Mutations in a new gene responsible for severe liver disease in children

New findings have revealed how essential the FOCAD gene is for maintaining a healthy liver, especially in children. In a study published in Natural genetics, scientists have found that children with loss-of-function mutations in FOCAD are presented with an early pediatric form of liver cirrhosis that can be fatal. The study was carried out by scientists from A*STAR’s Genome Institute of Singapore (GIS), in collaboration with hospitals and institutes in seven countries (India, USA, Saudi Arabia, Pakistan, Portugal, Brazil and France).

Liver disease is becoming a major health problem and is estimated to be the fifth leading cause of death worldwide[1]. A systematic review of the Global Burden of Disease Study identified 1.32 million deaths from cirrhosis of the liver in 2017, representing more than 2% of the total number of deaths worldwide. Liver cirrhosis is usually diagnosed late in life and is traditionally thought to be caused by environmental factors such as poor diet, viral hepatitis, or alcohol abuse.

Working with clinicians 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 that the FOCAD gene is essential for maintaining liver health in humans. Mutations in this gene cause a previously undocumented early form of liver cirrhosis. The findings of a single gene, or monogenic disorder, that leads to cirrhosis in children establishes a strong genetic component of liver disease that was previously unknown.

In further analysis, they found that FOCAD operates 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, the hepatocytes, have been shown to be highly dependent on this mechanism compared to 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 FOCAD-deficient patients and may play a key role in the progression of liver cirrhosis. Dr. Ricardo Moreno Traspas, postdoctoral researcher from the Laboratory of Human and Therapeutic Genetics at GIS, and first author of the study, explained: “FOCAD mutations lead to overproduction of a number of proteins that may be key drivers 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 cirrhotic patients.

Professor Bruno Reversade, Senior Group Leader at GIS and corresponding author of the study, commented: “We report the clinical impact of recessive loss-of-function variants in the FOCAD gene and provide evidence for the importance of SKI mRNA monitoring pathway for liver homeostasis.The research also produced the first animal model of human disease, as well as in vitro biological systems that are now used as platforms to identify and validate new anti-fibrotic therapeutic targets. »

Professor 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 disease such as fatty liver disease and fatty liver disease. liver cancer. Our clinical data will also help clinicians 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] OnlineWilliams, 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 as single genes are so fundamental that they are taught in high school. The enduring power of these principles is that they allow us to link mutations in a specific gene to an important human disease.

[3] A type of protein made by certain immune and non-immune cells that affects the immune system.

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