ICH researchers discover the cause of a new rare genetic syndrome

ICH researchers discover the cause of a new rare genetic syndrome that causes life-threatening symptoms in children.

The work, published last week in PNAS (https://www.pnas.org/content/early/2020/06/16/2002328117), was based on a family being cared for by Dr Aoife Waters, a Consultant Paediatric Nephrologist at Great Ormond Street Hospital (GOSH). The patient experienced kidney failure, cataracts, hearing loss and inflammation of the intestine, sadly resulting in early childhood mortality. Around the same time, a group based at Semmelweis University, Budapest, led by Dr Kalman Tory, discovered a second family with the same features.

Dr Waters and Tory decided to work together and investigate the causes of this novel syndrome, teaming up with Dr David Long, Reader in Paediatric Nephrology and Dr Jennifer Chandler, a postdoctoral researcher, at GOSH Institute of Child Health (ICH). They hoped to find ways of helping these families and others in the future, from understanding how the condition was likely to progress to identifying treatments that could help.

Using genetic sequencing, they were able to study the patients’ DNA – the unique set of instructions that control how the body grows, works and looks. The researchers found key ‘spelling mistakes’ in these instructions, in an area of DNA responsible for a process called pseudouridylation. This process is critical for the healthy functioning of cells, including the proper ‘reading’ and translation of genetic instructions.

To learn more, the team developed a laboratory model of the genetic problem they’d discovered, using zebrafish. They found that the fish developed the same kinds of symptoms seen in both families. From this, the group were able to demonstrate that disruption of pseudouridylation and its impact on cell functions is a key feature of this new syndrome.

Dr Waters says: “This work provides a great example of how understanding rare genetic mutations from our patients at GOSH can help us understand broader disease mechanisms. This collaborative work is the first to describe defective pseudouridylation in the context of kidney disease, adding to our understanding of childhood renal failure. While the circumstances of this work are devastating for those affected, we are incredibly grateful to the families who agreed to participate and help us learn more about the cause of this syndrome. Looking forward, this means we can investigate if this new mechanism is relevant to other aspects of kidney damage.”

The work has already received considerable attention with Dr Chandler winning Best Abstract Award of the 500+ submitted abstracts at UK Kidney Week in 2019. She also won funding from The Genetic Society to travel to Berlin and present this work at the Cell Symposia. This work is Jennie’s first leading author publication as a postdoctoral researcher after joining the Kidney Development and Disease group at GOSICH.

Dr Chandler recently obtained funding from the National Institute of Health Research (NIHR) Great Ormond Street Biomedical Research Centre (BRC), to fund a research stay at Yale School of Medicine, USA. There, working with Associate Professor Wendy Gilbert, a world-leading researcher in the field of pseudouridylation, Dr Chandler intends to determine the specific sections of genetic material (RNA) in which pseudouridylation is altered in this disease.

Dr Chandler says, “I am really excited that this BRC funding has provided me with an opportunity to further investigate the effects of disrupted pseudouridylation and how and why it causes damage to the organs that are implicated in this disease. Working with Dr Gilbert, we will be able to characterise which classes of RNAs are implicated, which in turn should reveal the biological processes that are most disrupted. I hope this work will lead to promising therapeutic targets for families affected by kidney disease.”