Mutations in a single protein, HNRNPU, cause learning difficulties, autism, and epilepsy by turning the DNA inside cells into a dysfunctional mess. This matters because scientists have recently discovered that many neurodevelopmental disorders stem from mutations in proteins that handle fundamental cellular housekeeping—specifically, how DNA is packaged and read inside the nucleus. Until now, no one understood exactly how a faulty HNRNPU protein disrupts this packaging. The researcher’s team has shown that HNRNPU normally teams up with RNA to form a gel-like protective layer around DNA, like cotton wool. When HNRNPU is mutated, that protective gel fails, and processes like reading DNA into RNA or repairing damage go wrong. This is fundamental science. If the team succeeds in mapping exactly how HNRNPU mutations alter DNA packaging and cellular function, it could provide new prognostic markers and open avenues for treatments. Similar fundamental discoveries about how cells organise their DNA have, in the past, led to breakthroughs in cancer therapies and genetic diagnostics—though any clinical application here remains years away.
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Recently scientists have developed tools for identifying mutations in individuals with complex neuro-development disorders. Surprisingly, many of these mutations are found in proteins that have a role in fundamental cellular functions. To understand the molecular basis of these diseases, with a hope of developing new prognostic markers and potential disease treatments, it is crucial to understand how the specific proteins function in the complex environment of the cell. My team is expert in analysing how DNA is packaged inside part of a human cell called the nucleus and we hypothesise that in some individuals their disease is caused by altered packaging of DNA so it does not function correctly. However, there are many steps to this process from packaging DNA to how the DNA is read to make RNA and then how the RNA is folded and exported to other parts of the cell to make protein. In this study we will focus on one specific protein, HNRNPU, that when mutated causes learning difficulties, autism, and epilepsy. So far, our research has shown that HNRNPU interacts with another molecule in the nucleus called RNA and together they form a gel that surrounds the DNA, similar to protective cotton wool. Together this gel facilitates processes that occur on the DNA such as reading into RNA, or repairing damage to the DNA. We will study how mutations in HNRNPU alter DNA packaging and how this affects many important cellular processes and disease.
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