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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, Tao Tian, Lei Song, Ying Zhang, 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, Tao Tian, Ying Liao, Lei Song, Di Zhang, 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, Peipei Lu, Haiying Wu, Huimin Zhang, Xue Zhang, Lei Song, 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, Peipei Lu, Huimin Zhang, Xue Zhang, Xu Meng, Lei Song, Ying Zhang, Di Zhang, 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, Xueqi Dong, Haiying Wu, Chaoxia Lu, Huimin Zhang, Xue Zhang, Xu Meng, Ying 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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Premature Stroke Secondary to Severe Hypertension Results from Liddle Syndrome Caused by a Novel SCNN1B Mutation.
Kidney & blood pressure research, 2020Co-Authors: Peng Fan, Kunqi Yang, Ying Zhang, Di Zhang, Xiao-cheng Pan, Qiong-yu Zhang, Xue-ying Liu, Huimin ZhangAbstract:INTRODUCTION Liddle syndrome (LS), an autosomal dominant and inherited monogenic hypertension syndrome caused by pathogenic mutations in the epithelial sodium channel (ENaC) genes SCNN1A, SCNN1B, and SCNN1G. OBJECTIVE This study was designed to identify a novel SCNN1B missense mutation in a Chinese family with a history of stroke, and to confirm that the identified mutation is responsible for LS in this family. METHODS DNA samples were collected from the proband and 11 additional relatives. Next-generation sequencing was performed in the proband to find candidate variants. In order to exclude genetic polymorphism, the candidate variantin SCNN1B was verified in other family members, 100 hypertensives, and 100 healthy controls by Sanger sequencing. RESULTS Genetic testing revealeda novel and rare heterozygous variant in SCNN1B in the proband. This variant resulted in a substitution of threonine instead of proline at codon 617, altering the PY motif of β-ENaC. The identified mutation was only verified in 5 relatives. In silico analyses indicated that this variant was highly pathogenic. In this family, phenotypic heterogeneity was present among 6 LS patients. Tailored medicine with amiloride was effective in controlling hypertension and improving the serum potassium concentration in patients with LS. CONCLUSIONS We identified a novel SCNN1B mutation (c.1849C>A) in a family affected by LS. Patients with LS, especially those with severe hypertension, should be alert for the occurrence of premature stroke. Timely diagnosis using genetic testing and tailored treatment with amiloride can help LS patients to avoid severe complications.
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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, Tao Tian, Lei Song, Ying Zhang, 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, Tao Tian, Ying Liao, Lei Song, Di Zhang, 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, Peipei Lu, Haiying Wu, Huimin Zhang, Xue Zhang, Lei Song, 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, Peipei Lu, Huimin Zhang, Xue Zhang, Xu Meng, Lei Song, Ying Zhang, Di Zhang, 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.
Huimin Zhang - One of the best experts on this subject based on the ideXlab platform.
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Premature Stroke Secondary to Severe Hypertension Results from Liddle Syndrome Caused by a Novel SCNN1B Mutation.
Kidney & blood pressure research, 2020Co-Authors: Peng Fan, Kunqi Yang, Ying Zhang, Di Zhang, Xiao-cheng Pan, Qiong-yu Zhang, Xue-ying Liu, Huimin ZhangAbstract:INTRODUCTION Liddle syndrome (LS), an autosomal dominant and inherited monogenic hypertension syndrome caused by pathogenic mutations in the epithelial sodium channel (ENaC) genes SCNN1A, SCNN1B, and SCNN1G. OBJECTIVE This study was designed to identify a novel SCNN1B missense mutation in a Chinese family with a history of stroke, and to confirm that the identified mutation is responsible for LS in this family. METHODS DNA samples were collected from the proband and 11 additional relatives. Next-generation sequencing was performed in the proband to find candidate variants. In order to exclude genetic polymorphism, the candidate variantin SCNN1B was verified in other family members, 100 hypertensives, and 100 healthy controls by Sanger sequencing. RESULTS Genetic testing revealeda novel and rare heterozygous variant in SCNN1B in the proband. This variant resulted in a substitution of threonine instead of proline at codon 617, altering the PY motif of β-ENaC. The identified mutation was only verified in 5 relatives. In silico analyses indicated that this variant was highly pathogenic. In this family, phenotypic heterogeneity was present among 6 LS patients. Tailored medicine with amiloride was effective in controlling hypertension and improving the serum potassium concentration in patients with LS. CONCLUSIONS We identified a novel SCNN1B mutation (c.1849C>A) in a family affected by LS. Patients with LS, especially those with severe hypertension, should be alert for the occurrence of premature stroke. Timely diagnosis using genetic testing and tailored treatment with amiloride can help LS patients to avoid severe complications.
