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Aaron Hanukoglu - One of the best experts on this subject based on the ideXlab platform.
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expression of the epithelial sodium channel enac in the endometrium implications for fertility in a patient with pseudohypoaldosteronism
The Journal of Steroid Biochemistry and Molecular Biology, 2018Co-Authors: Vijay Raju Boggula, Israel Hanukoglu, Aaron Hanukoglu, Ron Sagiv, Yehoshua EnukaAbstract:Abstract Pseudohypoaldosteronism type 1 (PHA) is a syndrome of unresponsiveness to aldosterone. The severe form of this disease results from mutations in the genes that encode for the epithelial sodium channel subunits, SCNN1A, SCNN1B, and SCNN1G. A PHA patient under our care failed to conceive after many years and IVF trials. Our earlier studies had shown that ENaC is expressed in the female reproductive tract. We hypothesized that a defective ENaC expression may be responsible for the infertility of the patient. To test this hypothesis we examined ENaC expression in endometrial Pipelle biopsy samples from three healthy women and the PHA patient with an Arg508X mutation in the SCNN1A gene. The formalin fixed samples were reacted with anti-ENaCA (alpha subunit) antisera, followed by secondary antibodies to visualize ENaC expression by immunofluorescence. Confocal microscopy imaging of the samples showed strong ENaC immunofluorescence along the luminal border (apical membrane) of the epithelial cells in Pipelle samples from healthy women. In contrast, none of the samples from the PHA patient showed ENaC immunofluorescence. The Arg508X mutation interrupts the transport of ENaC subunits to the cell surface, yet it would not be expected to disrupt ENaC localization in the cytoplasm. In contrast to endometrium where ENaC is localized in the apical membrane of the epithelial cells, in keratinocytes ENaC is expressed in cytoplasmic pools. Therefore, we examined ENaC immunofluorescence in plucked hair follicles. As expected, ENaC immunofluorescence was detected in the cytoplasm of keratinocytes of both normal and PHA samples. Our results support the hypothesis that lack of expression of ENaC on the endometrial surface may be responsible for the infertility of the PHA patient.
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epithelial sodium channel enac family phylogeny structure function tissue distribution and associated inherited diseases
Gene, 2016Co-Authors: Israel Hanukoglu, Aaron HanukogluAbstract:The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na(+) ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na(+) in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity. In multi-ciliated cells, ENaC is located in cilia and plays an essential role in the regulation of epithelial surface liquid volume necessary for cilial transport of mucus and gametes in the respiratory and reproductive tracts respectively. The subunits that form ENaC (named as alpha, beta, gamma and delta, encoded by genes SCNN1A, SCNN1B, SCNN1G, and SCNN1D) are members of the ENaC/Degenerin superfamily. The earliest appearance of ENaC orthologs is in the genomes of the most ancient vertebrate taxon, Cyclostomata (jawless vertebrates) including lampreys, followed by earliest representatives of Gnathostomata (jawed vertebrates) including cartilaginous sharks. Among Euteleostomi (bony vertebrates), Actinopterygii (ray finned-fishes) branch has lost ENaC genes. Yet, most animals in the Sarcopterygii (lobe-finned fish) branch including Tetrapoda, amphibians and amniotes (lizards, crocodiles, birds, and mammals), have four ENaC paralogs. We compared the sequences of ENaC orthologs from 20 species and established criteria for the identification of ENaC orthologs and paralogs, and their distinction from other members of the ENaC/Degenerin superfamily, especially ASIC family. Differences between ENaCs and ASICs are summarized in view of their physiological functions and tissue distributions. Structural motifs that are conserved throughout vertebrate ENaCs are highlighted. We also present a comparative overview of the genotype-phenotype relationships in inherited diseases associated with ENaC mutations, including multisystem pseudohypoaldosteronism (PHA1B), Liddle syndrome, cystic fibrosis-like disease and essential hypertension.
