Singapore – Led by scientists from Agency for Science, Technology and Research (A*STAR)’s Institute of Medical Biology (IMB), an international team of researchers has discovered a novel protein mutation which results in a rare premature skin ageing condition. The findings shed light on the underlying mechanisms of skin ageing, and bring us one step closer to maintaining skin youthfulness through targeting such enzymes. The study was published in the American Journal of Human Genetics and involved collaborations with over 16 hospitals and research centres across 11 countries.
As we age, our skin tends to become thinner, more fragile, and lacking in elasticity, leading to wrinkles. Understanding why and how our skin ages, then, is the first step to slowing down the effects.
The study examined the DNA samples of patients with suspected De Barsy Syndrome (DBS), otherwise known as ‘wrinkly skin syndrome’. It belongs to a group of rare connective tissue disorders, known as cutis laxa (CL) syndromes, in which the skin hangs loosely in folds and turns inelastic.
A previous study in 2009 had found that mutation of the PYCR1 gene was an underlying cause of DBS, making PYCR1 a prime target for anti-wrinkling treatments for common disorders related to ageing. Intriguingly though, in these patients’ cases, while they showed DBS-like symptoms, their PYCR1 genes did not bear any mutations, suggesting that other genes could be responsible.
It was found that a unique mutation in the enzyme P5CS affecting only the residue Arg138, was the cause for the observed symptoms and a prematurely-aged appearance. Having identified this, scientists can now develop treatments to counteract P5CS mutations, and therefore hope to recover skin elasticity.
This particular form of CL, while milder than DBS, was further found to be autosomal dominant, such that only one copy of a disease allele is necessary for one to be susceptible and there is a 50% chance the offspring will inherit the disease allele and suffer from the disorder. This is opposed to the autosomal recessive DBS, which bears only a 25% chance. This discovery will certainly ameliorate the diagnostics, treatment, and genetic counselling processes for patients.
Beyond CL patients, skin ageing and wrinkling is also a pertinent aspect of overall human ageing, and such insights can improve our management of ageing, particularly to address the global issue of an ageing population. Furthermore, this area is one of the hot focus areas for personal care companies, and this discovery identifies a novel target for the development of wrinkle-defying treatments, and improvement of the skin’s self-renewal capacity and youthful appearance.
IMB and IMCB Senior Principal Investigator Dr Bruno Reversade, one of the study’s corresponding authors, commented, “We are now certain that skin ageing in humans is under the control of proline metabolism, which both PYCR1 and P5CS are involved in. Our next challenge is to find out if these two enzymes are druggable to develop active compounds to slow down the effects of ageing.”
Professor Birgit Lane, Executive Director of IMB, stated, “By looking at rare disorders, we have successfully identified proteins critical to normal skin ageing. This discovery has opened up new possibilities in the fields of skin and ageing research, with crucial clinical implications. We will continue to explore rare diseases with the dual aims of changing the lives of rare disorder patients, and improving the scientific understanding of common conditions to help the general public.”
Notes to Editor:
The research findings described in this media release can be found in the American Journal of Human Genetics, under the title, “Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa” by Bjorn Fischer-Zirnsak1,2,25, Nathalie Escande-Beillard3,25, Jaya Ganesh4, Yu Xuan Tan3, Mohammed Al Bughaili1, Angela E. Lin5, Inderneel Sahai5, Paulina Bahena6, Sara L. Reichert4, Abigail Loh7, Graham D. Wright3, Jaron Liu3, Elisa Rahikkala8, Eniko K. Pivnick9, Asim F. Choudhri10,11,12,13, Ulrike Kruger1, Tomasz Zemojtel1,14, Conny van Ravenswaaij-Arts15, Roya Mostafavi9, Irene Stolte-Dijkstra15, Sofie Symoens16, Leila Pajunen8, Lihadh Al-Gazali17, David Meierhofer18, Peter N. Robinson1,2,19, Stefan Mundlos1,2,19, Camilo E. Villarroel6,Peter Byers20, Amira Masri21, Stephen P. Robertson22, Ulrike Schwarze23, Bert Callewaert16,26, Bruno Reversade3,7,24,26,* and Uwe Kornak1,2,19,26,*
1Institut fuer Medizinische Genetik und Humangenetik, Charite-Universitaetsmedizin Berlin, 13353 Berlin, Germany;
2FG Development & Disease, Max-Planck-Institut fuer Molekulare Genetik, 14195 Berlin, Germany;
