Whole-Exome Sequencing and hiPSC Cardiomyocyte Models Identify MYRIP, TRAPPC11, and SLC27A6 of Potential Importance to Left Ventricular Hypertrophy in an African Ancestry Population

Irvin, Marguerite R.; Aggarwal, Praful; Claas, Steven A.; Fuentes, Lisa de las; N., Anh; Gu, C. Charles; Matter, Andrea; Olson, Benjamin; Patki, Amit; Schwander, Karen; Smith, Joshua D.; Srinivasasainagendra, Vinodh; Tiwari, Hemant K.; Turner, Amy; Nickerson, Deborah A.; Rao, D. C.; Broeckel, Ulrich; Arnett, Donna K.

doi:10.3389/fgene.2021.588452

Cited by 5 publications

(6 citation statements)

References 70 publications

(81 reference statements)

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“…Other genes of interest in the HCM network included SLC27A6 which encodes fatty acid transport protein 6 (FATP6), the primary FATP in the heart. [21] FATPs enable cellular uptake of fatty acid, with fatty acid oxidation being the dominant source of ATP in healthy adult hearts, while classic pathologic transcription remodeling via the “fetal gene program” entails a switch to other substrates. [21] SLC27A6 was previously identified in an exome-wide association study for association with left ventricular internal diastolic dimension in the Hypertension Genetic Epidemiology Network of paired siblings with and without hypertension.…”

Section: Resultsmentioning

confidence: 99%

Personalized transcriptome signatures in a cardiomyopathy stem cell biobank

Monte,

Furihata,

Wang

et al. 2024

Preprint

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BACKGROUND: There is growing evidence that pathogenic mutations do not fully explain hypertrophic (HCM) or dilated (DCM) cardiomyopathy phenotypes. We hypothesized that if genetic background was influencing cardiomyopathy this should be detectable as signatures in gene expression. We built a cardiomyopathy biobank resource for interrogating personalized genotype phenotype relationships in human cell lines. METHODS: We recruited 308 diseased and control patients for our cardiomyopathy stem cell biobank. We successfully reprogrammed PBMCs (peripheral blood mononuclear cells) into induced pluripotent stem cells (iPSCs) for 300 donors. These iPSCs underwent whole genome sequencing and were differentiated into cardiomyocytes for RNA-seq. In addition to annotating pathogenic variants, mutation burden in a panel of cardiomyopathy genes was assessed for correlation with echocardiogram measurements. Line-specific co-expression networks were inferred to evaluate transcriptomic subtypes. Drug treatment targeted the sarcomere, either by activation with omecamtiv mecarbil or inhibition with mavacamten, to alter contractility. RESULTS: We generated an iPSC biobank from 300 donors, which included 101 individuals with HCM and 88 with DCM. Whole genome sequencing of 299 iPSC lines identified 78 unique pathogenic or likely pathogenic mutations in the diseased lines. Notably, only DCM lines lacking a known pathogenic or likely pathogenic mutation replicated a finding in the literature for greater nonsynonymous SNV mutation burden in 102 cardiomyopathy genes to correlate with lower left ventricular ejection fraction in DCM. We analyzed RNA-sequencing data from iPSC-derived cardiomyocytes for 102 donors. Inferred personalized co-expression networks revealed two transcriptional subtypes of HCM. The first subtype exhibited concerted activation of the co-expression network, with the degree of activation reflective of the disease severity of the donor. In contrast, the second HCM subtype and the entire DCM cohort exhibited partial activation of the respective disease network, with the strength of specific gene by gene relationships dependent on the iPSC-derived cardiomyocyte line. ADCY5 was the largest hubnode in both the HCM and DCM networks and partially corrected in response to drug treatment. CONCLUSIONS: We have a established a stem cell biobank for studying cardiomyopathy. Our analysis supports the hypothesis the genetic background influences pathologic gene expression programs and support a role for ADCY5 in cardiomyopathy.

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Section: Resultsmentioning

confidence: 99%

Personalized transcriptome signatures in a cardiomyopathy stem cell biobank

Monte,

Furihata,

Wang

et al. 2024

Preprint

View full text Add to dashboard Cite

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“… 31 Ingenuity pathway analysis of mRNA from TRAPPC11 knockdown model predicted deceases in RyR2 and NCX. 4 A TRAPPC11 variant have been associated with small-vessel ischemic stroke. 14 Numerous recessive variants have been identified limb girdle muscular dystrophy, movement disorder, and intellectual disability.…”

Section: Structure and Function Of Trappc Subunitsmentioning

confidence: 99%

“…Ingenuity pathway analysis using hiPSC-CM messenger RNA of this knockdown suggested downregulation of cardiac beta-adrenergic signaling and significant decreases in RYR2 and SLC8A1 , a member of NCX (Na + /Ca 2+ exchanger) that, when combined with protein transport changes, affects Ca 2+ handling. 4 …”

Section: Structure and Function Of Trappc Subunitsmentioning

confidence: 99%

“…TRAPPII and TRAPPIII are guanine nucleotide exchange factors (GEFs) for Rab11 and Rab1, respectively, and therefore may play an understudied role in modulating the cardiac action potential, 2 although direct studies exploring the relationship between cardiac ion channels and TRAPP have not been conducted. 3 , 4 Human variants in trafficking regulatory genes cause cardiac dysfunction. For instance, a variant in a trafficking regulatory protein for the voltage-gated sodium channel Na v 1.5 was shown to cause Brugada syndrome.…”

mentioning

confidence: 99%

“… 12 , 13 However, TRAPPC subunit variants and/or changes in expression have also been recently associated with structural cardiac diseases such as small-vessel stroke, cardiomyocyte apoptosis, heart looping/atrium placement, and coronary artery disease, and electrical cardiac dysfunction such as atrial fibrillation and Ca 2+ handling defects. 4 , 14 , 15 , 16 , 17 , 18 , 19 , 20 …”

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confidence: 99%

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