A novel AGK splicing mutation in a patient with Sengers syndrome and left ventricular non-compaction cardiomyopathy.

BACKGROUND: Sengers syndrome characterized by hypertrophic cardiomyopathy is an extremely rare genetic disorder. Sengers syndrome associated with left ventricular non-compaction (LVNC) has not been described. METHODS: Genetic testing was used to identify candidate AGK variants in the proband. The predicted molecular structures were constructed by protein modeling. Exon skipping caused by the identified splicing mutations was verified by in silico analyses and in vitro assays. The genotypic and phenotypic features of patients with AGK splicing mutations were extracted by a systematic review. RESULTS: The proband was characterized by Sengers syndrome and LVNC and caused by a novel compound heterozygous AGK splicing mutation. This compound mutation simultaneously perturbed the protein sequences and spatial conformation of the acylglycerol kinase protein. In silico and in vitro analyses demonstrated skipping of exons 7 and 8 and premature truncation as a result of exon 8 skipping. The systematic review indicated that patients with an AGK splicing mutation may have milder phenotypes of Sengers syndrome. CONCLUSIONS: The genotypic and phenotypic spectrums of Sengers syndrome have been expanded, which will provide essential information for genetic counseling. The molecular mechanism in AGK mutations can offer insights into the potential targets for treatment. IMPACT: First description of a child with Sengers syndrome and left ventricular non-compaction cardiomyopathy. A novel pathogenic compound heterozygous splicing mutation in AGK for Sengers syndrome was identified. The identified mutations led to exons skipping by in silico analyses and in vitro assays.

Genotype-phenotype analysis of F-helix mutations at the kinase domain of TGFBR2, including a type 2 Marfan syndrome familial study.

PURPOSE: Transforming growth factor beta receptor II (TGFBR2) gene mutations are associated with Marfan syndrome; however, the relationship between the mutations and clinical phenotypes are not clear. METHODS: Genomic DNA from peripheral blood leukocytes of a Chinese proband with Marfan syndrome, five of the proband's relatives, and 100 unrelated Chinese control subjects were isolated and screened for fibrillin-1 (FBN1) and TGFBR2 gene mutations by direct sequencing, and a genotype-phenotype study was performed following a review of the literature on TGFBR2 mutations in the search area. Also, the structure of TGFBR2 protein before and after gene mutation was analyzed. RESULTS: The results identified a novel missense TGFBR2 mutation p.V453E (c.1358T>A) in the proband and two relatives that was located in the F-helix in the kinase domain of TGFBR2. No such genetic change was observed in the unrelated controls. No FBN1 mutation was detected in any of the subjects. Genotype-phenotype analyses indicated that F-helix mutations are related to type 2 Marfan syndrome and Loeys-Dietz syndrome, and these mutations can lead to severe cardiovascular (93.8%) and skeletal (81.3%) lesions and minor ocular lesions (25%). Losartan treatment can slow-down the progression of aortic lesions. CONCLUSIONS: The findings extend the mutation spectrum of Marfan syndrome, and that mutations at the F-helix in the kinase domain of TGFBR2 may be associated with the development of severe cardiovascular and skeletal lesions and minor ocular lesions. These findings have implications for genetic testing, diagnosis, and treatment in individuals with transforming growth factor beta (TGF-ß) signaling-related disorders.

Pathogenicity and Long-Term Outcomes of Liddle Syndrome Caused by a Nonsense Mutation of SCNN1G in a Chinese Family.

