Friday, September 30, 2022

Mutation in novel gene found responsible for severe liver disease in children

New findings have revealed how essential the FOCAD gene is to maintaining a healthy liver, especially in children. In a research study published in nature geneticsIn this study, scientists have found that children with loss-of-function mutations in FOCAD present with an early-onset, pediatric form of liver cirrhosis that can be life-threatening. The study was conducted by scientists from A*STAR’s Genome Institute of Singapore (GIS) in collaboration with hospitals and institutions in seven countries (India, the US, Saudi Arabia, Pakistan, Portugal, Brazil and France).

Liver disease is becoming a major health concern and is estimated to be the fifth most common cause of death worldwide[1], A systematic review of the Global Burden of Disease Study identified 1.32 million deaths due to liver cirrhosis in 2017, accounting for more than two percent of total global deaths. Liver cirrhosis is usually diagnosed late in life, and has traditionally been thought to be caused by environmental factors such as poor diet, viral hepatitis, or alcohol abuse.

In collaboration with clinicians from around the world, the team combined classical tools such as Mendelian genetics and animal models[2] With modern technology, such as deep sequencing and state-of-the-art gene editing tools, to identify which FOCAD gene is indispensable for maintaining liver health in humans. Mutations in this gene cause an early-onset form of liver cirrhosis that has not previously been documented. Findings of a single gene, or monogenic, disorder that leads to cirrhosis in childhood establish a strong genetic component to liver disease, which was previously unknown.

In further analysis, they found that FOCAD functions as part of a molecular quality control mechanism that aids in translation, a fundamental cellular process by which proteins are made. The main cells of the liver, hepatocytes, were found to be more dependent on this mechanism than other cell types. This is the first time that this translation-dependent quality control machinery has been implicated in liver health.

The team also discovered a cytokine[3], CCL2, which is overproduced in patients with FOCAD deficiency and may play an important role in the progression of liver cirrhosis. Dr. Ricardo Moreno Traspas, a postdoctoral fellow in the Laboratory of Human Genetics and Therapeutics in GIS, and first author of the study, explained, “The FOCAD mutation causes an overproduction of several proteins that may be important drivers in the progression of the disease.” One example is the signaling mediator, CCL2, which attracts immune cells and promotes liver inflammation. Drugs that target this, or similar candidates, are potential therapeutic intervention points for patients with cirrhosis.”

Professor Bruno Reversade, senior group leader in GIS and corresponding author of the study, commented, “We report the clinical implications of recessive loss-of-function variants in the FOCAD gene, and the importance of the SKI mRNA surveillance pathway. provide evidence. Liver homeostasis. Research brings to the fore the first animal models of human disease, as well in vitro Biological systems that are now being used as platforms to identify and validate new anti-fibrotic therapeutic targets.”

Prof Patrick Tan, Executive Director of GIS, said, “The knowledge and tools generated in this study have the potential to aid in the development of innovative therapies for more common forms of liver diseases such as fatty liver disease and liver cancer. Our clinical data will help clinicians to identify new patients with this syndrome, better understand the cellular and molecular mechanisms of the disease, and, therefore, provide more accurate diagnosis, prognosis and treatment.”

[1] Williams, R. (2006). Global challenges in liver disease. Hepatology, 44(3), 521-526. https://doi.org/10.1002/hep.21347

[2] Mendel’s experiments of crossing peas to determine whether certain traits are inherited because single genes are so fundamental that they are taught in high school. The enduring power of these theories lies in the fact that they allow us to link mutations in a specific gene to a significant human disease.

[3] A type of protein that is made by certain immune and non-immune cells and has an effect on the immune system.

Nation World News Desk
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