April 20, 2017 Back row, l. to r.: Feng Zhao, Adam Richman, Junyi Zhu and Yiming Ma. Front row, l. to r.: Yulong Fu; Zhe Han, Ph.D., principal investigator and associate professor in the Center for Cancer & Immunology Research at Children's National Health System, and senior study author; Simone Kirkland; and Wen Huang. Credit: Children's National Health System <\/p>\n
An off-the-shelf dietary supplement available for pennies per dose demonstrated the ability to reverse cellular damage linked to specific genetic mutations in transgenic fruit flies, an experimental model of genetic mutation-induced renal cell injury that features striking similarities to humans, a Children's National Health System research team reports April 20 in Journal of the American Society of Nephrology. <\/p>\n
\"Transgenic Drosophila that carry mutations in this critical pathway are a clinically relevant model to shed light on the genetic mutations that underlie severe kidney disease in humans, and they could be instrumental for testing novel therapies for rare diseases, such as focal segmental glomerulosclerosis (FSGS), that currently lack treatment options,\" says Zhe Han, Ph.D., principal investigator and associate professor in the Center for Cancer & Immunology Research at Children's National and senior study author. <\/p>\n
Nephrotic syndrome (NS) is a cluster of symptoms that signal kidney damage, including excess protein in the urine, low protein levels in blood, swelling and elevated cholesterol. The version of NS that is resistant to steroids is a major cause of end stage renal disease. Of more than 40 genes that cause genetic kidney disease, the research team concentrated on mutations in genes involved in the biosynthesis of Coenzyme Q10 (CoQ10), an important antioxidant that protects the cell against damage from reactive oxygen. <\/p>\n
\"This represents a benchmark for precision medicine,\" Han adds. \"Our gene-replacement approach silenced the fly homolog in the tissue of interest - here, the kidney cells - and provided a human gene to supply the silenced function. When we use a human gene carrying a mutation from a patient for this assay, we can discover precisely how a specific mutation - in many cases only a single amino acid change - might lead to severe disease. We can then use this personalized fly model, carrying a patient-derived mutation, to perform drug testing and screening to find and test potential treatments. This is how I envision using the fruit fly to facilitate precision medicine.\" <\/p>\n
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Drosophila pericardial nephrocytes perform renal cell functions including filtering of hemolymph (the fly's version of blood), recycling of low molecular weight proteins and sequestration of filtered toxins. Nephrocytes closely resemble, in structure and function, the podocytes of the human kidney. The research team tailor-made a Drosophila model to perform the first systematic in vivo study to assess the roles of CoQ10 pathway genes in renal cell health and kidney function. <\/p>\n
One by one, they silenced the function of all CoQ genes in nephrocytes. As any individual gene's function was silenced, fruit flies died prematurely. But silencing three specific genes in the pathway associated with NS in humans - Coq2, Coq6 and Coq8 - resulted in abnormal localization of slit diaphragm structures, the most important of the kidney's three filtration layers; collapse of membrane channel networks surrounding the cell; and increased numbers of abnormal mitochondria with deformed inner membrane structure. <\/p>\n
The flies also experienced a nearly three-fold increase in levels of reactive oxygen, which the study authors say is a sufficient degree of oxidative stress to cause cellular injury and to impair function - especially to the mitochondrial inner membrane. Cells rely on properly functioning mitochondria, the cell's powerhouse, to convert energy from food into a useful form. Impaired mitochondrial structure is linked to pathogenic kidney disease. <\/p>\n
The research team was able to \"rescue\" phenotypes caused by silencing the fly CoQ2 gene by providing nephrocytes with a normal human CoQ2 gene, as well as by providing flies with Q10, a readily available dietary supplement. Conversely, a mutant human CoQ2 gene from an patient with FSGS failed to rescue, providing evidence in support of that particular CoQ2 gene mutation causing the FSGS. The finding also indicated that the patient could benefit from Q10 supplementation. <\/p>\n
Explore further: Drosophila effectively models human genes responsible for genetic kidney diseases <\/p>\n
More information: A Personalized Model of COQ2 Nephropathy Rescued by the Wild-Type COQ2 Allele or Dietary Coenzyme Q10 Supplementation, Journal of the American Society of Nephrology (2017). DOI: 10.1681\/ASN.2016060626 , http:\/\/jasn.asnjournals.org\/content\/early\/2017\/04\/19\/ASN.2016060626.abstract<\/a><\/p>\n The majority of genes associated with nephrotic syndrome (NS) in humans also play pivotal roles in Drosophila renal function, a conservation of function across species that validates transgenic flies as ideal pre-clinical ... <\/p>\n A Children's National Health System research team has uncovered a novel process by which the gene APOL1 contributes to renal disease, according to a paper published November 18 in the Journal of the American Society of Nephrology. ... <\/p>\n African Americans have a heightened risk of developing chronic and end-stage kidney disease. This association has been attributed to two common genetic variants - named G1 and G2in APOL1, a gene that codes for a human-specific ... <\/p>\n Specific genetic errors that trigger congenital heart disease (CHD) in humans can be reproduced reliably in Drosophila melanogaster - the common fruit fly - an initial step toward personalized therapies for patients in the ... <\/p>\n An international team of scientists has discovered that the gene, OGDHL, a key protein required for normal function of the mitochondriathe energy-producing factory of the celland its chaperone, nardilysin (NRD1) are ... <\/p>\n A genetic 'switch' has been discovered by MRC researchers at the University of Leicester which could help to prevent or delay the symptoms of Parkinson's disease. <\/p>\n (Medical Xpress)An international team of researchers has developed a way to use RNA sequencing to help in diagnosing patients with rare genetic muscle conditions. In their paper published in the journal Science Translational ... <\/p>\n Research published this week in Scientific Reports uses computer image and statistical shape analysis to shed light on which parts of the face are most likely to be inherited. <\/p>\n Salk scientists and collaborators have shed light on a long-standing question about what leads to variation in stem cells by comparing induced pluripotent stem cells (iPSCs) derived from identical twins. Even iPSCs made from ... <\/p>\n In a study published today in PLoS ONE, a team of researchers reports solving a medical mystery in a day's work. In record-time detective work, the scientists narrowed down the genetic cause of intellectual disability in ... <\/p>\n After nearly 40 years of searching, Johns Hopkins researchers report they have identified a part of the human genome that appears to block an RNA responsible for keeping only a single X chromosome active when new female embryos ... <\/p>\n It's not so hard anymore to find genetic variations in patients, said Brown University genomics expert William Fairbrother, but it remains difficult to understand whether and how those mutations undermine health. <\/p>\n Please sign in to add a comment. Registration is free, and takes less than a minute. Read more <\/p>\n <\/p>\n Go here to read the rest: April 20, 2017 Back row, l. to r.: Feng Zhao, Adam Richman, Junyi Zhu and Yiming Ma Continue reading
\nSupplement can lessen kidney damage linked to genetic mutations in transgenic fruit flies - Medical Xpress<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"