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Truncated beta epithelial sodium channel (ENaC) subunits responsible for multi-system pseudohypoaldosteronism support partial activity of ENaC
The Journal of Steroid Biochemistry and Molecular Biology, 2010Co-Authors: Oded Edelheit, Yafit Shriki, Matanel Tfilin, Nathan Dascal, David Gillis, Israel Hanukoglu, Aaron HanukogluAbstract:Abstract Aldosterone regulated epithelial sodium channels (ENaC) are constructed of three homologous subunits. Mutations in the α-, β- and γ-ENaC subunit genes (SCNN1A, SCNN1B and SCNN1G) are associated with multi-system pseudohypoaldosteronism (PHA), and mutations in the PY motif of carboxy-terminal region of β and γ subunits are associated with Liddle syndrome of hereditary hypertension. In this study we identified two frameshift mutations in the SCNN1B alleles of a female infant diagnosed with multi-system PHA inherited from her parents. This is the first case of PHA in an Ashkenazi family in Israel. The p.Glu217fs (c.648dupA in exon 4) and p.Tyr306fs (c.915delC in exon 6) mutations produce shortened β-ENaC subunits with 253 and 317 residues respectively instead of the 640 residues present in β-ENaC subunit. Expression of cRNAs carrying these mutations in Xenopus oocytes showed that the mutations drastically reduce but do not eliminate ENaC activity. The findings reveal that truncated β-ENaC subunits are capable of partially supporting intracellular transport of the other two subunits to the membrane and the final assembly of a weakly active channel together with normal α- and γ-ENaC subunits. Moreover, these results enhance our understanding of the long-term consequences of these types of mutations in PHA patients.
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Truncated beta epithelial sodium channel (ENaC) subunits responsible for multi-system pseudohypoaldosteronism support partial activity of ENaC.
The Journal of steroid biochemistry and molecular biology, 2010Co-Authors: Oded Edelheit, Yafit Shriki, Matanel Tfilin, Nathan Dascal, David Gillis, Israel Hanukoglu, Aaron HanukogluAbstract:Aldosterone regulated epithelial sodium channels (ENaC) are constructed of three homologous subunits. Mutations in the alpha-, beta- and gamma-ENaC subunit genes (SCNN1A, SCNN1B and SCNN1G) are associated with multi-system pseudohypoaldosteronism (PHA), and mutations in the PY motif of carboxy-terminal region of beta and gamma subunits are associated with Liddle syndrome of hereditary hypertension. In this study we identified two frameshift mutations in the SCNN1B alleles of a female infant diagnosed with multi-system PHA inherited from her parents. This is the first case of PHA in an Ashkenazi family in Israel. The p.Glu217fs (c.648dupA in exon 4) and p.Tyr306fs (c.915delC in exon 6) mutations produce shortened beta-ENaC subunits with 253 and 317 residues respectively instead of the 640 residues present in beta-ENaC subunit. Expression of cRNAs carrying these mutations in Xenopus oocytes showed that the mutations drastically reduce but do not eliminate ENaC activity. The findings reveal that truncated beta-ENaC subunits are capable of partially supporting intracellular transport of the other two subunits to the membrane and the final assembly of a weakly active channel together with normal alpha- and gamma-ENaC subunits. Moreover, these results enhance our understanding of the long-term consequences of these types of mutations in PHA patients.
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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 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
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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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, Di Zhang, Lei Song, Xu Meng, Ying 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....
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a novel frameshift mutation of epithelial sodium channel β subunit leads to liddle syndrome in an isolated case
Clinical Endocrinology, 2015Co-Authors: Kunqi Yang, X J Jiang, Chaoxia Lu, Xue Zhang, Yan Xiao, Xianliang ZhouAbstract:SummaryObjective Liddle syndrome, an autosomal dominant form of monogenic hypertension, is attributed to mutations in the genes encoding β and γ subunits (SCNN1B and SCNN1G) of the epithelial sodium channel (ENaC). The aim of this study was to search for pathogenic mutations of SCNN1B and SCNN1G in an adolescent under the impression of Liddle syndrome and no family history of hypertension. Design and Patients We screened the C-terminus of SCNN1B and SCNN1G in an adolescent with poorly controlled hypertension who was clinically diagnosed as having Liddle syndrome. We also screened for the mutation in his parents, 100 hypertensive patients and 100 controls. Results Genetic analysis of SCNN1B revealed a frameshift mutation induced by insertion of an additional cytosine into a string of six located between codons 617 and 618, which is predicted to introduce a new termination codon at position 621 and produce a protein truncated by 20 amino acids. This frameshift mutation was not detected in the patient's parents, the 100 hypertensive patients or the 100 controls, indicating that this is a de novo mutation and not a common genetic polymorphism. There was no mutation of SCNN1G in any of the individuals examined. Conclusion Based on direct DNA sequencing, we identified a novel frameshift mutation in the βENaC gene in an isolated case of Liddle syndrome. Confirmation of the diagnosis and effective tailored treatment in the patient were achieved, implying that genetic testing is a useful tool to diagnose Liddle syndrome.
