Epistatic interaction of PDE4DIP and DES mutations in familial atrial fibrillation with slow conduction.

The genetic causes of atrial fibrillation (AF) with slow conduction are unknown. Eight kindreds with familial AF and slow conduction, including a family affected by early-onset AF, heart block, and incompletely penetrant nonischemic dilated cardiomyopathy (DCM) underwent whole exome sequencing. A known pathogenic mutation in the desmin (DES) gene resulting in p.S13F substitution (NM_001927.3:c.38C>T) at a PKC phosphorylation site was identified in all four members of the kindred with early-onset AF and heart block, while only two developed DCM. Higher penetrance for AF and heart block prompted a genetic screening for DES modifier(s). A deleterious mutation in the phosphodiesterase-4D-interacting-protein (PDE4DIP) gene resulting in p.A123T substitution (NM_001002811:c.367G>A) was identified that segregated with early-onset AF, heart block, and the DES mutation. Three additional novel deleterious PDE4DIP mutations were identified in four other unrelated kindreds. Characterization of PDE4DIPA123T in vitro suggested impaired compartmentalization of PKA and PDE4D characterized by reduced colocalization with PDE4D, increased cAMP activation leading to higher PKA phosphorylation of the ß2-adrenergic-receptor, and decreased PKA phosphorylation of desmin after isoproterenol stimulation. Our findings identify PDE4DIP as a novel gene for slow AF and unravel its epistatic interaction with DES mutations in development of conduction disease and arrhythmia.

Pulmonary Embolism and Atrial Fibrillation: Two Sides of the Same Coin? A Systematic Review.

Pulmonary embolism (PE) is a common, potentially fatal thrombotic disease. Atrial fibrillation (AF), the most common arrhythmia, may also lead to thromboembolic complications. Although initially appearing as distinct entities, PE and AF may coexist. The direction and extent of this association has not been well characterized. We performed a search of PubMed, Scopus, and the Cochrane Database of Systematic Reviews for publications that reported coexisting AF in patients with PE, or vice versa, to provide a systematic overview of pathophysiological and epidemiological aspects of this association (last search: October 13, 2016). We screened 650 articles following the PubMed search, and 697 through Scopus. PE and AF share many common risk factors, including old age, obesity, heart failure, and inflammatory states. In addition, PE may lead to AF through right-sided pressure overload or inflammatory cytokines. AF, in turn, might lead to right atrial appendage clot formation and thereby PE. Epidemiological studies indicate that AF can be seen as a presenting sign, during the early phase, or later in the course of recovery from PE. Patients with AF are also at increased risk of developing PE, a risk that correlates with the CHA2DS2-VASc score. For the choice of antithrombotic therapy, PE-related factors (provoked or unproved, active cancer, and prior recurrence) and AF-related factors (CHA2DS2-VASc score), risk of bleeding, and patient preferences should be considered. In conclusion, PE and AF may coexist, with an understudied bidirectional association. Prognostication and choice of antithrombotic therapy in patients with both PE and AF might be different compared with those who present with only one of the two and warrants further investigation.

Metabolic syndrome: genetic insights into disease pathogenesis.

PURPOSE OF REVIEW: Metabolic syndrome (MetS) is a cluster of interrelated and heritable metabolic traits, which collectively impart unsurpassed risk for atherosclerotic cardiovascular disease and type 2 diabetes. Considerable work has been done to understand the underlying disease mechanisms by elucidating its genetic cause. RECENT FINDINGS: Genome-wide association studies have been widely utilized albeit with modest success in identifying variants that are associated with more than two metabolic traits. Another limitation of this approach is the inherent small effect of the common variants, a major barrier for dissecting their cognate pathways. Modest advances in this venue have been also made by genetic studies of kindreds at the extreme ends of quantitative distributions. These efforts have led to the discovery of a number of disease genes with large effects that underlie the association of diverse traits of this syndrome. SUMMARY: Substantial progress has been made over the last decade in identification of genetic risk factors associated with the various traits of MetS. The heterogeneity and multifactorial heritability of MetS, however, has been a challenge toward understanding the factors underlying the association of these traits. Genetic investigations of outlier kindreds or homogenous populations with high prevalence for the disease can potentially improve our knowledge of the disease pathophysiology.

Dyrk1b promotes autophagy during skeletal muscle differentiation by upregulating 4e-bp1.