Objective: Liddle syndrome (LS) is a monogenic hypertension consistent with autosomal dominant inheritance, often with early onset high blood pressure in childhood or adolescence. This study aimed to identify the pathogenicity of a nonsense mutation in SCNN1G in a Chinese family with LS and the long-term outcomes of tailored treatment with amiloride. Methods: To explore the pathogenicity of candidate variant reported in 2015 by our team, we constructed mutant and wild-type models in vitro and measured amiloride-sensitive current in Chinese Hamster Ovary (CHO) cells using patch clamp technique. Participants were followed up for 7 years after tailored treatment with amiloride. Results: A nonsense variant was detected in six members, two of whom were pediatric patients. This mutation resulted in a termination codon at codon 572, truncating the Pro-Pro-Pro-X-Tyr motif. The mutant epithelial sodium channels displayed higher amiloride-sensitive currents than the wild-type channels (P < 0.05). Tailored treatment with amiloride achieved ideal blood pressure control in all patients with normal cardiorenal function, and no adverse events occurred during follow-up. Conclusion: We found the pathogenicity of a nonsense SCNN1G mutation (p.Glu571*) with enhanced amiloride-sensitive currents in a LS family with young patients. Tailored treatment with amiloride may be an effective strategy for the long-term control of blood pressure and protection from target organ damage or cardiovascular events, including children and youth patients with LS.

Corrigendum: Pathogenicity and Long-Term Outcomes of Liddle Syndrome Caused by a Nonsense Mutation of SCNN1G in a Chinese Family.

[This corrects the article DOI: 10.3389/fped.2022.887214.].

Clinical characteristics, target organ damage and associate risk factors of resistant hypertension determined by ambulatory blood pressure monitoring in patients aged ≥ 80 years.

OBJECTIVES: To investigate clinical characteristics, target organ damage, and the associated risk factors of the patients aged ≥ 80 years with true resistant hypertension (RH). METHODS: Patients aged ≥ 80 years with hypertension (n = 1163) were included in this study. The included participants attended a structured clinical examination and an evaluation of RH was carried out. The prevalence, clinical characteristics and target organ damage of patients with RH were assessed. The associated clinical risk factors were analyzed by using logistic regression. RESULTS: The prevalence of RH diagnosis by 24-h ambulatory blood pressure monitoring assessment was 21.15%. End-diastolic left ventricular internal dimension, left ventricular mass index as well as prevalence of left ventricular hypertrophy were significantly greater in patients with RH than in control group. The common carotid artery intimal media thickness, carotid walls thickness, common carotid artery diameter and relative wall thickness were significant greater in RH group than in control. A relatively higher level of creatinine, estimated glomerular filtration rate, microalbuminuria and retinal changes was found in RH group than in control. A multivariate analysis showed that patients with a history of diabetes, higher body mass index (BMI) and lipid profiles were independent risk factors of RH. CONCLUSIONS: The prevalence of RH in patients aged ≥ 80 years was within the range of reported rates of the general population. Subjects with RH diagnosis showed a higher occurrence of target organ damage than patients with well controlled blood pressure. Patients with diabetes, higher BMI and serum lipid profiles were independent risk factors for RH in patients aged ≥ 80 years.

Establishing a predictive model for aspirin resistance in elderly Chinese patients with chronic cardiovascular disease.

BACKGROUND: Resistance to anti-platelet therapy is detrimental to patients. Our aim was to establish a predictive model for aspirin resistance to identify high-risk patients and to propose appropriate intervention. METHODS: Elderly patients (n = 1130) with stable chronic coronary heart disease who were taking aspirin (75 mg) for > 2 months were included. Details of their basic characteristics, laboratory test results, and medications were collected. Logistic regression analysis was performed to establish a predictive model for aspirin resistance. Risk score was finally established according to coefficient B and type of variables in logistic regression. The Hosmer-Lemeshow (HL) test and receiver operating characteristic curves were performed to respectively test the calibration and discrimination of the model. RESULTS: Seven risk factors were included in our risk score. They were serum creatinine (> 110 µmol/L, score of 1); fasting blood glucose (> 7.0 mmol/L, score of 1); hyperlipidemia (score of 1); number of coronary arteries (2 branches, score of 2; ≥ 3 branches, score of 4); body mass index (20-25 kg/m(2), score of 2; > 25 kg/m(2), score of 4); percutaneous coronary intervention (score of 2); and smoking (score of 3). The HL test showed P ≥ 0.05 and area under the receiver operating characteristic curve ≥ 0.70. CONCLUSIONS: We explored and quantified the risk factors for aspirin resistance. Our predictive model showed good calibration and discriminative power and therefore a good foundation for the further study of patients undergoing anti-platelet therapy.

