Pluronic F127 hydrogel-loaded extracellular vesicles from adipose-derived mesenchymal stem cells promote tracheal cartilage regeneration via SCNN1B delivery.

Extracellular vesicles (EVs) derived from adipose-derived mesenchymal stem cells (AMSC-EVs) have been highlighted as a cell-free therapy due to their regenerative capability to enhance tissue and organ regeneration. Herein, we aimed to examine the mechanism of PF127-hydrogel@AMSC-EVs in promoting tracheal cartilage defect repair. Based on bioinformatics methods, SCNN1B was identified as a key gene for the osteogenic differentiation of AMSCs induced by AMSC-EVs. EVs were isolated from rat AMSCs and then loaded onto thermo-sensitive PF-127 hydrogel to develop PF127-hydrogel@AMSC-EVs. It was established that PF127-hydrogel@AMSC-EVs could effectively deliver SCNN1B into AMSCs, where SCNN1B promoted AMSC osteogenic differentiation. The promotive effect was evidenced by enhanced ALP activity, extracellular matrix mineralization, and expression of s-glycosaminoglycan, RUNX2, OCN, collagen II, PERK, and ATF4. Furthermore, the in vivo experiments revealed that PF127-hydrogel@AMSC-SCNN1B-EVs stimulated tracheal cartilage regeneration in rats through PERK/ATF4 signaling axis activation. Therefore, PF127-hydrogel@AMSC-SCNN1B-EVs may be a novel cell-free biomaterial to facilitate tracheal cartilage regeneration and cartilage injury repair.

A frameshift mutation in the SCNN1B gene in a family with Liddle syndrome: A case report and systematic review.

Liddle syndrome is an autosomal dominant form of monogenic hypertension that is caused by mutations in SCNN1A, SCNN1B or SCNN1G, which respectively encode the α, ß and γ subunits of the epithelial sodium channel. In the present study, DNA was extracted from leukocytes in peripheral blood obtained from all members of a family with Liddle syndrome. Whole­exome sequencing and Sanger sequencing were performed to assess the candidate variant and a co­segregation analysis was conducted. A frameshift mutation in SCNN1B (NM_ 000336: c.1806dupG, p.Pro603Alafs*5) in the family was identified, characterized by early­onset hypertension and hypokalemia. The mutation led to the truncation of the ß subunit of the epithelial sodium channel and a lack of the conservative PY motif. Furthermore, a systematic review of follow­up data from patients with Liddle syndrome with SCNN1B mutations was performed. The follow­up data of 108 patients with pathogenic SCNN1B mutations from 47 families were summarized. Phenotypic heterogeneity was evident in patients with Liddle syndrome and early­onset hypertension was the most frequent symptom. Patients responded well to targeted amiloride therapy with significant improvements in blood pressure and serum potassium concentration. The present study demonstrates that confirmatory genetic testing and targeted therapy can prevent premature onset of clinical endpoint events in patients with Liddle syndrome.

SNSP113 (PAAG) improves mucociliary transport and lung pathology in the Scnn1b-Tg murine model of CF lung disease.

BACKGROUND: Mucus stasis, a hallmark of muco-obstructive disease, results from impaired mucociliary transport and leads to lung function decline and chronic infection. Although therapeutics that target mucus stasis in the airway, such as hypertonic saline or rhDNAse, show some therapeutic benefit, they do not address the underlying electrostatic defect apparent in mucins in CF and related conditions. We have previously shown poly (acetyl, arginyl) glucosamine (PAAG, developed as SNSP113), a soluble, cationic polymer, significantly improves mucociliary transport in a rat model of CF by normalizing the charge defects of CF mucin. Here, we report efficacy in the CFTR-sufficient, ENaC hyperactive, Scnn1b-Tg mouse model that develops airway muco-obstruction due to sodium hyperabsorption and airway dehydration. METHODS: Scnn1b-Tg mice were treated with either 250 µg/mL SNSP113 or vehicle control (1.38% glycerol in PBS) via nebulization once daily for 7 days and then euthanized for analysis. Micro-Optical Coherence Tomography-based evaluation of excised mouse trachea was used to determine the effect on the functional microanatomy. Tissue analysis was performed by routine histopathology. RESULTS: Nebulized treatment of SNSP113 significantly improved mucociliary transport in the airways of Scnn1b-Tg mice, without altering the airway surface or periciliary liquid layer. In addition, SNSP113 significantly reversed epithelial hypertrophy and goblet cell metaplasia. Finally, SNSP113 significantly ameliorated eosinophilic crystalline pneumonia and lung consolidation in addition to inflammatory macrophage influx in this model. CONCLUSION: Overall, this study extends the efficacy of SNSP113 as a potential therapeutic to alleviate mucus stasis in muco-obstructive diseases in CF and potentially in related conditions.

