Overexpression of Perilipin 2 Induces Cardiac Steatosis and Atrial Fibrillation via Connexin 43 Remodeling

Sato, Satsuki; Suzuki, Jinya; Hirose, Masao; Nakaya, Takahiro; Yamada, Mika; Ichikawa, Mai; Imagawa, Michiko; Zenimaru, Yasuo; Takahashi, Sadao; Kraemer, Fredric B.; Konoshita, Tadashi; Ishizuka, Tamotsu

doi:10.2337/db18-1903-p

Cited by 3 publications

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“…Using their own method, Fukui and others demonstrated that hyperleptinemia increased AF susceptibility in mice maintained on a high-fat diet (Fukui et al, 2017). Another study reported that perilipin 2 (Plin2) overexpression increased sustained AF in mice due to atrial steatosis (Sato et al, 2019). While these authors defined sustained AF as an episode lasting longer than 5 min, other definitions have been more commonly used, including 10 s (Aschar-Sobbi et al, 2015), 15 s (Bruegmann et al, 2018), and 30 s (Jansen et al, 2017;Jansen et al, 2019).…”

Section: Examples Of Usementioning

confidence: 99%

Overview of programmed electrical stimulation to assess atrial fibrillation susceptibility in mice

2023

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Atrial fibrillation (AF) is the most common human arrhythmia and is associated with increased risk of stroke, dementia, heart failure, and death. Among several animal models that have been used to investigate the molecular determinants of AF, mouse models have become the most prevalent due to low cost, ease of genetic manipulation, and similarity to human disease. Programmed electrical stimulation (PES) using intracardiac or transesophageal atrial pacing is used to induce AF as most mouse models do not develop spontaneous AF. However, there is a lack of standardized methodology resulting in numerous PES protocols in the literature that differ with respect to multiple parameters, including pacing protocol and duration, stimulus amplitude, pulse width, and even the definition of AF. Given this complexity, the selection of the appropriate atrial pacing protocol for a specific model has been arbitrary. Herein we review the development of intracardiac and transesophageal PES, including commonly used protocols, selected experimental models, and advantages and disadvantages of both techniques. We also emphasize detection of artifactual AF induction due to unintended parasympathetic stimulation, which should be excluded from results. We recommend that the optimal pacing protocol to elicit an AF phenotype should be individualized to the specific model of genetic or acquired risk factors, with an analysis using several definitions of AF as an endpoint.

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Section: Examples Of Usementioning

confidence: 99%

Overview of programmed electrical stimulation to assess atrial fibrillation susceptibility in mice

2023

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Unsupervised clustering of missense variants in the HNF1A gene using multidimensional functional data aids clinical interpretation

Althari

Najmi

Bennett

et al. 2019

Preprint

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Background: Exome sequencing in diabetes presents a diagnostic challenge as depending on frequency, functional impact and genomic and environmental contexts, HNF1A variants can cause Maturity-onset Diabetes of the Young (MODY), increase type 2 diabetes risk, or be benign. A correct diagnosis matters as it informs on treatment, progression, and family risk. We describe a multi-dimensional functional dataset of 73 HNF1A missense variants identified in exomes of 12,940 individuals. Our aim was to develop an analytical framework for stratifying variants along the HNF1A phenotypic continuum to facilitate diagnostic interpretation. Methods: HNF1A variant function was determined by 4 different molecular assays. Structure of the multi-dimensional dataset was explored using principal component analysis, k-means, and hierarchical clustering. Weights for tissue-specific isoform expression and functional domain were integrated. Functionally annotated variant subgroups were used to re-evaluate genetic diagnoses in national MODY diagnostic registries. Findings: HNF1A variants demonstrated a range of behaviours across the assays. The structure of the multi-parametric data was shaped primarily by transactivation. Using unsupervised learning methods, we obtained high-resolution functional clusters of the variants which separated known causal MODY variants from benign and type 2 diabetes risk variants and led to reclassification of 4% and 9% of HNF1A variants identified in the UK and Norway MODY diagnostic registries, respectively. Interpretation: Our proof-of-principle analyses facilitated informative stratification of HNF1A variants along the continuum, allowing improved evaluation of clinical significance, management and precision medicine in diabetes clinics. Transcriptional activity appears a superior readout supporting pursuit of transactivation-centric experimental designs for high-throughput functional screens.

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The penetrance of age-related monogenic disease depends on ascertainment context

Mirshahi

Colclough

Wright

et al. 2021

Preprint

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BACKGROUND: Accurate penetrance of monogenic disorders is often unknown due to a phenotype-first approach to genetic testing. Here, we use a genotype-first approach in four large cohorts with different ascertainment contexts to accurately estimate penetrance of the three commonest causes of monogenic diabetes, Maturity Onset Diabetes of the Young (MODY). We contrast HNF1A-MODY / HNF4A-MODY which causes an age-related progressive diabetes and GCK-MODY, which causes life-long mild hyperglycaemia. METHODS: We analysed clinical and genetic sequencing data from four different cohorts: 1742 probands referred for clinical MODY testing; 2194 family members of the MODY probands; 132,194 individuals from an American hospital-based cohort; and 198,748 individuals from a UK population-based cohort. RESULTS: Age-related penetrance of diabetes for pathogenic variants in HNF1A and HNF4A was substantially lower in the clinically unselected cohorts compared to clinically referred probands (ranging from 32% to 98% at age 40yrs for HNF1A, and 21% to 99% for HNF4A). The background rate of diabetes, but not clinical features or variant type, explained the reduced penetrance in the unselected cohorts. In contrast, penetrance of mild hyperglycaemia for pathogenic GCK variants was similarly high across cohorts (ranging from 89 to 97%) despite substantial variation in the background rates of diabetes. CONCLUSIONS: Ascertainment context is crucial when interpreting the consequences of monogenic variants for age-related variably penetrant disorders. This finding has important implications for opportunistic screening during genomic testing.

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Overexpression of Perilipin 2 Induces Cardiac Steatosis and Atrial Fibrillation via Connexin 43 Remodeling

Cited by 3 publications

References 0 publications

Overview of programmed electrical stimulation to assess atrial fibrillation susceptibility in mice

Overview of programmed electrical stimulation to assess atrial fibrillation susceptibility in mice

Unsupervised clustering of missense variants in the HNF1A gene using multidimensional functional data aids clinical interpretation

The penetrance of age-related monogenic disease depends on ascertainment context

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