Coenzyme Q10 treatment of cardiovascular disorders of ageing including heart failure, hypertension and endothelial dysfunction.

Advancing age is a major risk factor for the development of cardiovascular diseases. The aetiology of several cardiovascular disorders is thought to involve impaired mitochondrial function and oxidative stress. Coenzyme Q10 (CoQ10) acts as both an antioxidant and as an electron acceptor at the level of the mitochondria. Furthermore, in cardiac patients, plasma CoQ10 has been found to be an independent predictor of mortality. Based on the fundamental role of CoQ10 in mitochondrial bioenergetics and its well-acknowledged antioxidant properties, several clinical trials evaluating CoQ10 have been undertaken in cardiovascular disorders of ageing including chronic heart failure, hypertension, and endothelial dysfunction. CoQ10 as a therapy appears to be safe and well tolerated.

Molecular genetics of Liddle's syndrome.

Liddle's syndrome, an autosomal dominant form of monogenic hypertension, is characterized by salt-sensitive hypertension with early penetrance, hypokalemia, metabolic alkalosis, suppression of plasma rennin activity and aldosterone secretion, and a clear-cut response to epithelial sodium channel (ENaC) blockers but not spironolactone therapy. Our understanding of ENaCs and Na(+) transport defects has expanded greatly over the past two decades and provides detailed insight into the molecular basis of Liddle's syndrome. In this review, we offer an overview of recent advances in understanding the molecular genetics of Liddle's syndrome, involving mutation analysis, molecular mechanisms and genetic testing. The ENaC in the distal nephron is composed of α, ß and γ subunits that share similar structures. Mutations associated with Liddle's syndrome are positioned in either ß or γ subunits and disturb or truncate a conserved proline-rich sequence (i.e., PY motif), leading to constitutive activation of the ENaC. Genetic testing has made it possible to make accurate diagnoses and develop tailored therapies for mutation carriers.

Influence of omega-3 polyunsaturated fatty acid-supplementation on platelet aggregation in humans: a meta-analysis of randomized controlled trials.

OBJECTIVE: Increased platelet activity predicts adverse cardiovascular events. The objective was to assess the effects of long-chain omega-3 polyunsaturated fatty acid (n-3 PUFA)-supplementation on platelet aggregation. METHODS AND RESULTS: We conducted a meta-analysis of randomized controlled trials identified using PubMed, Embase and the Cochrane Library. Fifteen studies were included. In comparison to placebo using the random-effect model, n-3 PUFA-supplementation significantly reduced adenosine diphosphate-induced platelet aggregation (standard mean difference [SMD] = -1.23 with 95% confidence interval [CI] -2.24 to -0.23, p = 0.02) and platelet aggregation units, determined using the VerifyNow(®) rapid platelet-function assay system (SMD = -6.78 with 95% CI -12.58 to -0.98, p = 0.02). There was a trend toward decreased collagen-induced (SMD = -0.70 with 95% CI -0.72 to 0.33, p = 0.18) and arachidonic acid-induced platelet aggregation (SMD = -0.43 with 95% CI -2.26 to 1.40, p = 0.64) compared with controls; however, statistical significance was not reached. CONCLUSIONS: Our meta-analysis demonstrates that n-3 PUFA-supplementation is associated with a significant reduction in platelet aggregation when the participants were at poor health status, but not in healthy persons. High-risk patients with cardiovascular disease and even diabetics may potentially benefit from n-3 PUFAs therapy. However, n-3 PUFAs may not be effective in primary prevention. Larger trials need to be carried out to confirm the present findings.

The association of an adenine insertion variant in the 5'UTR of the endothelin-1 gene with hypertension and orthostatic hypotension.

