysis of the proband revealed a novel frameshift mutation c.1838delC (p.Pro613Glnfs*675) in exon 13 of SCNN1B. This heterozygous mutation involved the deletion of a cytosine from a string of three consecutive cytosines located at codons 612 to 613 and resulted in deletion of the crucial PY motif and elongation of the β-ENaC protein. The identical mutation was also found in 12 affected family members. Amiloride was effective in alleviating LS for patients. There were no SCNN1A or SCNN1G mutations in this family. Our study emphasizes the importance of considering LS in the differential diagnosis of early-onset hypertension. The identification of a novel frameshift mutation of SCNN1B enriches the genetic spectrum of LS and has allowed treatment of this affected family to prevent severe complications.