Rare gain of function mutations in the gene encoding Dyrk1b, a key regulator of skeletal muscle differentiation, have been associated with sarcopenic obesity (SO) and metabolic syndrome (MetS) in humans. So far, the global gene networks regulated by Dyrk1b during myofiber differentiation have remained elusive. Here, we have performed untargeted proteomics to determine Dyrk1b-dependent gene-network in differentiated C2C12 myofibers. This analysis led to identification of translational inhibitor, 4e-bp1 as a post-transcriptional target of Dyrk1b in C2C12 cells. Accordingly, CRISPR/Cas9 mediated knockout of Dyrk1b in zebrafish identified 4e-bp1 as a downstream target of Dyrk1b in-vivo. The Dyrk1b knockout zebrafish embryos exhibited markedly reduced myosin heavy chain 1 expression in poorly developed myotomes and were embryonic lethal. Using knockdown and overexpression approaches in C2C12 cells, we found that 4e-bp1 enhances autophagy and mediates the effects of Dyrk1b on skeletal muscle differentiation. Dyrk1bR102C, the human sarcopenic obesity-associated mutation impaired muscle differentiation via excessive activation of 4e-bp1/autophagy axis in C2C12 cells. Strikingly, the defective muscle differentiation in Dyrk1bR102C cells was rescued by reduction of autophagic flux. The identification of Dyrk1b-4e-bp1-autophagy axis provides significant insight into pathways that are relevant to human skeletal muscle development and disorders.

Severe extra-glandular involvement and pleural effusions complicating primary Sjogren's syndrome: a case report.

BACKGROUND: Sjogren's syndrome, an autoimmune disease of the exocrine glands, results in keratoconjunctivitis sicca, xerostomia, and dental caries. It is often overlooked, considered by clinicians to be a benign disease. However, it can cause life-threatening extra-glandular complications that affect multiple organ systems. CASE PRESENTATION: Here we present a 78-year-old Caucasian woman with a history of primary Sjogren's syndrome (pSS) whose symptoms of keratoconjunctivitis sicca were managed managed conservatively. She was evaluated for sub-acute shortness of breath. Imaging showed severe bronchiectasis with features of lymphocytic interstitial pneumonia. She also had exudative bilateral pleural effusions and skin ulcers, likely vasculitic in origin. The workup was significant for anti-Ro antibody, pancytopenia, hypocomplementia, cryoglobulinemia and monoclonal gammopathy, all of which reflect disease severity. Although there was no evidence of malignancy, she developed B-cell non-Hodgkin lymphoma during follow-up. CONCLUSIONS: Primary Sjogren's syndrome can result in severe multi-organ disease. Pleural effusions are a rare complication of pSS, with only ten cases reported in the literature over the last 30 years, and tend to respond well to steroids. Prognostic biomarkers for disease severity include hypocomplementia, cryoglobulinemia, monoclonal gammopathy, and hypergammaglobulinemia. In this report we review the literature and the management of the disease.

The interplay of canonical and noncanonical Wnt signaling in metabolic syndrome.

Metabolic syndrome is a cluster of inherited metabolic traits, which centers around obesity and insulin resistance and is a major contributor to the growing prevalence of cardiovascular disease. The factors that underlie the association of metabolic traits in this syndrome are poorly understood due to disease heterogeneity and complexity. Genetic studies of kindreds with severe manifestation of metabolic syndrome have led to the identification of casual rare mutations in the LDL receptor-related protein 6, which serves as a co-receptor with frizzled protein receptors for Wnt signaling ligands. Extensive investigations have since unraveled the significance of the Wnt pathways in regulating body mass, glucose metabolism, de novo lipogenesis, low-density lipoprotein clearance, vascular smooth muscle plasticity, liver fat, and liver inflammation. The impaired canonical Wnt signaling observed in the R611C mutation carriers and the ensuing activation of noncanonical Wnt signaling constitute the underlying mechanism for these cardiometabolic abnormalities. Transcription factor 7-like 2 is a key transcription factor activated through LDL receptor-related protein 6 canonical Wnt and reciprocally inhibited by the noncanonical pathway. TC7L2 increases insulin receptor expression, decreases low-density lipoprotein and triglyceride synthesis, and inhibits vascular smooth muscle proliferation. Canonical Wnt also inhibits noncanonical protein kinase C, Ras homolog gene family member A, and Rho associated coiled-coil containing protein kinase 2 activation, thus inhibiting steatohepatitis and transforming growth factor ß-mediated extracellular matrix deposition and hepatic fibrosis. Therefore, dysregulation of the highly conserved Wnt signaling pathway underlies the pleiotropy of metabolic traits of the metabolic syndrome and the subsequent end-organ complications.

Wnt signaling, a novel pathway regulating blood pressure? State of the art review.