INTRODUCTION: An adenine insertion polymorphism in the 5' untranslated region of the endothelin-1 gene is functional and increases the expression of endothelin mRNA and protein in the insertion homozygote. In the present study we hypothesized that this functional polymorphism might be associated with hypertension and/or orthostatic hypotension. MATERIAL AND METHODS: The adenine insertion polymorphism was genotyped in 381 untreated hypertensive patients and 298 normotensive subjects, all of whom underwent an upright posture study for orthostatic blood pressure measurements. Orthostatic hypotension was defined as a drop in blood pressure of 20/10 mm Hg or more within 3 min of assuming the upright posture. RESULTS: The allele frequency of the adenine insertion was similar in hypertensive and normotensive subjects (15.2% vs. 15.3%, p > 0.05). After adjustment for age, sex and body mass index, blood pressure levels did not differ significantly among the genotypes in both hypertensives and normotensives. No associations were found between the distribution of the adenine insertion genotypes and the risk of orthostatic hypotension in both hypertensive patients and normotensive subjects even after adjustment for demographic parameters and supine systolic or diastolic blood pressure. Neither hypertensive nor normotensive subjects showed significant differences in orthostatic systolic or diastolic blood pressure changes among the genotype groups (all p > 0.05). CONCLUSIONS: We concluded that the functional adenine insertion polymorphism in the endothelin-1 gene is not associated with either hypertension or orthostatic hypotension risk in Chinese.

Plasma concentrations of interleukin-6, C-reactive protein, tumor necrosis factor-α and matrix metalloproteinase-9 in aortic dissection.

BACKGROUND: The role of inflammation in aortic dissection (AD) has not fully been investigated. We evaluated the potential relationships between interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase-9 (MMP-9) and AD. METHODS: Plasma concentrations of IL-6, TNF-α, MMP-9 and CRP were determined in 64 acute AD patients, 42 patients with chronic AD, 98 patients with hypertension alone, and 96 healthy subjects. RESULTS: IL-6 concentrations were higher in acute AD than that in hypertension and healthy controls (10.98±2.38 vs. 3.79±1.56 and 3.32±1.60 pg/ml, P<0.05, respectively). Increased CRP concentrations were found in acute AD compared with chronic AD and hypertension as well as healthy subjects (13.48±3.74 vs. 4.12±2.99, 1.62±0.65 and 1.12±0.35 mg/l, P<0.001, respectively). Higher MMP-9 concentrations were detected in acute AD, chronic AD and hypertension compared with healthy controls (37.75±9.38, 55.78±6.41 and 31.03±7.94 vs. 21.24±7.28 ng/ml, P<0.05, P<0.001 and P<0.05, respectively), and in the dead compared to the survived (107.29±9.38 vs. 86.80±7.93 ng/ml, P<0.001) among acute AD patients. In acute AD, the time after onset had positive correlation with TNF-α (r=0.497, P=0.000), and negative correlation with CRP (r=-0.424, P=0.000). Plasma CRP levels decreased significantly when the onset time increased (P=0.013). Moreover, in the patients with acute AD who underwent surgery and stenting, plasma MMP-9 concentrations increased immediately after surgical treatment and stenting, and reached the peak values at 24h, then decreased at 1 week (P<0.001). CONCLUSIONS: Our findings confirmed and extended previous studies that increased plasma inflammatory markers were significantly associated with AD.

Genetic diagnosis of Liddle's syndrome by mutation analysis of SCNN1B and SCNN1G in a Chinese family.

BACKGROUND: Liddle's syndrome is a rare autosomal-dominant monogenic form of salt-sensitive hypertension. This study aimed to screen the gene mutation in ß and γ subunits of the epithelial sodium channel (ENaC) of a Chinese family with Liddle's syndrome, an autosomal dominant form of hypertension. METHODS: DNA samples from the proband with early-onset, treatment-resistant hypertension and suppressed plasma renin activity were initially screened for mutations in the C-terminal exons of the ENaC ß or γ subunit genes, using amplification by polymerase chain reaction and direct DNA sequencing. We also screened the C-terminus of SCNN1B and SCNN1G in family members, and screened for the mutation in 150 controls. RESULTS: Genetic analysis of the ß ENaC gene revealed a missense mutation of CCC to TCC at codon 616 in the proband, her mother and her grandmother. One hundred and fifty randomly selected controls had not the mutation, indicating that this is not a common genetic polymorphism. There was no mutation of the γ ENaC gene in any of the individuals examined. CONCLUSIONS: Through direct DNA sequencing analysis, we established the diagnosis of Liddle's syndrome for the proband and her families, and provided tailored therapies to this abnormality. These results provide further evidence that Pro616Ser is a critical amino acid that has a key role in the inhibition of sodium channel activity.