Systemic Pseudohypoaldosteronism Type 1 Due to a Novel Mutation in SCNN1B Gene: A Case Report.

Pseudo hypoaldosteronism (PHA) is a type of channelopathy leading to life-threatening hyperkalemia, hyponatremia and metabolic acidosis in neonates. Type I PHA (PHAI) is characterized by either mutation in NR3C2 (MLR) gene or genes related to subunit of ENaC channel, whereas Type II (A to E) PHA is due to mutations in other genes. Type I PHA is further divided into systemic and renal forms based on the gene and organ involved. Systemic PHAI is a rare, multisystem disease presenting as severe salt wasting in neonates. In this article, we report a case of systemic pseudohypoaldosteronism type 1 in a 2 days old neonate with a novel mutation involving SCNN1B gene. Our patient appears to be the first reported case of systemic PHAI due to SCNN1B mutation from India.

A Novel Frame-Shift Mutation in SCNN1B Identified in a Chinese Family Characterized by Early-Onset Hypertension.

Background: Liddle syndrome is a form of monogenic hypertension caused by mutations in the three homologous subunits of the epithelial sodium channels (ENaCs), α, ß, and γ. It is characterized by early-onset refractory hypertension, hypokalemia, low renin activity, and hypoaldosteronism. In this study, we report a novel frame-shift mutation in SCNN1B responsible for Liddle syndrome in a Chinese family. Methods: DNA samples were collected from all participants. Whole-exome sequencing was performed in the proband to detect possible causative variants. Sanger sequencing was then conducted in the other family members to verify the candidate variant, and in 100 patients with hypertension and 100 normotensive controls to exclude population genetic polymorphism. Results: We identified a novel frame-shift mutation (c.1691_1693delinsG) in SCNN1B that was responsible for Liddle syndrome in this family. This mutation leads to the substitution of Arg in place of Gln at codon site 564 and generates a new stop codon at 592, influencing the crucial PY motif and resulting in reduced inactivation of the ENaCs. Aside from the proband, eight family members carried the mutation. Intra-familial phenotypic heterogeneity was observed in the blood pressure and serum potassium levels. Amiloride therapy combined with a low sodium diet is effective to alleviate the symptoms of patients with Liddle syndrome. Conclusion: c.1691_1693delinsG, a novel frame-shift mutation in the ß subunit of ENaC, was identified in a Chinese family with Liddle syndrome by whole-exome sequencing. Phenotypic heterogeneity can make diagnosis of Liddle syndrome difficult on the basis of clinical or biochemical characteristics alone. Genetic analysis is a useful tool allowing timely and accurate diagnosis of Liddle syndrome and playing a guiding role in precise treatment of the disease.

Regulation of hyperoxia-induced neonatal lung injury via post-translational cysteine redox modifications.

Preterm infants and patients with lung disease often have excess fluid in the lungs and are frequently treated with oxygen, however long-term exposure to hyperoxia results in irreversible lung injury. Although the adverse effects of hyperoxia are mediated by reactive oxygen species, the full extent of the impact of hyperoxia on redox-dependent regulation in the lung is unclear. In this study, neonatal mice overexpressing the beta-subunit of the epithelial sodium channel (ß-ENaC) encoded by Scnn1b and their wild type (WT; C57Bl6) littermates were utilized to study the pathogenesis of high fraction inspired oxygen (FiO2)-induced lung injury. Results showed that O2-induced lung injury in transgenic Scnn1b mice is attenuated following chronic O2 exposure. To test the hypothesis that reversible cysteine-redox-modifications of proteins play an important role in O2-induced lung injury, we performed proteome-wide profiling of protein S-glutathionylation (SSG) in both WT and Scnn1b overexpressing mice maintained at 21% O2 (normoxia) or FiO2 85% (hyperoxia) from birth to 11-15 days postnatal. Over 7700 unique Cys sites with SSG modifications were identified and quantified, covering more than 3000 proteins in the lung. In both mouse models, hyperoxia resulted in a significant alteration of the SSG levels of Cys sites belonging to a diverse range of proteins. In addition, substantial SSG changes were observed in the Scnn1b overexpressing mice exposed to hyperoxia, suggesting that ENaC plays a critically important role in cellular regulation. Hyperoxia-induced SSG changes were further supported by the results observed for thiol total oxidation, the overall level of reversible oxidation on protein cysteine residues. Differential analyses reveal that Scnn1b overexpression may protect against hyperoxia-induced lung injury via modulation of specific processes such as cell adhesion, blood coagulation, and proteolysis. This study provides a landscape view of protein oxidation in the lung and highlights the importance of redox regulation in O2-induced lung injury.

