Rare diseases: De novo mutation leading to Fanconi anemia identified

December 22, 2015

An international team of researchers has established the cause of rare syndrome consistent with Fanconi Anemia: a de novo mutation in a so called RAD51 gene, which is responsible for repairing damages in the DNA. Fanconi Anemia is a chromosome instability disorder which occurs in one of around about 350,000 new born children. It is clinically typified by susceptibility to bone marrow failure, leukemia, different types of solid tumors and a strongly reduced life expectance of the affected persons. The investigators at the Institute of Systems Biology (ISB, Seattle), Free University Medical Center (VUMC, Amsterdam), and the Luxembourg Centre for Systems Biomedicine (LCSB) at the University of Luxembourg in collaboration with several other institutions in the United States and Europe have just published their results in the journal Nature Communications (DOI: 10.1038/ncomms9829).

For their investigations, the researchers used advanced whole genome sequencing as well as other cell and molecular biology techniques. "This way we identified a mutation in the so called RAD51 gene, "says Dr Patrick May of the LCSB´s Bioinformatics Core research group at the University of Luxembourg and there a driving force in the collaborative project. RAD51 is responsible for repairing damages in the DNA which occur regularly during cell proliferation.

The team made its findings in a child affected by Fanconi Anemia - with healthy parents and a healthy sister. "The particular mutation in this patient was a surprise to us," says Patrick May: "It occurred only in one of the two RAD51 gene copies, which every person carries in the genome, but every RAD51 gene copy was normal in the child´s parents." The scientists´ conclusion: The examined patient is carrier of a not inherited but a novel and in the same time dominant mutation. Until this case, the state of scientific knowledge was that mutations leading to Fanconi Anemia showed recessive inheritance and therefore had to be derived from both parents to lead to Fanconi Anemia. Spontaneous mutations of the RAD51 gene like in this case were not observed so far. "In consequence the protein with the altered amino acid sequence due to the mutation interfered with the activity of the normal protein," says May. "This are the reasons why the child is affected by Fanconi Anemia although his or her relatives are not carrier of the mutation."

This finding has implications for genetic counseling of families with a high risk for Fanconi Anemia. Until now people who wanted to become parents and who had relatives suffering from Fanconi Anemia were screened if one of the 17 genes connected with the disease showed a mutation. Now the risk of having a sick baby has to be recalculated. "Furthermore, understanding this mutation teaches us more about how the RAD51 gene product protects the DNA and how disruptions of DNA repair may lead to leukemia and solid tumors," says Patrick May. "Of course, understanding the origins of human cancer will help us diagnose it with more confidence earlier and devise new therapies to prevent or mitigate it. We could also support a yet weak association between Fanconi Anemia and mental retardation and neurodevelopment involving mutations in proteins of the downstream branch of the Fanconi Anemia DNA repair pathway, like shown before for a gene called BRCA1 and now in this study for RAD51."
This work was organised and sponsored by collaborations between the Institute for Systems Biology, Seattle (USA) with the Luxembourg Center for Systems Biomedicine (Luxembourg), the Free University Medical Center (Amsterdam) with the assistance of several other institutions or universities in Europe and the United States.

About the Institute for Systems Biology: The Institute for Systems Biology is a nonprofit biomedical research organisation based in Seattle, Washington. It was founded in 2000 by systems biologist Leroy Hood, immunologist Alan Aderem, and protein chemist Ruedi Aebersold. ISB was established on the belief that the conventional models for exploring and funding breakthrough science have not caught up with the real potential of what is possible today. ISB serves as the ultimate environment where scientific collaboration stretches across disciplines, where our researchers have the intellectual freedom to challenge the status quo, and where grand visions for breakthroughs in human health inspire a collective drive to achieve the seemingly impossible. Since 2000, ISB has grown to about 200 employees, which includes 9 faculty members and laboratory groups. See more at http://www.systemsbiology.org

About the Luxembourg Centre for Systems Biomedicine: The Luxembourg Centre for Systems Biomedicine develops and applies systems-level approaches to gain insight into the molecular and cellular mechanisms of human diseases. Experimental and computational approaches are combined to analyse the complexity of biological systems underlying disease pathogenesis. The LCSB is pioneering the way for a predictive, preventive and personalised medicine. Neurodegenerative diseases, especially Parkinson's disease are major targets within LCSB's research activities. See more at http://www.uni.lu/lcsb

University of Luxembourg

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