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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, Tao Tian, Lei Song, Ying Zhang, 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, Tao Tian, Ying Liao, Lei Song, Di Zhang, 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, Peipei Lu, Haiying Wu, Huimin Zhang, Xue Zhang, Lei Song, 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, Peipei Lu, Huimin Zhang, Xue Zhang, Xu Meng, Lei Song, Ying Zhang, Di Zhang, 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.
Richard C Boucher - One of the best experts on this subject based on the ideXlab platform.
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Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease.
Mucosal immunology, 2016Co-Authors: Alessandra Livraghi-butrico, Christopher M Evans, Wanda K. O'neal, Barbara R Grubb, Allison S Volmer, Kristen J. Wilkinson, Kimberly A Burns, Richard C BoucherAbstract:Airway diseases, including cigarette smoke-induced chronic bronchitis, cystic fibrosis, and primary ciliary dyskinesia are associated with decreased mucociliary clearance (MCC). However, it is not known whether a simple reduction in MCC or concentration-dependent mucus adhesion to airway surfaces dominates disease pathogenesis or whether decreasing the concentration of secreted mucins may be therapeutic. To address these questions, Scnn1b-Tg mice, which exhibit airway mucus dehydration/adhesion, were compared and crossed with Muc5b- and Muc5ac-deficient mice. Absence of Muc5b caused a 90% reduction in MCC, whereas Scnn1b-Tg mice exhibited an ∼50% reduction. However, the degree of MCC reduction did not correlate with bronchitic airway pathology, which was observed only in Scnn1b-Tg mice. Ablation of Muc5b significantly reduced the extent of mucus plugging in Scnn1b-Tg mice. However, complete absence of Muc5b in Scnn1b-Tg mice was associated with increased airway inflammation, suggesting that Muc5b is required to maintain immune homeostasis. Loss of Muc5ac had few phenotypic consequences in Scnn1b-Tg mice. These data suggest that: (i) mucus hyperconcentration dominates over MCC reduction alone to produce bronchitic airway pathology; (ii) Muc5b is the dominant contributor to the Scnn1b-Tg phenotype; and (iii) therapies that limit mucin secretion may reduce plugging, but complete Muc5b removal from airway surfaces may be detrimental.
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neonatal pulmonary macrophage depletion coupled to defective mucus clearance increases susceptibility to pneumonia and alters pulmonary immune responses
American Journal of Respiratory Cell and Molecular Biology, 2016Co-Authors: Kristen J. Wilkinson, Kimberlie A. Burns, Alessandra Livraghibutrico, Wanda K Oneal, Yogesh Saini, Kristy A Terrell, Claire M Doerschuk, Richard C BoucherAbstract:Resident immune cells (e.g., macrophages [MΦs]) and airway mucus clearance both contribute to a healthy lung environment. To investigate interactions between pulmonary MΦ function and defective mucus clearance, a genetic model of lysozyme M (LysM) promoter–mediated MΦ depletion was generated, characterized, and crossed with the sodium channel β subunit transgenic (Scnn1b-Tg) mouse model of defective mucus clearance. Diphtheria toxin A–mediated depletion of LysM+ pulmonary MΦs in wild-type mice with normal mucus clearance resulted in lethal pneumonia in 24% of neonates. The pneumonias were dominated by Pasteurella pneumotropica and accompanied by emaciation, neutrophilic inflammation, and elevated Th1 cytokines. The incidence of emaciation and pneumonia reached 51% when LysM+ MΦ depletion was superimposed on the airway mucus clearance defect of Scnn1b-Tg mice. In LysM+ MΦ-depleted Scnn1b-Tg mice, pneumonias were associated with a broader spectrum of bacterial species and a significant reduction in airway m...
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mucus clearance myd88 dependent and myd88 independent immunity modulate lung susceptibility to spontaneous bacterial infection and inflammation
Mucosal Immunology, 2012Co-Authors: Alessandra Livraghibutrico, Richard C Boucher, Elizabeth J Kelly, Erich Klem, Hong Dang, Matthew C Wolfgang, Scott H Randell, Wanda K OnealAbstract:It has been postulated that mucus stasis is central to the pathogenesis of obstructive lung diseases. In Scnn1b-transgenic (Scnn1b-Tg+) mice, airway-targeted overexpression of the epithelial Na+ channel β subunit causes airway surface dehydration, which results in mucus stasis and inflammation. Bronchoalveolar lavage from neonatal Scnn1b-Tg+ mice, but not wild-type littermates, contained increased mucus, bacteria, and neutrophils, which declined with age. Scnn1b-Tg+ mice lung bacterial flora included environmental and oropharyngeal species, suggesting inhalation and/or aspiration as routes of entry. Genetic deletion of the Toll–interleukin-1 receptor adapter molecule MyD88 in Scnn1b-Tg+ mice did not modify airway mucus obstruction, but caused defective neutrophil recruitment and increased bacterial infection, which persisted into adulthood. Scnn1b-Tg+ mice derived into germ-free conditions exhibited mucus obstruction similar to conventional Scnn1b-Tg+ mice and sterile inflammation. Collectively, these data suggest that dehydration-induced mucus stasis promotes infection, compounds defects in other immune mechanisms, and alone is sufficient to trigger airway inflammation.