Pseudohypoaldosteronism Type 1: The Presentation and Management of a Neonate With a Novel Mutation of the SCNN1B Gene Found in Two Hispanic Siblings.

Pseudohypoaldosteronism type 1 (PHA1) may manifest in the neonatal period as a life-threatening salt-wasting syndrome providing challenges in recognition and treatment. This case describes a newborn who developed severe dehydration and electrolyte imbalances and subsequently was found to have a novel SCNN1B gene variant resulting in autosomal recessive systemic PHA1.

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

Background: Pseudohypoaldosteronism (PHA) diseases are difficult to diagnose because symptoms are often non-specific and an in-depth pathogenesis study is still lacking. Case Presentation: We 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. Conclusions: Our 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.

Airway epithelial cell-specific deletion of HMGB1 exaggerates inflammatory responses in mice with muco-obstructive airway disease.

High mobility group box 1 (HMGB1), a ubiquitous chromatin-binding protein required for gene transcription regulation, is released into the extracellular microenvironment by various structural and immune cells, where it is known to act as an alarmin. Here, we investigated the role of airway epithelium-specific HMGB1 in the pathogenesis of muco-obstructive lung disease in Scnn1b-transgenic (Tg+) mouse, a model of human cystic fibrosis (CF)-like lung disease. We hypothesized that airway epithelium-derived HMGB1 modulates muco-inflammatory lung responses in the Tg+ mice. The airway epithelium-specific HMGB1-deficient mice were generated and the effects of HMGB1 deletion on immune cell recruitment, airway epithelial cell composition, mucous cell metaplasia, and bacterial clearance were determined. The airway epithelium-specific deletion of HMGB1 in wild-type (WT) mice did not result in any morphological alterations in the airway epithelium. The deficiency of HMGB1 in airway epithelial cells in the Tg+ mice, however, resulted in significantly increased infiltration of macrophages, neutrophils, and eosinophils which was associated with significantly higher levels of inflammatory mediators, including G-CSF, KC, MIP-2, MCP-1, MIP-1α, MIP-1ß, IP-10, and TNF-α in the airspaces. Furthermore, as compared to the HMGB1-sufficient Tg+ mice, the airway epithelial cell-specific HMGB1-deficient Tg+ mice exhibited poor resolution of spontaneous bacterial infection. The HMGB1 deficiency in the airway epithelial cells of Tg+ mice did not alter airway epithelial cell-specific responses including epithelial cell proliferation, mucous cell metaplasia, and mucus obstruction. Collectively, our findings provide novel insights into the role of airway epithelial cell-derived HMGB1 in the pathogenesis of CF-like lung disease in Tg+ mice.

A novel nonsense mutation in the ß-subunit of the epithelial sodium channel causing Liddle syndrome.