3Institute of Medical Biology, A*STAR, 138648 Singapore, Singapore;
4Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA;
5Medical Genetics and Metabolism, Mass General Hospital for Children, Boston, MA 02114, USA;
6Departamento de Genetica Humana, Instituto Nacional de Pediatrıa, Mexico City 19050, Mexico;
7Institute of Molecular and Cellular Biology, A*STAR, 138648 Singapore, Singapore;
8PEDEGO Research Group and Medical Research Centre Oulu, University of Oulu and Department of Clinical Genetics, Oulu University
Hospital, 90029 OYS Oulu, Finland;
9Department of Paediatrics, Division of Medical Genetics and Department of Ophthalmology, University of Tennessee Health Science Centre, Memphis, TN 38163, USA;
10Department of Radiology, University of Tennessee Health Science Centre, Memphis, TN 38163, USA;
11Department of Ophthalmology, University of Tennessee Health Science Centre, Memphis, TN 38163, USA;
12Department of Neurosurgery, University of Tennessee Health Science Centre, Memphis, TN 38163, USA;
13Le Bonheur Children’s Hospital, Memphis, TN 38163, USA;
14Labor-Berlin, 13353 Berlin, Germany;
15Department of Genetics, University Medical Centre Groningen, University of Groningen, 9712 Groningen, the Netherlands;
16Centre for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium;
17Departments of Paediatrics, Pathology, and Radiology, Faculty of Medicine and
Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates;
18Mass-Spectrometry Facility, Max-Planck-Institut fuer Molekulare Genetik, 14195 Berlin, Germany;
19Berlin-Brandenburg Centre for Regenerative Therapies, Charite-Universitaetsmedizin Berlin, 13353 Berlin, Germany;
20Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195-7470, USA;
21Department of Paediatrics, Faculty of Medicine, University of Jordan, 11942 Amman, Jordan;
22Department of Women’s and Children’s Health, University of Otago, 9016 Dunedin, New Zealand;
23Department of Pathology, University of Washington, Seattle, WA 98195-7470, USA;
24Department of Paediatrics, National University of Singapore, 119077 Singapore, Singapore
25These authors contributed equally to this work
26These authors contributed equally to this work
*Correspondence: [email protected] (B.R.), [email protected] (U.K.)
Full text of the American Journal of Human Genetics paper can be accessed online from: http://dx.doi.org/10.1016/j.ajhg.2015.08.001
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About A*STAR’s Institute of Medical Biology (IMB)
IMB is one of the Biomedical Sciences Institutes of the Agency for Science, Technology and Research (A*STAR). It was formed in 2007, with a mission to study mechanisms of human disease in order to discover new and effective therapeutic strategies for improved quality of life.
IMB has 20 research teams working in three primary focus areas - stem cells, genetic disease, and skin biology. The teams work closely with clinical collaborators as well as industry partners, to target the challenging interface between basic science and clinical medicine. IMB’s strategic research topics are targeted at translational research to understand the mechanisms of human disease so as to identify new strategies for disease amelioration, cure and eradication and to improve health and wellbeing. Since 2011, IMB has also hosted the inter-research institute Skin Biology Cluster platform, and leads major strategic funding programs in rare genetic diseases and in skin biology. In 2013 IMB became a founding institute of the Skin Research Institute of Singapore.
For more information about IMB, please visit www.imb.a-star.edu.sg.
About the Agency for Science, Technology and Research (A*STAR)
The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector agency that spearheads economic oriented research to advance scientific discovery and develop innovative technology. Through open innovation, we collaborate with our partners in both the public and private sectors to benefit society.
As a Science and Technology Organisation, A*STAR bridges the gap between academia and industry. Our research creates economic growth and jobs for Singapore, and enhances lives by contributing to societal benefits such as improving outcomes in healthcare, urban living, and sustainability.
We play a key role in nurturing and developing a diversity of talent and leaders in our Agency and Research Institutes, the wider research community and industry. A*STAR oversees 18 biomedical sciences and physical sciences and engineering research entities primarily located in Biopolis and Fusionopolis.
For more information on A*STAR, please visit www.a-star.edu.sg.