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How zebrafish are helping scientists to unlock the secrets of a new kidney disease

29 October 2020

Working at Great Ormond Street Hospital, it’s not surprising that Dr Aoife Waters, a consultant paediatric nephrologist, has seen a range of kidney diseases. However, one morning a family came  through her clinic doors with a set of symptoms that puzzled her.

Unusual kidney cases and coincidences

Aoife has helped hundreds of families over the years and has a good eye to spot conditions associated with kidney disease – where their symptoms are a clear sign that their kidneys not working properly. These signs could be anything from rashes, to swelling, children who wet the bed or who have blood in their urine.

When Aoife sat with a family who were suffering from hearing loss, blurred vision, inflamed intestines and scarring inside the kidney – on a part called the glomerulus – she realised that this was unusual. The family also told her about tragic events within their family, of another child passing away at an early age with similar features. She immediately knew she had to investigate this and fast.

A short while later at a conference, Aoife was speaking with Dr Kalman Tory, a scientist working at Semmelweis University in Budapest, about the unique family she was seeing. Remarkably, he had also discovered a second family with the same symptoms and they started to work together to uncover answers. They wanted to help these families and others in the future, to understand how the condition was likely to progress and find treatments that could help.

Dr Jennifer Chandler and Dr Aoife Waters
Dr Aoife Waters (left) and Dr Jennifer Chandler

A collaboration to find answers

The pair teamed up with Professor David Long and Dr Jennifer Chandler at Great Ormond Street Hospital Institute of Child Health.

The scientists started to look closely at the DNA from both sets of patients. They found that the patients in the UK had a variation in one gene and the patients in Budapest had a variation in a different one.

At first, this was confusing as they weren’t expecting to see two families with the same symptoms with variations in different parts of their DNA. But using sophisticated computer modelling the scientists found that the changes to the two genes worked in tandem, which is why the two families had the same symptoms.

The variations in the DNA of the patients were responsible for a specialised process called pseudouridylation. Pseudouridylation is a complex process that helps to turn genes on or off. This process is part of epigenetics – where the environment influences your genes. In the case of pseudouridylation it specifically affects our RNA (an important molecule present in all our cells that’s like a working copy of your DNA).

Identifying these genes was just the first step of a long road. The scientists still had to figure out how these gene changes translated into particular symptoms and how they were causing the disease.


Using fish to understand human disease

Scientists use a variety of lab techniques to search for genetic causes of human diseases, including kidney disease. They use patients’ cells or samples where possible, but to find if a mutation in a specific gene can cause a patients’ symptoms they often have no choice but to use animal models.

Zebrafish might not seem an obvious choice as humans appear to be extremely different from zebrafish, but we are more similar than you might think. Surprisingly, 84% of genes involved in human disease have an exact zebrafish counterpart, making them especially useful for biomedical modelling.

Using zebrafish model of loss of the same gene discovered in the families, the team discovered that the RNA (the important molecule present in all our cells we mentioned earlier) was not processed normally and is a key feature of the new disease being shown by the two families.

This discovery is a new cause of progressive kidney disease and it plays a key role in our understanding of the complex features of childhood kidney failure. The work has already received considerable attention from the scientific community; Jennifer went to Berlin and presented the findings to hundreds of other researchers. She says, “I hope this work will lead to new ways to treat families affected by kidney disease.”

This exciting research is a great example of how understanding a disease at the genetic level in fish could help scientists to one day identify new ways to treat disease in people and stop more children dying.

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