PURPOSE: Liddle syndrome is a hereditary form of arterial hypertension caused by mutations in the genes coding of the epithelial sodium channel - SCNN1A, SCNN1B and SCNN1G. It is characterised by early onset of hypertension and variable biochemical features such as hypokalaemia and low plasma concentrations of renin and aldosterone. Phenotypic variability is large and, therefore, LS is probably underdiagnosed. Our objective was to examine a family suspected from Liddle syndrome including genetic testing and evaluate clinical and biochemical features of affected family members. MATERIALS AND METHODS: Thirteen probands from the Czech family, related by blood, underwent physical examination, laboratory tests, and genetic testing. Alleles of SCNN1B and SCNN1G genes were examined by PCR amplification and Sanger sequencing of amplicons. RESULTS: We identified a novel mutation in the ß-subunit of an epithelial sodium channel coded by the SCNN1B gene, causing the nonsense mutation in the protein sequence p.Tyr604*. This mutation was detected in 7 members of the family. The mutation carriers differed in the severity of hypertension and hypokalaemia which appeared only after diuretics in most of them; low aldosterone level (< 0.12 nmol/l) was, however, present in all. CONCLUSIONS: This finding expands the spectrum of known mutations causing Liddle syndrome. Hypoaldosteronemia was 100% sensitive sign in the mutation carriers. Low levels are observed especially in the Caucasian population reaching 96% sensitivity. Assessment of plasma aldosterone concentration is helpful for differential diagnosis of arterial hypertension. CONDENSED ABSTRACT: Liddle syndrome is a hereditary form of arterial hypertension caused by mutations in the genes encoding the epithelial sodium channel's α-, ß- and γ-subunit. It is usually manifested by early onset of hypertension accompanied by low potassium and aldosterone levels. We performed a physical examination, laboratory tests and genetic screening in 13 members of a Czech family. We found a new mutation of the SCNN1B gene which encodes the ß-subunit of the epithelial sodium channel. We describe the variability of each family member phenotype and point out the relevance of using aldosterone levels as a high sensitivity marker of Liddle syndrome in Caucasians.

A Unique Genotype of Pseudohypoaldosteronism Type 1b in a Highly Consanguineous Population.

CONTEXT: Pseudohypoaldosteronism (PHA) is a condition in which serum aldosterone level is normal or elevated but its action is deficient. OBJECTIVE: This study describes the molecular genetics of PHA 1b in the highly consanguineous population of 2 Arabian Gulf countries, Saudi Arabia and Oman. METHODS: This study enrolled 22 patients from 13 unrelated families (2 families with 5 patients from Oman and 11 families with 17 patients from Saudi Arabia). All of these patients had presented within the first 10 days of life with nausea and vomiting, hyponatremia, hyperkalemia, and hypotension. We isolated DNA from peripheral blood and PCR-sequenced all exons and exon-intron boundaries of SCNN1A and, if negative, SCNN1B and SCNN1G using the Dideoxy Chain termination method. RESULTS: We found a total of 8 mutations in 13 families as follows: 6 mutations in SCNN1A, 1 in SCNN1B, and 1 in SCNN1G. All of these mutations were novel except one. SCNN1A mutations were: c.1496A>G, p.Q499R (novel) in 1 patient; c.1453C>T, p.Q485X (novel) in 1 patient; c.1322_1322delA, p.N441Tfs*41 (novel) in 2 patients of 1 family; c.876 + 2 delGAGT (novel) in 3 patients of 1 family; c.203_204 delTC, p.I68Tfs*76 (a known mutation) in 8 patients of 5 families; and whole SCNN1A gene deletion (novel) in 2 patients of 2 families. In addition, a nonsense SCNN1B mutation c.1694C>A, p.S565X (novel) was found in 3 siblings from 1 Omani family, and an SCNN1G deletion mutation c.527_528 delCA, p.T176Rfs*9 (novel) in 2 siblings from another Omani family. CONCLUSION: We characterized a unique genotype of PHA 1b with several novel gene structure-disrupting mutations in SCNN1A, SCNN1B, and SCNN1G in a highly consanguineous population.

Liddle syndrome: A case report.

INTRODUCTION: Liddle syndrome is an autosomal dominant hereditary disease caused by a single gene mutation. Typical clinical manifestations are early-onset hypertension and hypokalaemia and can be treated using ENaC blockers (amiloride and aminopterin). PATIENTS AND METHODS: This report describes a 17-year-old male with hypertension and hypokalaemia. We performed a Captopril inhibition test and a postural stimulation test for the diagnosis and typing of primary aldosteronism. RESULTS: The serum renin was low, and aldosterone was high, so the patient was initially misdiagnosed as primary aldosteronism. After a genetic analysis, a diagnosis of Liddle syndrome was made due to the presence of an SCNN1B p.Pro617Ser mutation. After diagnosis, the patient was administered one tablet of amiloride twice a day (each tablet contains 2.5mg of amiloride hydrochloride and 25mg of hydrochlorothiazide 25mg). The patient's blood pressure (average of 120-135/70-80mmHg) and serum potassium levels (3.6-4.0mmol/L) returned to normal and were well-controlled after treatment. DISCUSSION: The patient is an atypical case of Liddle syndrome; genetic analysis is helpful and essential for diagnosis.

