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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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
This study also identified the cardiac myocyte as a significant local source of BDNF, as cardiac myocyte-specific deletion of BDNF induced a similar cardiomyopathy phenotype. While these results do not exclude a role for other neurotrophins, particularly in injury states, they point to the requirement for continued, local synthesis of BDNF to maintain optimal cardiac function. A major, unresolved question relates to how the truncated TrkB isoform (TrkBT1) transduces the inotropic effects of BDNF, which will require additional study. A concurrent study evaluated the potential impact of the BDNF-mediated activation of the k...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
In conclusion, FGF21 belongs to a promising class of cytokines that are induced in response to stress and that can be used as a drug, drug target, or through a biomarker, depending on the physio-pathological context. All these findings will become clear when FGF21 will be used as a therapeutic molecule, exploiting the beneficial effects of FGF21 for treating metabolic disease or when it will be blocked to ameliorate disease progression and the onset of disease. Author Contributions CT and MS wrote the manuscript. VR contributed to the discussion. Funding This work was supported from the AFM-Telethon (19524), Italian Mi...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
This study was carried out in accordance with the recommendations of “Guide for the Care and Use of Laboratory Animals, National Institutes of Health.” The protocol was approved by the “China Pharmaceutical University.” Surgical Preparation The mice were anesthetized with chloral hydrate (4% chloral hydrate, ip). The HF model was induced by CAL as previously reported (Gao et al., 2010). Successful ligation of the coronary artery was confirmed by the occurrence of ST-segment elevation in electrocardiogram. Sham operated mice were performed the same process except left CAL. After ligation, the heart...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
In conclusion, long-term aerobic exercise appears to attenuate the decline in endothelial vascular function, a benefit which is maintained during chronological aging. However, currently there is not enough evidence to suggest that exercise interventions improve vascular function in previously sedentary healthy older adults. Hijacking the Proteasome to Dispose of Unwanted Molecules in Age-Related Disease https://www.fightaging.org/archives/2019/03/hijacking-the-proteasome-to-dispose-of-unwanted-molecules-in-age-related-disease/ Cells are equipped with a protein disposal system in the form of the proteaso...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
AbstractPurpose of ReviewDue to advancements in oncologic treatment strategies and techniques, the number of survivors who have undergone hematopoetic stem cell transplant (HCT) continues to increase in the United States; this number is projected to reach 502,000 by the year 2030. There is significant interest within the field of cardio-oncology to identify cardiotoxicity and cardiovascular disease in the HCT population. Epidemiologic studies analyzing both short- and long-term cardiovascular effects, risk stratification modeling, cardioprotective strategies, and expert consensus documents for cardiotoxicity surveillance r...
Source: Current Oncology Reports - Category: Cancer & Oncology Source Type: research
CONCLUSIONS: Notably, observed gene expression characteristics specific to hiPSC-CMs might be relevant regarding further investigations of the response to external stressors like radiation. The genes and biological processes highlighted in our study present promising starting points for functional follow-up studies for which hiPSC-CMs could pose an appropriate cell model when cell type specific peculiarities are taken into account. PMID: 30247079 [PubMed - as supplied by publisher]
Source: International Journal of Radiation Biology - Category: Radiology Tags: Int J Radiat Biol Source Type: research
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