A novel splice site mutation of the beta subunit gene of epithelial sodium channel (ENaC) in one Turkish patient with a systemic form of pseudohypoaldosteronism type 1

Doğan, Çağla Serpil; Durmaz, Erdem; Parlak, Mesut; Merve, Akan; Akcurin, Sema; Bircan, İffet; Berdeli, Afig

doi:10.1515/jpem-2012-0083

Cited by 9 publications

(6 citation statements)

References 8 publications

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“…These mutations were inherited from the parents, who did not exhibit typical PHA clinical symptoms. Although several cases of patients with PHA type I have previously been presented, and mutations such as c.1466 +1 G > A, c.1288delC, and c.1266-1G > C have been reported ( 9 , 23 – 26 ). This neonate carried novel compound heterozygote mutations in the SCNN1B gene, both of which resulted in an abnormal stop codon.…”

Section: Discussionmentioning

confidence: 99%

“…PHA type I results in excessive salt wasting despite very high plasma aldosterone and renin levels, whereas PHA type II leads to blood pressure disorder-related diseases (4)(5)(6). Molecular level research on PHA type I shows the SCNN1A (12p13), SCNN1B (16p12.2-p12.1), and SCNN1G (16p12) genes encoding the three homologous α, β, and γ subunits of ENaCs (7)(8)(9)(10), which are membranebound ion channels that are selectively permeable to Na + ions. Changes in Na?…”

Section: Introductionmentioning

confidence: 99%

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Case Report: A Novel Compound Heterozygote Mutation of the SCNN1B Gene Identified in a Chinese Familial Pseudohypoaldosteronism Disease Type I With Persistent Hyperkalemia

et al. 2022

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BackgroundPseudohypoaldosteronism (PHA) diseases are difficult to diagnose because symptoms are often non-specific and an in-depth pathogenesis study is still lacking.Case PresentationWe present the case of a 19-day-old neonate who presented with unexplained recurrent hyperkalaemia, hypovolemia and metabolic acidosis, whose parents did not have significant clinical disease characteristics. Whole-exome sequencing was performed to confirm the disease and genetic pattern of the neonate. Sanger sequencing was performed to identify the mutation sites. Secondary structure comparisons and 3D model construction were used to predict changes in protein structure. Two novel frameshift mutations in the SCNN1B gene were identified (c.1290delA and c.1348_1361del), which resulted in amino acid synthesis termination (p.Gln431ArgfsTer2 and p.Thr451AspfsTer6). Considering the clinical phenotype and genetic analysis, this case was finally identified as a PHA type I disease. Genetic analysis showed that the neonate suffered complex heterozygosity in the SCNN1B gene inherited from the parents, which is passed on in an autosomal recessive inheritance pattern. These two deleterious mutations resulted in an incomplete protein 3D structure.ConclusionsOur results have confirmed the associations of mutations in the SCNN1B gene with recurrent hyperkalaemia, which can cause severe PHA type I disease, meanwhile suggested clinical attention should be paid when persistent recurrent hyperkalemia is accompanied by these types of mutations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Case Report: A Novel Compound Heterozygote Mutation of the SCNN1B Gene Identified in a Chinese Familial Pseudohypoaldosteronism Disease Type I With Persistent Hyperkalemia

et al. 2022

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“…Most of them, including the one here described, involve the SCNN1A gene [ 18 ]. These are mainly deletions, insertions, or splicing mutations, which may cause abolition or severe malfunctioning of the encoded protein (subunit of ENaC) [ 1 , 3 , 19 , 20 ]. Correlations between missense mutations and milder forms of disease are hypothesized.…”

Section: Discussionmentioning

confidence: 99%

Novel SCNN1A gene splicing-site mutation causing autosomal recessive pseudohypoaldosteronism type 1 (PHA1) in two Italian patients belonging to the same small town