Liddle Syndrome due to a Novel c.1713 Deletion in the Epithelial Sodium Channel ß-Subunit in a Normotensive Adolescent.

OBJECTIVE: Liddle syndrome (LS) is a rare autosomal dominant condition secondary to a gain-of-function mutation affecting the epithelial sodium channels (ENaCs) in the distal nephron. It presents with early-onset hypertension, hypokalemia, and metabolic alkalosis in the face of hyporeninemia and hypoaldosteronism. We report a novel mutation affecting the ENaCs in a normotensive adolescent with LS. METHODS: We describe a pediatric case of LS with a novel mutation and review the condition's presentation and management. To date, 31 different mutations in the ß- or γ-subunit of ENaCs have been reported as associated with LS. RESULTS: We describe a 16-year-old girl presenting with muscle cramps with a strong family history of hypertension and hypokalemia. Initial investigations revealed hypokalemia together with hypoaldosteronism and hyporeninemia. Subsequent genetic testing revealed a novel mutation in SCNN1B (deletion: c.1713delC), leading to the premature termination of the sodium channel epithelial 1 subunit-ß protein and the LS phenotype. Treatment with triamterene (50 mg, twice daily) and potassium chloride (20 mEq, once daily) normalized the serum potassium and led to resolution of her muscle cramps. CONCLUSION: It is essential to consider investigating the presence of rare genetic syndromes, like LS, when a patient presents with hypokalemia. Further studies are needed to understand the variable presentation of this condition.

Clinical Management in Systemic Type Pseudohypoaldosteronism Due to SCNN1B Variant and Literature Review

Systemic pseudohypoaldosteronism (PHA) is a rare, salt-wasting syndrome that is caused by inactivating variants in genes encoding epithelial sodium channel subunits. Hyponatremia, hyperkalemia, metabolic acidosis, increased aldosterone and renin levels are expected findings in PHA. Clinical management is challenging due to high dose oral replacement therapy. Furthermore, patients with systemic PHA require life-long therapy. Here we report a patient with systemic PHA due to SCNN1B variant whose hyponatremia and hyperkalemia was detected at the 24th hour of life. Hyperkalemia did not improve with conventional treatments and dialysis was required. He also developed myocarditis and hypertension in follow-up. Challenges for diagnosis and treatment in this patient are discussed herein. In addition, published evidence concerning common features of patients with SCNN1B variant are reviewed.

Premature Stroke Secondary to Severe Hypertension Results from Liddle Syndrome Caused by a Novel SCNN1B Mutation.

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 ß-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.

Pseudohypoaldosteronism Type 1 Newborn Patient with a Novel Mutation in SCNN1B.

Pseudohypoaldosteronism is a rare disease characterized by resistance to aldosterone-targeted organs, hyponatremia, hyperkalemia, metabolic acidosis, and severe salt loss in hyperaldosteronism. Homozygous mutations in SCNN1A , SCNN1B, and SCNN1G genes were found to be responsible for the etiology. About 80 cases with molecular basis have been reported to date. In this case, a newborn patient admitted to our neonatal intensive care unit due to feeding problems was examined. The parents of the patient had a consanguineous marriage, and they had lost their three sons due to hyperkalemia. Since she had hyponatremia and hyperkalemia, congenital adrenal hyperplasia was primarily considered. Although the initial evaluation was made in this direction, the patient was diagnosed as pseudohypoaldosteronism type 1 with the findings obtained during the process such as dehydration, cortisol levels, adrenocorticotropic hormone levels, and negative CYP21A2 analysis result. This clinical diagnosis was confirmed by the novel homozygous frame-shift variant c.1245_1246insC (p.N416Qfs*35) in SCNN1B shown by gene analysis. In this report, we seek to emphasize that aldosterone deficiency should be one of the first diagnoses to be considered in neonatal patients with hyponatremia, hyperkalemia, metabolic acidosis, and dehydration.

[Liddle syndrome as a rare cause of hypertension - a case report]. / Zespól Liddle'a jako rzadka przyczyna nadcisnienia tetniczego ­ opis przypadku.

