Loss-of-Function Variants in the SYNPO2L Gene Are Associated With Atrial Fibrillation

Clausen, Alexander Guldmann; Vad, Oliver Bundgaard; Andersen, John Rastrup; Olesen, Morten S.

doi:10.3389/fcvm.2021.650667

Cited by 20 publications

(12 citation statements)

References 29 publications

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“…In addition, 10 of the 43 upregulated proteins (20.9%) were proteins that were accessories and regulators for myocardial contractile apparatuses including Smyd1 ( Tan et al, 2006. ), Synpo2l ( Clausen et al, 2021 ), Mtpn ( Sen et al, 1990 ), Csrp3 ( Walsh et al, 2022 ), Unc45b ( Myhre et al, 2014 ), Sox5 ( Smits et al, 2001 ), Abra ( Wallace et al, 2012 ), Mylk3 ( Seguchi et al, 2007 ), Hspb2 ( Sugiyama et al, 2000 ), and Lmod1 ( Nworu et al, 2015 ). These findings indicate that proteins with increased expression that are associated with myofibrillogenesis are highly enriched in the heart primordium after heartbeat initiation compared with those in the heart primordium before heartbeat initiation.…”

Section: Resultsmentioning

confidence: 99%

Ultrastructural Assessment and Proteomic Analysis in Myofibrillogenesis in the Heart Primordium After Heartbeat Initiation in Rats

et al. 2022

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Myofibrillogenesis is an essential process for cardiogenesis and is closely related to excitation-contraction coupling and the maintenance of heartbeat. It remains unclear whether the formation of myofibrils and sarcomeres is associated with heartbeat initiation in the early embryonic heart development. Here, we investigated the association between the ultrastructure of myofibrils assessed by transmission electron microscopy and their proteomic profiling assessed by data-independent acquisition mass spectrometry (DIA-MS) in the rat heart primordia before and after heartbeat initiation at embryonic day 10.0, when heartbeat begins in rats, and in the primitive heart tube at embryonic day 11.0. Bundles of myofilaments were scattered in a few cells of the heart primordium after heartbeat initiation, whereas there were no typical sarcomeres in the heart primordia both before and after heartbeat initiation. Sarcomeres with Z-lines were identified in cells of the primitive heart tube, though myofilaments were not aligned. DIA-MS proteome analysis revealed that only 43 proteins were significantly upregulated by more than 2.0 fold among a total of 7,762 detected proteins in the heart primordium after heartbeat initiation compared with that before heartbeat initiation. Indeed, of those upregulated proteins, 12 (27.9%) were constituent proteins of myofibrils and 10 (23.3%) were proteins that were accessories and regulators for myofibrillogenesis, suggesting that upregulated proteins that are associated with heartbeat initiation were enriched in myofibrillogenesis. Collectively, our results suggest that the establishment of heartbeat is induced by development of bundles of myofilaments with upregulated proteins associated with myofibrillogensis, whereas sarcomeres are not required for the initial heartbeat.

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Section: Resultsmentioning

confidence: 99%

Ultrastructural Assessment and Proteomic Analysis in Myofibrillogenesis in the Heart Primordium After Heartbeat Initiation in Rats

et al. 2022

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“…These 28 genes include Synpo2l , Abhd16a , Ece1 , Shroom3 ( Fig 2B ), and Rbfox2 all of which are implicated in cardiovascular disorders including hypertension in humans ( Yasuda et al, 2007 ; Nutter et al, 2016 ; Xu et al, 2018 ; Durbin et al, 2020 ; Clausen et al, 2021 ). Loss of function (LoF) mutations in human SHROOM3 and SYNOP2L genes have been shown to be associated with congenital heart defects ( Durbin et al, 2020 ) and arterial fibrillation ( Clausen et al, 2021 ), respectively. Dysregulation of RBFOX2 has been shown to be an early event in cardiac pathogenesis of diabetes in human ( Nutter et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

Cap analysis of gene expression reveals alternative promoter usage in a rat model of hypertension

et al. 2022

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The role of alternative promoter usage in tissue-specific gene expression has been well established; however, its role in complex diseases is poorly understood. We performed cap analysis of gene expression (CAGE) sequencing from the left ventricle of a rat model of hypertension, the spontaneously hypertensive rat (SHR), and a normotensive strain, Brown Norway to understand the role of alternative promoter usage in complex disease. We identified 26,560 CAGE-defined transcription start sites in the rat left ventricle, including 1,970 novel cardiac transcription start sites. We identified 28 genes with alternative promoter usage between SHR and Brown Norway, which could lead to protein isoforms differing at the amino terminus between two strains and 475 promoter switching events altering the length of the 5′ UTR. We found that the shift in Insr promoter usage was significantly associated with insulin levels and blood pressure within a panel of HXB/BXH recombinant inbred rat strains, suggesting that hyperinsulinemia due to insulin resistance might lead to hypertension in SHR. Our study provides a preliminary evidence of alternative promoter usage in complex diseases.

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“…SYNPO2L is an acting binding protein. ( 42 ) Loss‐of‐function mutations in SYNPO2L have been associated with atrial fibrillation, ( 43 ) but a relation to bone has not been documented. GSX2 has been implicated to be involved in the Notch signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing in Two Southeast Asian Families With Atypical Femur Fractures

et al. 2022

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Atypical femur fractures (AFFs) are rare complications of anti‐resorptive therapy. Devastating to the affected individual, they pose a public health concern because of reduced uptake of an effective treatment for osteoporosis due to patient concern. The risk of AFF is increased sixfold to sevenfold in patients of Asian ethnicity compared with Europeans. Genetic factors may underlie the AFF phenotype. Given the rarity of AFFs, studying familial AFF cases is valuable in providing insights into any genetic predisposition. We present two Singaporean families, one comprising a mother (1‐a) and a daughter (1‐b), and the other comprising two sisters (2‐a and 2‐b). All four cases presented with bisphosphonate‐associated AFF. Whole‐exome sequencing (WES) was performed on 1‐b, 2‐a, and 2‐b. DNA for 1‐a was not available. Variants were examined using a candidate gene approach comprising a list of genes previously associated with AFF in the literature, as well as using unbiased filtering based on dominant and/or recessive inheritance patterns. Using a candidate gene approach, rare variants shared between all three cases were not identified. A rare variant in TMEM25, shared by the two sisters (2‐a and 2‐b), was identified. A rare heterozygous PLOD2 variant was present in the daughter case with AFF (1‐b), but not in the sisters. A list of potential genetic variants for AFF was identified after variant filtering and annotation analysis of the two sisters (2‐a and 2‐b), including a Gly35Arg variant in TRAF4, a gene required for normal skeletal development. Although the findings from this genetic analysis are inconclusive, a familial aggregation of AFFs is suggestive of a genetic component in AFF pathogenesis. We provide a comprehensive list of rare variants identified in these AFF familial cases to aid future genetic studies. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Loss-of-Function Variants in the SYNPO2L Gene Are Associated With Atrial Fibrillation

Cited by 20 publications

References 29 publications

Ultrastructural Assessment and Proteomic Analysis in Myofibrillogenesis in the Heart Primordium After Heartbeat Initiation in Rats

Ultrastructural Assessment and Proteomic Analysis in Myofibrillogenesis in the Heart Primordium After Heartbeat Initiation in Rats

Cap analysis of gene expression reveals alternative promoter usage in a rat model of hypertension

Whole Exome Sequencing in Two Southeast Asian Families With Atypical Femur Fractures

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