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airway and lung pathology due to mucosal surface dehydration in β epithelial na channel overexpressing mice role of tnf α and il 4rα signaling influence of neonatal development and limited efficacy of glucocorticoid treatment
Journal of Immunology, 2009Co-Authors: Alessandra Livraghi, Richard C Boucher, Barbara R Grubb, Kristen J. Wilkinson, Wanda K Oneal, Elizabeth J Hudson, John K Sheehan, Marcus A Mall, Scott H RandellAbstract:Overexpression of the epithelial Na+ channel β subunit (Scnn1b gene, βENaC protein) in transgenic (Tg) mouse airways dehydrates mucosal surfaces, producing mucus obstruction, inflammation, and neonatal mortality. Airway inflammation includes macrophage activation, neutrophil and eosinophil recruitment, and elevated KC, TNF-α, and chitinase levels. These changes recapitulate aspects of complex human obstructive airway diseases, but their molecular mechanisms are poorly understood. We used genetic and pharmacologic approaches to identify pathways relevant to the development of Scnn1b-Tg mouse lung pathology. Genetic deletion of TNF-α or its receptor, TNFR1, had no measurable effect on the phenotype. Deletion of IL-4Rα abolished transient mucous secretory cell (MuSC) abundance and eosinophilia normally observed in neonatal wild-type mice. Similarly, IL-4Rα deficiency decreased MuSC and eosinophils in neonatal Scnn1b-Tg mice, which correlated with improved neonatal survival. However, chronic lung pathology in adult Scnn1b-Tg mice was not affected by IL-4Rα status. Prednisolone treatment ablated eosinophilia and MuSC in adult Scnn1b-Tg mice, but did not decrease mucus plugging or neutrophilia. These studies demonstrate that: 1) normal neonatal mouse airway development entails an IL-4Rα-dependent, transient abundance of MuSC and eosinophils; 2) absence of IL-4Rα improved neonatal survival of Scnn1b-Tg mice, likely reflecting decreased formation of asphyxiating mucus plugs; and 3) in Scnn1b-Tg mice, neutrophilia, mucus obstruction, and airspace enlargement are IL-4Rα- and TNF-α-independent, and only MuSC and eosinophilia are sensitive to glucocorticoids. Thus, manipulation of multiple pathways will likely be required to treat the complex pathogenesis caused by airway surface dehydration.
Eddie M. K. Chung - One of the best experts on this subject based on the ideXlab platform.
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a novel splice site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families
Nature Genetics, 1996Co-Authors: S S Strautnieks, R. M. Gardiner, R. J. Thompson, Eddie M. K. ChungAbstract:Pseudohypoaldosteronism type 1 (PHA1, OMIM 264350) is an uncommon inherited disorder characterized by salt-wasting and end-organ unrespon-siveness to mineralocorticoids1. A complete genome search using homozygosity mapping in eleven consanguineous families with PHA1 provided conclusive evidence of linkage with heterogeneity2. The disease locus mapped to chromosome 16p12.2–13.11 in six families and to 12p13.1–pter in the other five families. These two chromosomal regions harbour the genes encoding the three sub-units of the human amiloride sensitive epithelial sodium channel (hENaC): SCNN1B and SCNN1G on 16p and SCNN1A on 12p3,4. Our linkage results have been further supported by the recent report of mutations in the a and p subunit genes in PHA1 patients5. We now report the identification of a 3′ splice site mutation in SCNN1G (318-1 G→A) in three families showing linkage to 16p. Abnormal splicing results with the production of two messenger RNAs, one arising from activation of an adjacent cryptic splice site and the other from skipping of the downstream exon. The two corresponding mutant γhENaC subunits are predicted to have three highly conserved amino acids in the extracellular domain replaced by a novel amino acid (KYS106–108→N) and truncation from 649 to 134 amino acids respectively. These three families all originate from the Indian sub-continent and the probands have severe generalized PHA. They share a common haplotype which suggests the presence of a founder mutation in this sub-population.
