UCL Great Ormond Street Institute of Child Health


Great Ormond Street Institute of Child Health


ICH researchers discover cause of new rare genetic syndrome

6 July 2020

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

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

The work, published in PNAS, was based on a family being cared for by Dr Aoife Waters, a Consultant Paediatric Nephrologist at Great Ormond Street Hospital (GOSH). The patients 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 Kálmán 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 cellular function 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.”



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About the UCL Great Ormond Street Institute of Child Health (ICH) 

The UCL Great Ormond Street Institute of Child Health (ICH) is part of the Faculty of Population Health Sciences within the School of Life and Medical Sciences at University College London. Together with its clinical partner Great Ormond Street Hospital for Children NHS Foundation Trust (GOSH), it forms the UK's only paediatric National Institute for Health Research (NIHR) Biomedical Research Centre and has the largest concentration of children's health research in Europe. For more information visit www.ucl.ac.uk/child-health

About Great Ormond Street Hospital for Children NHS Foundation Trust 

Founded in 1852, Great Ormond Street Hospital is one of the world’s leading children’s hospitals with the broadest range of dedicated, children’s healthcare specialists under one roof in the UK. With more than 252,000 outpatient and 43,000 inpatient visits every year, the hospital’s pioneering research and treatment gives hope to children from across the UK with the rarest, most complex and often life-threatening conditions. As an international centre of excellence in child healthcare, our patients and families are central to everything we do – from the moment they come through the door and for as long as they need us. Visit www.gosh.nhs.uk

Research at GOSH is underpinned by support from the National Institute of Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre (BRC) and GOSH Charity.

About Great Ormond Street Hospital Children’s Charity

Great Ormond Street Hospital Children’s Charity needs to raise money to support the hospital to give seriously ill children, the best chance for life. The charity funds research into pioneering new treatments for children, provides the most up to date medical equipment, funds support services for children and their families and supports the essential rebuilding and refurbishment of the hospital. You can help us to provide world class care for our patients and families. For more information visit www.gosh.org  

About the NIHR

The National Institute for Health Research (NIHR) is the nation's largest funder of health and care research. The NIHR:

  • Funds, supports and delivers high quality research that benefits the NHS, public health and social care
  • Engages and involves patients, carers and the public in order to improve the reach, quality and impact of research
  • Attracts, trains and supports the best researchers to tackle the complex health and care challenges of the future
  • Invests in world-class infrastructure and a skilled delivery workforce to translate discoveries into improved treatments and services
  • Partners with other public funders, charities and industry to maximise the value of research to patients and the economy

The NIHR was established in 2006 to improve the health and wealth of the nation through research, and is funded by the Department of Health and Social Care. In addition to its national role, the NIHR supports applied health research for the direct and primary benefit of people in low- and middle-income countries, using UK aid from the UK government.