02:59am Saturday 29 February 2020

Variations of a single gene can lead to too much or too little growth, study shows

Intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies syndrome (IMAGe syndrome) is a rare developmental disorder that can affect fetal growth, resulting in smaller than average body and organ size. Without treatment, the disorder can have potentially life-threatening consequences as a result of adrenal gland failure.

The condition was first identified 20 years ago by Eric Vilain, then a researcher in France. Now, Professor Vilain and colleagues at the University of California, Los Angeles – together with researchers at the UCL Institute of Child Health in the UK – have identified the disorder as being caused by a particular mutation of a gene known as CDKN1C, found on chromosome 11.

They made their discovery after analysing DNA samples from an Argentinian family affected by IMAGe syndrome and existing samples from patients collected over the past two decades.

Scientists have known for some time that CDKN1C plays an important part in regulating cell growth. Mutations of this gene have been previously associated with an ‘overgrowth’ syndrome called Beckwith-Wiedemann syndrome, which causes large body parts, large organs and an increased risk of tumours. The link with IMAGe is the first time the gene has been associated with growth restriction.

“We discovered a mutation in chromosome 11 that consistently appeared in every family member affected by IMAGe Syndrome,” explains Professor Vilain. “We were a little surprised, though, because the mutation was located on a gene previously recognised as causing Beckwith-Wiedemann Syndrome.

“Finding dual functions in one molecule is an unusual biological phenomenon. These two diseases are polar opposites of each other.

“The results are particularly special for me as we have finally been able to identify the cause of the condition that I first encountered twenty years ago. This is a big step forward and should help affected families in the future. We can now use gene sequencing as a tool to screen for the mutation and diagnose children early enough for them to benefit from medical intervention.”

In fact, the researchers found that IMAGe syndrome was only associated with changes in the maternal CDKN1C gene. If only the copy of the gene inherited from the father carried the mutation, the child was unaffected.

This process of ‘switching on’ genes differently depending on whether they are inherited from the mother or the father is known as ‘imprinting’. Some scientists believe that imprinted genes have evolved to play an important part in how the fetus develops in the womb; a smaller fetus carries an advantage to the mother as it increases her chances of survival during childbirth, while the father’s genes may work to increase the birth size (and, hence, chances of survival) of the offspring.

Dr John Achermann, a Wellcome Trust Senior Research Fellow at the UCL Institute of Child Health, UCL, says: “Our surprising finding shows that different changes in the same gene can lead to very different effects. The results give us clues not only in relation to growth during human development but also to how cells grow and divide and lead to tumours.”

The research was funded by the Wellcome Trust, the Doris Duke Charitable Foundation and the National Institute of Child Health and Human Development.

Image: An ultrasound image of a fetus at 24 weeks. Credit: Wellcome Photo Library, Wellcome Images.



Craig Brierley
Senior Media Officer
Wellcome Trust
+44 (0)20 7611 7329

Notes for editors


Arboleda VA et al. Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet 2012 (epub ahead of print).

About the Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust’s breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests.

About UCL (University College London)
Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender, and the first to provide systematic teaching of law, architecture and medicine. UCL is among the world’s top universities, as reflected by performance in a range of international rankings and tables. Alumni include Marie Stopes, Jonathan Dimbleby, Lord Woolf, Alexander Graham Bell, and members of the band Coldplay. UCL currently has over 13 000 undergraduate and 9000 postgraduate students. Its annual income is over £700 million.

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