Recent antihypertensive trials show conflicting results on blood pressure (BP) targets in patient populations with different metabolic profiles, with lowest benefit from tight BP control observed in patients with type 2 diabetes mellitus. This paradox could arise from the heterogeneity of study populations and underscores the importance of precision medicine initiatives towards understanding and treating hypertension. Wnt signaling pathways and genetic variations in its signaling peptides have been recently associated with metabolic syndrome, hypertension and diabetes, generating a breakthrough for advancement of precision medicine in the field of hypertension. We performed a review of PubMed for publications addressing the contributions of Wnt to BP regulation and hypertension. In addition, we performed a manual search of the reference lists for relevant articles, and included unpublished observations from our laboratory. There is emerging evidence for Wnt's role in BP regulation and its involvement in the pathogenesis of hypertension. Wnt signaling has pleiotropic effects on distinct pathways that involve vascular smooth muscle plasticity, and cardiac, renal, and neural physiology. Hypertension is a heterogeneous disease with unique molecular pathways regulating its response to therapy. Recognition of these pathways is a prerequisite to identify novel targets for drug development and personalizing medicine. A review of Wnt signaling reveals its emerging role in BP regulation and as a target for novel drug development that has the potential to transform the therapy of hypertension in specific populations.

Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults.

BACKGROUND: With the advent of high throughput sequencing, the identification of genetic causes of cardiovascular disease (CVD) has become an integral part of medical diagnosis and management and at the forefront of personalized medicine in this field. The use of whole exome sequencing for clinical diagnosis, risk stratification, and management of inherited CVD has not been previously evaluated. METHODS AND RESULTS: We analyzed the results of whole exome sequencing in first 200 adult patients with inherited CVD, who underwent genetic testing at the Yale Program for Cardiovascular Genetics. Genetic diagnosis was reached and reported with a success rate of 26.5% (53 of 200 patients). This compares to 18% (36 of 200) that would have been diagnosed using commercially available genetic panels (P=0.04). Whole exome sequencing was particularly useful for clinical diagnosis in patients with aborted sudden cardiac death, in whom the primary insult for the presence of both depressed cardiac function and prolonged QT had remained unknown. The analysis of the remaining cases using genome annotation and disease segregation led to the discovery of novel candidate genes in another 14% of the cases. CONCLUSIONS: Whole exome sequencing is an exceptionally valuable screening tool for its capability to establish the clinical diagnosis of inherited CVDs, particularly for poorly defined cases of sudden cardiac death. By presenting novel candidate genes and their potential disease associations, we also provide evidence for the use of this genetic tool for the identification of novel CVD genes. Creation and sharing of exome databases across centers of care should facilitate the discovery of unknown CVD genes.

Rare mutation in the SLC26A3 transporter causes life-long diarrhoea with metabolic alkalosis.

SLC26A3, a chloride/bicarbonate transporter mainly expressed in the intestines, plays a pivotal role in chloride absorption. We present a 23-year-old woman with a history of congenital chloride diarrhoea (CCD) and renal transplant who was admitted for rehydration and treatment of acute kidney injury after she presented with an acute diarrhoeal episode. Laboratory investigations confirmed metabolic alkalosis and severe hypochloraemia, consistent with her underlying CCD. This contrasts with most other forms of diarrhoea, which are normally associated with metabolic acidosis. Genetic testing was offered and revealed a homozygous non-sense mutation in SLC26A3 (Gly-187-Stop). This loss-of-function mutation results in bicarbonate retention in the blood and chloride loss into the intestinal lumen. Symptomatic management with daily NaCl and KCl oral syrups was supplemented with omeprazole therapy. The loss of her own kidneys is most likely due to crystal-induced nephropathy secondary to chronic volume contraction and chloride depletion. This case summarises the pathophysiology and management of CCD.

Prevalence of the apolipoprotein E Arg145Cys dyslipidemia at-risk polymorphism in African-derived populations.

Apolipoprotein E, a protein component of blood lipid particles, plays an important role in lipid transport. Different mutations in the apolipoprotein E gene have been associated with various clinical phenotypes. In an initiated study of Qataris, we observed that 17% of the African-derived genetic subgroup were heterozygotes for a rare Arg145Cys (R145C) variant that functions as a dominant trait with incomplete penetrance associated with type III hyperlipoproteinemia. On the basis of this observation, we hypothesized that the R145C polymorphism might be common in African-derived populations. The prevalence of the R145C variant was assessed worldwide in the "1000 Genomes Project" and in 1,012 whites and 1,226 African-Americans in New York, New York. The 1000 Genomes Project data demonstrated that the R145C polymorphism is rare in non-African-derived populations but present in 5% to 12% of Sub-Saharan African-derived populations. The R145C polymorphism was also rare in New York whites (1 of 1,012, 0.1%); however, strikingly, 53 of the 1,226 New York African-Americans (4.3%) were R145C heterozygotes. The lipid profiles of the Qatari and New York R145C heterozygotes were compared with those of controls. The Qatari R145C subjects had higher triglyceride levels than the Qatari controls (p <0.007) and the New York African-American R145C subjects had an average of 52% greater fasting triglyceride levels than the New York African-American controls (p <0.002). From these observations, likely millions of people worldwide derived from Sub-Saharan Africans are apolipoprotein E R145C. In conclusion, although larger epidemiologic studies are necessary to determine the long-term consequences of this polymorphism, the available evidence suggests it is a common cause of a mild triglyceride dyslipidemia.