et al. 2021

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Introduction Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease due to the peripheral resistance to aldosterone. Its clinical spectrum includes neonatal salt loss syndrome with hyponatremia and hypochloraemia, hyperkalemia, metabolic acidosis and increased plasmatic levels of aldosterone. Two genetically distinct forms of disease, renal and systemic, have been described, showing a wide clinical expressivity. Mutations in the genes encoding for the subunits of the epithelial sodium channels (ENaC) are responsible for generalized PHA1. Patients’ presentation We hereby report on two Italian patients with generalized PHA1, coming from the same small town in the center of Sicily. The first patient is a male child, born from the first pregnancy of healthy consanguineous Sicilian parents. A novel SCNN1A (sodium channel epithelial subunit alpha) gene mutation, inherited from both heterozygous parents, was identified by next generation sequencing (NGS) in the homozygous child (and later, also in the heterozygous maternal aunt). A more detailed family history disclosed a possible related twenty-year-old girl, belonging to the same Sicilian small town, with referred neonatal salt loss syndrome associated to hyperkalemia, and subsequent normal growth and neurodevelopment. This second patient had a PHA1 clinical diagnosis when she was about 1 year old. The genetic investigation was, then, extended to her and to her family, revealing the same mutation in the homozygous girl and in the heterozygous parents. Conclusions The neonatologist should consider PHA1 diagnosis in newborns showing hyponatremia, hyperkalemia and metabolic acidosis, after the exclusion of a salting-loss form of adrenogenital syndrome. The increased plasmatic levels of aldosterone and aldosterone/renin ratio, associated to a poor response to steroid administration, confirmed the diagnosis in the first present patient. An accurate family history may be decisive to identify the clinical picture. A multidisciplinary approach and close follow-up evaluations are requested, in view of optimal management, adequate growth and development of patients. Next generation sequencing (NGS) techniques allowed the identification of the SCNN1A gene mutation either in both patients or in other heterozygous family members, enabling also primary prevention of disease. Our report may broaden the knowledge of the genetic and molecular bases of PHA1, improving its clinical characterization and providing useful indications for the treatment of patients. Clinical approach must be personalized, also in relation to long-term survival and potential multiorgan complications.

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“…Most of them, including the one here described, involve the SCNN1A gene [18]. These are mainly deletions, insertions, or splicing mutations, which may cause abolition or severe malfunctioning of the encoded protein (subunit of ENaC) [1,3,19,20]. Correlations between missense mutations and milder forms of disease are hypothesized.…”

Section: Discussionmentioning

confidence: 99%

Novel SCNN1A Gene Splicing-site Mutation Causing Autosomal Recessive Pseudohypoaldosteronism type 1 (PHA1) in two Italian Patients Belonging to the Same Small Town

Serra

Antona

D’Alessandro

et al. 2021

Preprint

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IntroductionPseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease due to the peripheral resistance to aldosterone. Its clinical spectrum includes neonatal salt loss syndrome with hyponatremia and hypochloraemia, hyperkalemia, metabolic acidosis and increased plasmatic levels of aldosterone. Two genetically distinct forms of disease, renal and systemic, have been described, showing a wide clinical expressivity. Mutations in the genes encoding for the subunits of the epithelial sodium channels (ENaC) are responsible for generalized PHA1. Patients’ presentationWe hereby report on two Italian patients with generalized PHA1, coming from the same small town in the center of Sicily. The first patient is a male child, born from the first pregnancy of healthy consanguineous Sicilian parents. A novel SCNN1A (sodium channel epithelial subunit alpha) gene mutation, inherited from both heterozygous parents, was identified by next generation sequencing (NGS) in the homozygous child (and later, also in the heterozygous maternal aunt). A more detailed family history disclosed a possible related twenty-year-old girl, belonging to the same Sicilian small town, with referred neonatal salt loss syndrome associated to hyperkalemia, and subsequent normal growth and neurodevelopment. This second patient had a PHA1 clinical diagnosis when she was about one year old. The genetic investigation was, then, extended to her and to her family, revealing the same mutation in the homozygous girl and in the heterozygous parents.ConclusionsThe neonatologist should consider PHA1 diagnosis in newborns showing hyponatremia, hyperkalemia and metabolic acidosis, after the exclusion of a salting-loss form of adrenogenital syndrome. The increased plasmatic levels of aldosterone and aldosterone/renin ratio, associated to a poor response to steroid administration, confirmed the diagnosis in the first present patient. An accurate family history may be decisive to identify the clinical picture. A multidisciplinary approach and close follow-up evaluations are requested, in view of optimal management, adequate growth and development of patients. Next generation sequencing (NGS) techniques allowed the identification of the SCNN1A gene mutation either in both patients or in other heterozygous family members, enabling also primary prevention of disease. Our report may broaden the knowledge of the genetic and molecular bases of PHA1, improving its clinical characterization and providing useful indications for the treatment of patients. Clinical approach must be personalized, also in relation to long-term survival and potential multiorgan complications.

show abstract

A novel splice site mutation of the beta subunit gene of epithelial sodium channel (ENaC) in one Turkish patient with a systemic form of pseudohypoaldosteronism type 1

Cited by 9 publications

References 8 publications

Case Report: A Novel Compound Heterozygote Mutation of the SCNN1B Gene Identified in a Chinese Familial Pseudohypoaldosteronism Disease Type I With Persistent Hyperkalemia

Case Report: A Novel Compound Heterozygote Mutation of the SCNN1B Gene Identified in a Chinese Familial Pseudohypoaldosteronism Disease Type I With Persistent Hyperkalemia

Novel SCNN1A gene splicing-site mutation causing autosomal recessive pseudohypoaldosteronism type 1 (PHA1) in two Italian patients belonging to the same small town

Novel SCNN1A Gene Splicing-site Mutation Causing Autosomal Recessive Pseudohypoaldosteronism type 1 (PHA1) in two Italian Patients Belonging to the Same Small Town

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