The splice of life – insights into genetic disease | Children's Charity

The splice of life – insights into genetic disease

This research was completed on 30 April 2010

Published on 30 January 2007

Evidence suggests that disruption of a fundamental genetic process, called ‘alternative splicing’, can cause all sorts of devastating inherited diseases. Yet we know very little about even the basics of splicing. Researchers are striving to find out more, in the ultimate hope of developing therapies for a wide range of different diseases.

What's the problem and who does it affect?

What is ‘splicing’?

A major challenge of modern genetics is to interpret how mutations – or faults – in our genetic make-up can cause disease. We’ve already found genes for several illnesses, such as breast cancer, cystic fibrosis and haemophilia. This is an important step along the way to finding new treatments. But the underlying causes of many genetic diseases remain unknown. It used to be thought that one gene encoded instructions on how to make one particular protein. If the gene was mutated, then the protein might be faulty and that might cause disease. But more recent discoveries show things are more complicated than that. Many genes can code for more than one protein, because of alternative pathways for interpreting genes, which involve a process called splicing. Evidence suggests that a substantial number of genetic diseases might be caused by defective splicing. But our understanding of the molecular mechanisms involved is very limited. Finding out more could lead to benefits for people with a wide range of inherited diseases.

What is the project trying to achieve?

Proteins are synthesised by following instructions in a copy of a gene, made of a substance called RNA. Splicing involves cutting unwanted sections out of the RNA. In this project, researchers are trying to identify mutations that cause faulty splicing. They are focusing on mutations identified by doctors at Addenbrookes hospital when diagnosing their patients’ illnesses. Many of these mutations are known to cause disease but no-one knows how. The team is using three sophisticated laboratory tests, called the hybrid minigene assay, the in vitro splicing assay and direct RNA analysis. They hope to characterise how each mutation leads to faulty splicing on a molecular level. They also hope to develop the tests to see if they could be used routinely in the diagnostic process. The researchers are studying various relatively common, genetic diseases that affect patients of all ages. These include cystic fibrosis, Neurofibromatosis type, tuberous sclerosis and Marfans syndrome.

What are the researchers' credentials?

Project LeaderDr D Baralle BSc, MBBs, MRCP, MD
LocationClincial Genetics Department, Princess Anne Hospital, Southampton
DurationTwo years
Grant awarded30 October 2006
Start date30 April 2007
End date30 April 2010
Grant amount£90,214.00
Grant codeSP4175

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Dr Diana Baralle is well placed to lead this study. She is experienced in researching the mechanisms involved in alternative splicing. She has published papers on her work in peer-reviewed journals and lectured at international meetings. Throughout this project Dr Baralle will be drawing on the support of invaluable collaborations with other world experts in this field. The research will take place at the University of Cambridge, which is well-known for its world-class academic environment. The project team will have access to excellent facilities within the University’s Department of Pathology and the Regional Genetics Laboratories at Addenbrookes Hospital. The latter provides a molecular diagnostics service, giving the team access to samples from patients with genetic diseases.

Who stands to benefit from this research and how?

Helping patients understand their illness

The results of this project will be of direct relevance to people who are suffering from the devastating genetic disorders that are being studied. These include cystic fibrosis, Neurofibromatosis type, tuberous sclerosis and Marfans syndrome. Researchers hope their work will give some of these people a precise diagnosis, explaining the cause of their disease on a molecular level. It can be a huge relief for a family just to understand what’s going on, and how the disease might progress in the future. It may also enable doctors to recommend better treatments. The team hopes to develop simple tests that will help in the diagnostic process and enable other members of the family to find out whether they are carrying the faulty gene – important information for people who are considering having children.

Towards new genetic therapies

In the longer term, many more patients with a much wider range of genetic disorders may ultimately benefit. Researchers hope to boost our fundamental understanding of how faulty splicing causes disease. This will be invaluable as we strive to develop new genetic therapies

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