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 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
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, Di Zhang, Ying 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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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, Di Zhang, Lei Song, Xu Meng, Ying 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....
Israel Hanukoglu - One of the best experts on this subject based on the ideXlab platform.
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expression of the epithelial sodium channel enac in the endometrium implications for fertility in a patient with pseudohypoaldosteronism
The Journal of Steroid Biochemistry and Molecular Biology, 2018Co-Authors: Vijay Raju Boggula, Israel Hanukoglu, Aaron Hanukoglu, Ron Sagiv, Yehoshua EnukaAbstract:Abstract Pseudohypoaldosteronism type 1 (PHA) is a syndrome of unresponsiveness to aldosterone. The severe form of this disease results from mutations in the genes that encode for the epithelial sodium channel subunits, SCNN1A, SCNN1B, and SCNN1G. A PHA patient under our care failed to conceive after many years and IVF trials. Our earlier studies had shown that ENaC is expressed in the female reproductive tract. We hypothesized that a defective ENaC expression may be responsible for the infertility of the patient. To test this hypothesis we examined ENaC expression in endometrial Pipelle biopsy samples from three healthy women and the PHA patient with an Arg508X mutation in the SCNN1A gene. The formalin fixed samples were reacted with anti-ENaCA (alpha subunit) antisera, followed by secondary antibodies to visualize ENaC expression by immunofluorescence. Confocal microscopy imaging of the samples showed strong ENaC immunofluorescence along the luminal border (apical membrane) of the epithelial cells in Pipelle samples from healthy women. In contrast, none of the samples from the PHA patient showed ENaC immunofluorescence. The Arg508X mutation interrupts the transport of ENaC subunits to the cell surface, yet it would not be expected to disrupt ENaC localization in the cytoplasm. In contrast to endometrium where ENaC is localized in the apical membrane of the epithelial cells, in keratinocytes ENaC is expressed in cytoplasmic pools. Therefore, we examined ENaC immunofluorescence in plucked hair follicles. As expected, ENaC immunofluorescence was detected in the cytoplasm of keratinocytes of both normal and PHA samples. Our results support the hypothesis that lack of expression of ENaC on the endometrial surface may be responsible for the infertility of the PHA patient.
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epithelial sodium channel enac family phylogeny structure function tissue distribution and associated inherited diseases
Gene, 2016Co-Authors: Israel Hanukoglu, Aaron HanukogluAbstract:The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na(+) ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na(+) in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity. In multi-ciliated cells, ENaC is located in cilia and plays an essential role in the regulation of epithelial surface liquid volume necessary for cilial transport of mucus and gametes in the respiratory and reproductive tracts respectively. The subunits that form ENaC (named as alpha, beta, gamma and delta, encoded by genes SCNN1A, SCNN1B, SCNN1G, and SCNN1D) are members of the ENaC/Degenerin superfamily. The earliest appearance of ENaC orthologs is in the genomes of the most ancient vertebrate taxon, Cyclostomata (jawless vertebrates) including lampreys, followed by earliest representatives of Gnathostomata (jawed vertebrates) including cartilaginous sharks. Among Euteleostomi (bony vertebrates), Actinopterygii (ray finned-fishes) branch has lost ENaC genes. Yet, most animals in the Sarcopterygii (lobe-finned fish) branch including Tetrapoda, amphibians and amniotes (lizards, crocodiles, birds, and mammals), have four ENaC paralogs. We compared the sequences of ENaC orthologs from 20 species and established criteria for the identification of ENaC orthologs and paralogs, and their distinction from other members of the ENaC/Degenerin superfamily, especially ASIC family. Differences between ENaCs and ASICs are summarized in view of their physiological functions and tissue distributions. Structural motifs that are conserved throughout vertebrate ENaCs are highlighted. We also present a comparative overview of the genotype-phenotype relationships in inherited diseases associated with ENaC mutations, including multisystem pseudohypoaldosteronism (PHA1B), Liddle syndrome, cystic fibrosis-like disease and essential hypertension.