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a novel splice site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families
Nature Genetics, 1996Co-Authors: S S Strautnieks, R. M. Gardiner, Richard Thompson, Eddie M. K. ChungAbstract:Pseudohypoaldosteronism type 1 (PHA1, OMIM 264350) is an uncommon inherited disorder characterized by salt-wasting and end-organ unresponsiveness to mineralocorticoids. A complete genome search using homozygosity mapping in eleven consanguineous families with PHA1 provided conclusive evidence of linkage with heterogeneity. The disease locus mapped to chromosome 16p12.2-13.11 in six families and to 12p13.1-pter in the other five families. These two chromosomal regions harbour the genes encoding the three subunits of the human amiloride sensitive epithelial sodium channel (hENaC): SCNN1B and SCNN1G on 16p and SCNN1A on 12p. Our linkage results have been further supported by the recent report of mutations in the alpha and beta subunit genes in PHA1 patients. We now report the identification of a 3' splice site mutation in SCNN1G (318-1 G-->A) in three families showing linkage to 16p. Abnormal splicing results with the production of two messenger RNAs, one arising from activation of an adjacent cryptic splice site and the other from skipping of the downstream exon. The two corresponding mutant gamma hENaC subunits are predicted to have three highly conserved amino acids in the extracellular domain replaced by a novel amino acid (KYS106-108-->N) and truncation from 649 to 134 amino acids respectively. These three families all originate from the Indian sub-continent and the probands have severe generalized PHA. They share a common haplotype which suggests the presence of a founder mutation in this sub-population.
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localisation of pseudohypoaldosteronism genes to chromosome 16p12 2 13 11 and 12p13 1 pter by homozygosity mapping
Human Molecular Genetics, 1996Co-Authors: S S Strautnieks, Israel Hanukoglu, Aaron Hanukoglu, Richard Thompson, M J Dillon, U Kuhnle, Jonathan R Seckl, Mark R Gardiner, Eddie M. K. ChungAbstract:Pseudohypoaldosteronism type 1 (PHA1, OMIM264350) is a rare Mendelian disorder characterised byend-organ unresponsiveness to mineralocorticoids.Most steroid hormone insensitivity syndromes arisefrom mutations in the corresponding receptor, butavailable genetic evidence is against involvement ofthe mineralocorticoid receptor gene, MLR, in PHA1. Acomplete genome scan for PHA1 genes was under-taken using homozygosity mapping in 11 consan-guineous families. Conclusive evidence of linkage withheterogeneity was obtained with a maximum two-locus admixture lod score of 9.9. The disease locusmapped to chromosome 16p12.2–13.11 in six familiesand to 12p13.1-pter in the other five families. The twochromosomal regions harbour genes for subunits ofthe amiloride-sensitive epithelial sodium channel:SCNN1B and SCNN1G on 16p and SCNN1A on 12p.Liddle’s syndrome of hypertension and pseudoaldos-teronism has been shown to arise from mutations inSCNN1B and SCNN1G . These results strongly suggestthat PHA1 and Liddle’s syndrome are allelic variantscaused by mutations in genes encoding subunits ofthis sodium channel. These genes are of broad biologi-cal interest both in relation to sodium and water home-ostasis in mammals and by virtue of their homology tothe mec genes of Caenorhabditis elegans involved inmechanosensitivity and neuronal degeneration.INTRODUCTIONPseudohypoaldosteronism type 1 (PHA1, OMIM 264350) is anuncommon inherited disorder characterised by target-organunresponsiveness to mineralocorticoids. Since the first report byCheek and Perry in 1958 (1) over 100 cases have been reported.Marked elevation of serum aldosterone levels is present in allcases, and is associated with salt-wasting, hyponatraemia,hyperkalaemia and increased plasma renin activity. Clinicalexpression of the disease varies from severely affected infantswho may die to apparently asymptomatic individuals (2).Familial and sporadic cases have been reported. Inheritance isMendelian and may be either autosomal dominant or recessive.The inheritance pattern appears to correspond to whether thehormonal insensitivity is renal or multisystem (3). MultisystemPHA1 is more severe with salt loss from all aldosterone sensitiveend organs including salivary glands, sweat glands, colon andkidney, and is usually inherited as an autosomal recessive trait.The renal form of PHA1 is characterised by renal salt-wastingonly and is usually inherited as an autosomal dominant trait (3).The majority of reported cases falls into one of these categories(2,3). There is a high incidence of consanguinuity in autosomalrecessive PHA1.The molecular basis of PHA1 is unknown ( 4). By analogy withother end-organ hormone insensitivity syndromes a defect at the