09:32pm Wednesday 22 January 2020

Genetic cause for extreme form of dwarfism uncovered

This discovery could open up new avenues of research into how growth disorders occur and offer people with severe growth disorders a chance of better and earlier diagnosis.

Primordial dwarfism is a group of incredibly rare growth disorders which significantly limit growth at every stage of life, from before birth to adulthood and includes the smallest people in the world. Many of those whose size is limited by these genes have small ears, no knee caps and an adult height can be as little as one metre. They may also have a reduced head size, in proportion to their body size, in contrast with other forms of dwarfism. Without a clear understanding of what causes the disorders, it can often be difficult for patients to get an accurate diagnosis and provide the best management of their condition.

The group of genes, collectively called the ‘pre-replication complex’, is known to play an important role in controlling the copying of DNA in our cells, but until now their formative link with primordial microcephalic dwarfism and developmental problems remained hidden.

The first study, led by Dr Mark O’Driscoll and Professor Penny Jeggo at the MRC Genome Damage and Stability Centre at the University of Sussex and Dr Andrew Jackson at the MRC Human Genetics Unit in Edinburgh, reveals that the gene ORC1, plays a key role in triggering the copying of our genetic material (DNA). This impacts upon the rate at which cells multiply and so lead to fewer cells being produced, thereby limiting growth. The researchers were able to substantiate this in zebrafish by removing ORC1 and observing how it impaired their growth.

The second study, by the team at the MRC Human Genetics Unit in conjunction with Dr Ernie Bongers and colleagues at Radboud University Nijmegen Medical Centre in the Netherlands, supports this finding and reveals that four further genes that are known to function in the pre-replication complex with ORC1 also cause this condition, suggesting that these genes and this complex are important for human growth.

Corresponding author, Dr Andrew Jackson at the MRC Human Genetics Unit in Edinburgh, says:

 “This is the first time we’ve been able to find a link between genes controlling the basic process which copies our DNA in cells and an extreme form of dwarfism. We’re very excited that these discoveries not only help us understand what causes primordial dwarfism but could also offer us a general insight into how these genes may more widely influence human height and body size.”

Senior author on the first paper, Professor Penny Jeggo at the MRC Centre for Genome Damage and Stability at the University of Sussex, says:

 “It’s exciting to discover that a protein complex that plays a key role in how cells copy their DNA has such a significant impact on development. This demonstrates that the investment in understanding basic mechanisms underlying cell growth and replication is critical for understanding development of organisms and disorders of human health.”

The two papers, together with a third led by researchers in Canada, are published online today in Nature Genetics.




Notes to editors

To arrange an interview with the researchers of this paper, please call the MRC Press Office on 0207 395 2345.


1. For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. www.mrc.ac.uk

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