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Truncated beta epithelial sodium channel (ENaC) subunits responsible for multi-system pseudohypoaldosteronism support partial activity of ENaC
The Journal of Steroid Biochemistry and Molecular Biology, 2010Co-Authors: Oded Edelheit, Yafit Shriki, Matanel Tfilin, Nathan Dascal, David Gillis, Israel Hanukoglu, Aaron HanukogluAbstract:Abstract Aldosterone regulated epithelial sodium channels (ENaC) are constructed of three homologous subunits. Mutations in the α-, β- and γ-ENaC subunit genes (SCNN1A, SCNN1B and SCNN1G) are associated with multi-system pseudohypoaldosteronism (PHA), and mutations in the PY motif of carboxy-terminal region of β and γ subunits are associated with Liddle syndrome of hereditary hypertension. In this study we identified two frameshift mutations in the SCNN1B alleles of a female infant diagnosed with multi-system PHA inherited from her parents. This is the first case of PHA in an Ashkenazi family in Israel. The p.Glu217fs (c.648dupA in exon 4) and p.Tyr306fs (c.915delC in exon 6) mutations produce shortened β-ENaC subunits with 253 and 317 residues respectively instead of the 640 residues present in β-ENaC subunit. Expression of cRNAs carrying these mutations in Xenopus oocytes showed that the mutations drastically reduce but do not eliminate ENaC activity. The findings reveal that truncated β-ENaC subunits are capable of partially supporting intracellular transport of the other two subunits to the membrane and the final assembly of a weakly active channel together with normal α- and γ-ENaC subunits. Moreover, these results enhance our understanding of the long-term consequences of these types of mutations in PHA patients.
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Truncated beta epithelial sodium channel (ENaC) subunits responsible for multi-system pseudohypoaldosteronism support partial activity of ENaC.
The Journal of steroid biochemistry and molecular biology, 2010Co-Authors: Oded Edelheit, Yafit Shriki, Matanel Tfilin, Nathan Dascal, David Gillis, Israel Hanukoglu, Aaron HanukogluAbstract:Aldosterone regulated epithelial sodium channels (ENaC) are constructed of three homologous subunits. Mutations in the alpha-, beta- and gamma-ENaC subunit genes (SCNN1A, SCNN1B and SCNN1G) are associated with multi-system pseudohypoaldosteronism (PHA), and mutations in the PY motif of carboxy-terminal region of beta and gamma subunits are associated with Liddle syndrome of hereditary hypertension. In this study we identified two frameshift mutations in the SCNN1B alleles of a female infant diagnosed with multi-system PHA inherited from her parents. This is the first case of PHA in an Ashkenazi family in Israel. The p.Glu217fs (c.648dupA in exon 4) and p.Tyr306fs (c.915delC in exon 6) mutations produce shortened beta-ENaC subunits with 253 and 317 residues respectively instead of the 640 residues present in beta-ENaC subunit. Expression of cRNAs carrying these mutations in Xenopus oocytes showed that the mutations drastically reduce but do not eliminate ENaC activity. The findings reveal that truncated beta-ENaC subunits are capable of partially supporting intracellular transport of the other two subunits to the membrane and the final assembly of a weakly active channel together with normal alpha- and gamma-ENaC subunits. Moreover, these results enhance our understanding of the long-term consequences of these types of mutations in PHA patients.
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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 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