Molecular analysis for diagnosis of Marfan syndrome and Marfan-associated disorders.

Marfan syndrome is a systemic disorder of connective tissue, caused by mutations in the FBN1, TGFBR1 or TGFBR2 genes. This syndrome is characterized by involvement of three major systems, skeletal, ocular, and cardiovascular. The continuing improvements in molecular biology and increasing availability of molecular diagnosis in clinical practice allow recognition of Marfan syndrome in patients with incomplete phenotypes. Additionally, molecular analyses could also be used for preimplantation genetic diagnosis. The identification of a mutation allows for early diagnosis, prognosis, genetic counseling, preventive management of carriers and reassurance for unaffected relatives. The importance of knowing in advance the location of the putative family mutation is highlighted by its straightforward application to prenatal and postnatal screening.

Recent molecular biological progress in Marfan syndrome and Marfan-associated disorders.

Marfan syndrome (MFS) is a connective tissue disorder with autosomal dominant inheritance. Advances in medicine and surgery have increased the average lifespan of classically affected patients. Serious visual and/or musculoskeletal impairment often has detrimental effects on day-to-day activities and quality of life. MFS patients suffer from many problems at younger ages and with higher frequencies than the general population because of the degenerative nature of the genetic condition. In classical MFS, changes are caused by mutations in the fibrillin-1 gene (FBN1). Mutations in the fibrillin-2 gene were discovered in individuals with a phenotypically related disorder, congenital contractural arachnodactyly. Some of the clinical manifestations of MFS cannot be explained by mechanical properties alone. Recently, mutations in the genes required for transforming growth factor-beta signaling (TGFBR1 and TGFBR2) have been found in several disorders with varying degrees of overlap with classical MFS, including Loeys-Dietz syndrome and familial thoracic aortic aneurysms and dissections. MFS is a disorder that is variable in its phenotypic expression. Specific information about mutations in the large FBN1 gene will give rise to more information about the phenotype-genotype correlations. Possible molecular mechanisms for the pathogenesis of MFS will be discussed which may assist healthcare professionals to control environmental factors that provoke individual complications in MFS.

Identification of a novel lethal fibrillin-1 gene mutation in a Chinese Marfan family and correlation of 3' fibrillin-1 gene mutations with phenotype.

BACKGROUND: Mutations in the fibrillin-1 gene have been identified in patients with Marfan syndrome (MFS). This study aimed to identify the molecular defects in the fibrillin-1 gene in a Chinese family with Marfan syndrome, accompanied by aortic aneurysms/dissection. METHODS: Two patients and one non-carrier in the family underwent complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of these individuals in the family as well as 50 healthy normal controls. Polymerase chain reaction amplification and direct sequencing of all 65 coding exons of fibrillin-1 gene were analyzed. RESULTS: We found a novel mutation (c.8547T > G, p.Tyr2849X) in exon 65 of fibrillin-1 gene in a Chinese proband with Marfan syndrome, accompanied by aortic aneurysms/dissection. Sudden death at a young age of affected members was seen due to aortic aneurysms/dissection. By evaluating genotype-phenotype correlations of patients with mutations in the 3' end of fibrillin-1 gene (exons 64 and 65), we also found that the presence of nonsense mutations occurring in exons 64 and 65 appeared to be an indicator of early-onset aortic risk and sudden death. CONCLUSIONS: These results expand the mutation spectrum of fibrillin-1 gene and help in the study of the molecular pathogenesis of Marfan syndrome, indicating that mutations occurring in the 3' end of fibrillin-1 gene may play an independent functional role in the pathogenesis of Marfan syndrome.