Oligogenic inheritance of a human heart disease involving a genetic modifier

Complex genetic mechanisms are thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human cardiac anomaly can be caused by a combination of rare, inherited heterozygous mutations. Whole-exome sequencing of a nuclear family revealed that three offspring with childhood-onset cardiomyopathy had inherited three missense single-nucleotide variants in the MKL2, MYH7, and NKX2-5 genes. The MYH7 and MKL2 variants were inherited from the affected, asymptomatic father and the rare NKX2-5 variant (minor allele frequency, 0.0012) from the unaffected mother. We used CRISPR-Cas9 to generate mice encoding the orthologous variants and found that compound heterozygosity for all three variants recapitulated the human disease phenotype. Analysis of murine hearts and human induced pluripotent stem cell–derived cardiomyocytes provided histologic and molecular evidence for the NKX2-5 variant’s contribution as a genetic modifier.
Source: ScienceNOW - Category: Science Authors: Tags: Genetics, Medicine, Diseases r-articles Source Type: news

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Contributors : Elisa Giacomelli ; Viviana Meraviglia ; Giulia Campostrini ; Amy Cochrane ; Xu Cao ; Ruben van Helden ; Ana Krotenberg Garcia ; Maria Mircea ; Sarantos Kostidis ; Richard P Davis ; Berend J van Meer ; Carolina R Jost ; Abraham J Koster ; Hailiang Mei ; David G M íguez ; Aat A Mulder ; Mario Ledesma-Terrón ; Giulio Pompilio ; Luca Sala ; Daniela Salvatori ; Roderick Slieker ; Elena Sommariva ; Antoine de Vries ; Martin Giera ; Stefan Semrau ; Leon Tertoolen ; Valeria V Orlova ; Milena Bellin ; Christine L MummerySeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapi...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research
Contributors : Elisa Giacomelli ; Viviana Meraviglia ; Giulia Campostrini ; Amy Cochrane ; Xu Cao ; Ruben van Helden ; Ana Krotenberg Garcia ; Maria Mircea ; Sarantos Kostidis ; Richard P Davis ; Berend J van Meer ; Carolina R Jost ; Abraham J Koster ; Hailiang Mei ; David G M íguez ; Aat A Mulder ; Mario Ledesma-Terrón ; Giulio Pompilio ; Luca Sala ; Daniela Salvatori ; Roderick Slieker ; Elena Sommariva ; Antoine de Vries ; Martin Giera ; Stefan Semrau ; Leon Tertoolen ; Valeria V Orlova ; Milena Bellin ; Christine L MummerySeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapi...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research
CF, Slieker RC, Sommariva E, de Vries AAF, Giera M, Semrau S, Tertoolen LGJ, Orlova VV, Bellin M, Mummery CL Abstract Cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) are functionally immature, but this is improved by incorporation into engineered tissues or forced contraction. Here, we showed that tri-cellular combinations of hiPSC-derived CMs, cardiac fibroblasts (CFs), and cardiac endothelial cells also enhance maturation in easily constructed, scaffold-free, three-dimensional microtissues (MTs). hiPSC-CMs in MTs with CFs showed improved sarcomeric structures with T-tubules, enhanced cont...
Source: Cell Stem Cell - Category: Stem Cells Authors: Tags: Cell Stem Cell Source Type: research
We report a new class of natural-product-inspired covalent inhibitors of telomerase that target the catalytic active site. Age-Related Epigenetic Changes that Suppress Mitochondrial Function https://www.fightaging.org/archives/2020/03/age-related-epigenetic-changes-that-suppress-mitochondrial-function/ Today's open access research reports on two specific epigenetic changes observed in old individuals that act to reduce mitochondrial function. This joins an existing list of genes for which expression changes are known to impact mitochondrial function with age. A herd of hundreds of mitochondria are found ...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
In this study, we hypothesized that moderately and chronically reducing ACh could attenuate the deleterious effects of aging on NMJs and skeletal muscles. To test this hypothesis, we analyzed NMJs and muscle fibers from heterozygous transgenic mice with reduced expression of the vesicular ACh transporter (VAChT), VKDHet mice, which present with approximately 30% less synaptic ACh compared to control mice. Because ACh is constitutively decreased in VKDHet, we first analyzed developing NMJs and muscle fibers. We found no obvious morphological or molecular differences between NMJs and muscle fibers of VKDHet and contro...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Today's open access research is an interesting demonstration of the importance of chronic inflammation in aging. Researchers generate a mouse lineage in which the NLRP3 gene is deleted, and show that these mice live significantly longer, and in better health, as a result. The protein produced from the NLRP3 gene is important in the innate immune response; it is a component part of one of the inflammasomes, protein complexes with a central role in regulation of the inflammatory response. NLRP3 appears important in the inflammatory signaling generated by senescent cells as well. Inflammation is a necessary part of wou...
Source: Fight Aging! - Category: Research Authors: Tags: Medicine, Biotech, Research Source Type: blogs
ConclusionsIn this phase 1 trial, direct intramyocardial injection of autologous BMSCs in conjunction with TMR or CABG was technically feasible and could be performed safely. Preliminary results demonstrate improved cardiac function and quality of life in patients at one year after treatment.
Source: The Annals of Thoracic Surgery - Category: Cardiovascular & Thoracic Surgery Source Type: research
CONCLUSIONS: In this phase 1 trial, direct intramyocardial injection of autologous BMSCs in conjunction with TMR or CABG was technically feasible and could be performed safely. Preliminary results demonstrate improved cardiac function and quality of life in patients at one year after treatment. PMID: 31526779 [PubMed - as supplied by publisher]
Source: The Annals of Thoracic Surgery - Category: Cardiovascular & Thoracic Surgery Authors: Tags: Ann Thorac Surg Source Type: research
In conclusion, with study of the frailty syndrome still in its infancy, frailty analysis remains a major challenge. It is a challenge that needs to be overcome in order to shed light on the multiple mechanisms involved in the pathogenesis of this syndrome. Although several mechanisms contribute to frailty, immune system alteration seems to play a central role: this syndrome is characterized by increased levels of pro-inflammatory markers and the resulting pro-inflammatory status can have negative effects on various organs. Future studies should aim to better clarify the immune system alteration in frailty, and seek to esta...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
The innate immune cells called macrophages are vitally important to the health and function of tissues. They help to coordinate the intricate dance of stem cells, somatic cells, and immune cells that produces tissue regrowth and tissue maintenance. They destroy errant cells and pathogens. They have a variety of other roles as well. But where do macrophages come from? While some macrophages are generated within tissues, it is generally the case that in damaged or diseased tissues, most macrophages were originally monocytes. Circulating monocytes in the bloodstream enter tissues in response to chemical cues and then transfor...
Source: Fight Aging! - Category: Research Authors: Tags: Medicine, Biotech, Research Source Type: blogs
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