Liddle syndrome is an uncommon genetic disorder featuring hypertension, hypokalemia, metabolic alcalosis, decreased rennin and aldosterone secretion. It is caused by a point mutation of a gene encoding one of the three subunits of the epithelial sodium channel (ENaC). Because of its rarity, the availability of the literature on the diagnosis of this syndrome is limited. A CASE REPORT: The 14 years old adolescent with resistant hypertension was analyzed genetically, because of the family history. The significance of it and biochemical findings in recognition of Liddle Syndrome was discussed. It has been concluded that performing a genetic test at the suspicion of monogenic background of hypertension allows for accurate and effective treatment.

Phenotypic diversity and correlation with the genotypes of pseudohypoaldosteronism type 1.

Background Type I pseudohypoaldosteronism (PHA1) is a rare condition characterised by profound salt wasting, hyperkalaemia and metabolic acidosis due to renal tubular resistance to aldosterone (PHA1a) or defective sodium epithelial channels (PHA1b or systemic PHA). Our aim was to review the clinical presentation related to the genotype in patients with PHA1. Methods A questionnaire-based cross-sectional survey was undertaken through the British Society of Paediatric Endocrinology and Diabetes (BSPED) examining the clinical presentation and management of patients with genetically confirmed PHA1. We also reviewed previously reported patients where genotypic and phenotypic information were reported. Results Genetic confirmation was made in 12 patients with PHA1; four had PHA1a, including one novel mutation in NR3C2; eight had PHA1b, including three with novel mutations in SCNN1A and one novel mutation in SCNN1B. It was impossible to differentiate between types of PHA1 from early clinical presentation or the biochemical and hormonal profile. Patients presenting with missense mutations of SCNN1A and SCNN1B had a less marked rise in serum aldosterone suggesting preservation in sodium epithelial channel function. Conclusions We advocate early genetic testing in patients with presumed PHA1, given the challenges in differentiating between patients with PHA1a and PHA1b. Clinical course differs between patients with NR3C2 and SCNN1A mutations with a poorer prognosis in those with multisystem PHA. There were no obvious genotype-phenotype correlations between mutations on the same gene in our cohort and others, although a lower serum aldosterone may suggest a missense mutation in SCNN1 in patients with PHA1b.

Genetics of Hypertension in African Americans and Others of African Descent.

Hypertension is the leading cause of cardiovascular disease in the United States, affecting up to one-third of adults. When compared to other ethnic or racial groups in the United States, African Americans and other people of African descent show a higher incidence of hypertension and its related comorbidities; however, the genetics of hypertension in these populations has not been studied adequately. Several genes have been identified to play a role in the genetics of hypertension. They include genes regulating the renin-aldosterone-angiotensin system (RAAS), such as Sodium Channel Epithelial 1 Beta Subunit (SCNN1B), Armadillo Repeat Containing 5 (ARMC5), G Protein-Coupled Receptor Kinase 4 (GRK4), and Calcium Voltage-Gated Channel Subunit Alpha1 D (CACNA1D). In this review, we focus on recent genetic findings available in the public domain for potential differences between African Americans and other populations. We also cover some recent and relevant discoveries in the field of low-renin hypertension from our laboratory at the National Institutes of Health. Understanding the different genetics of hypertension among various groups is essential for effective precision-guided medical therapy of high blood pressure.

Association of Genetic Variation in the Epithelial Sodium Channel Gene with Urinary Sodium Excretion and Blood Pressure.

This study was performed to investigate whether genetic variation in the epithelial sodium channel (ENaC) is associated with 24-h urinary sodium excretion and blood pressure. A total of 3345 participants of the KoGES_Ansan and Ansung study were eligible for this study. Genomic DNA samples were isolated from peripheral blood and genotyped on the Affymetrix Genome-Wide Human SNP Array 5.0. Thirty-four single nucleotide polymorphisms (SNPs) were extracted for gene regions (SCNN1A, SCNN1B, and SCNN1G) as additive components by using Plink. Twenty-four-hour sodium excretions were estimated from spot urine samples using the Tanaka formula. The general linear model (GLM) was applied to assess the association between SNPs and urinary sodium excretion or blood pressure. In the SCNN1G gene, six SNPs (rs4073291, rs12934362, rs7404408, rs4494543, rs5735, and rs6497657) were significantly different in 24-h urinary sodium excretion according to gene variants. However, no difference was found in blood pressure among participants with gene variants of ENaC. Our finding indicated that 24-h urinary sodium excretions were different according to variants of the SCNN1G gene in large samples. Further studies to replicate these findings are warranted.