Public Release: 

Gene mutation responsible for premature skin aging disease identified

Singapore scientist says novel discovery suggests new approach for age-defying, anti-wrinkling treatments

Agency for Science, Technology and Research (A*STAR), Singapore

In the new print issue of Nature Genetics, scientists in Singapore and Germany report that mutations in the PYCR1 gene cause the rare genetic condition that results in premature skin aging and that is known as "wrinkly skin syndrome."

Their findings not only suggest that increasing levels of the PYCR1 protein could reverse conditions that cause fast aging and wrinkly skin but also provide insight into how some unexpected genes help maintain youthful skin.

Bruno Reversade, Ph.D. of Singapore's Institute of Medical Biology (IMB) led the international research team that involved collaborations with over 15 hospitals and research centres in 13 countries.

Using bioinformatics tools, Dr. Reversade and his team analyzed DNA samples collected worldwide from patients who, at a young age, displayed signs of premature aging. They identified the PYCR1 gene on chromosome 17 of these patients to be defective and found specific mutations in the gene that led to conditions often seen in elderly people, such as loose skin, loss of bone density, hip dislocation and cataract.

They also determined that skin and bone were the two tissues most severely affected in patients with wrinkly skin syndrome. Since skin and bone contain high levels of the PYCR1 protein under normal circumstances, developing therapies that could increase the activity of the PYCR1 protein could possibly reverse the process of aging in affected individuals or slow it down in normal people.

The scientists found that the PYCR1 protein is located in mitochondria, the cell's "power house," providing energy for the cell's consumption. In their experiments, they observed changes in mitochondrial morphology and cell death in the connective tissues of individuals with PYCR1 mutations.

To determine the effects of reduced levels of PYCR1 protein, the scientists studied the growth of frog and fish models in which the PYCR1 gene had been experimentally shut off. They found that the mitochondrial function in the animal models' skin was altered, and there was also an increased occurrence of cell death.

"Our findings confirm the significance of mitochondrial function in the aging process," said Dr. Reversade. "They also unexpectedly highlight the importance of metabolism as PYCR1 is important in the synthesis of proline, a common amino acid involved in metabolism. Age-defying and anti-wrinkling treatments for common disorders related to ageing may also benefit from sustaining proline metabolism."

"We are excited by these findings of Bruno and colleagues, which open up new possibilities in the field of aging and skin research," added Birgit Lane, Ph.D., a skin biologist and Executive Director of IMB, one of the research institutes sponsored by Singapore's A*STAR (Agency for Science, Technology and Research).

"The study is a great example of scientific synergy - when clinicians and scientists from around the world come together to share their specialist skills and knowledge, they can discover new insights into complex medical conditions," said Dr. Lane. "Rare genetic disorders often provide surprising revelations. Pooling resources and targeting research to find new ways of combating disease - and benefiting people faster - is exactly what we try to do at IMB."


Dr. Reversade, a developmental biologist, holds a Principal Investigator position at IMB and an adjunct faculty position at the National University of Singapore. In previously published papers in such journals as Cell and Nature Cell Biology, he has reported several landmark discoveries explaining how identical twins can be produced from a single embryo. A

Fellow of the Branco Weiss Foundation, he is the first recipient of an A*STAR Investigatorship, a programme that provides competitive and prestigious fellowships to support the next generation of international scientific leaders, offering them funding support for set-up costs and research staff, and access to state-of-the-art scientific equipment and facilities at A*STAR.

Notes to reporters/editors:

The research findings described in the press release can be found in the article titled "Mutations in PYCR1 cause cutis laxa with progeroid features," published in the 1 Sept. 2009 print issue of Nature Genetics.

Authors: Bruno Reversade1,33, Nathalie Escande-Beillard1,33, Aikaterini Dimopoulou2, Björn Fischer2, Serene C Chng1, Yun Li3, Mohammad Shboul1, Puay-Yoke Tham1, Hu¨lya Kayserili4, Lihadh Al-Gazali5, Monzer Shahwan6, Francesco Brancati7,8, Hane Lee9, Brian D O'Connor9, Mareen Schmidt-von Kegler2,10, Barry Merriman9, Stanley F Nelson9, Amira Masri11, Fawaz Alkazaleh11, Deanna Guerra12, Paola Ferrari13, Arti Nanda14, Anna Rajab15, David Markie16, Mary Gray16, John Nelson17, Arthur Grix18, Annemarie Sommer19, Ravi Savarirayan20, Andreas R Janecke21, Elisabeth Steichen22, David Sillence23, Ingrid Hauβer24, Birgit Budde25, Gudrun Nürnberg25, Peter Nürnberg25, Petra Seemann10,26, Désirée Kunkel26, Giovanna Zambruno27, Bruno Dallapiccola7, Markus Schuelke28, Stephen Robertson29, Hanan Hamamy6, Bernd Wollnik3,30,31, Lionel Van Maldergem32, Stefan Mundlos2,10,26 & Uwe Kornak2,10

1. Institute of Medical Biology, A*STAR, Singapore.
2. Institute of Medical Genetics, Charité Universitaetsmedizin Berlin, Germany.
3. Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
4. Medical Genetics Department, Istanbul Medical Faculty, University of Istanbul, Turkey.
5. Department of Paediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
6. National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan.
7. Ospedale Casa Sollievo della Sofferenza (CSS), San Giovanni Rotondo and Istituto CSS-Mendel, Rome, Italy.
8. Centro Studi Invecchiamento (Ce.S.I.), Department of Biomedical Sciences, Gabriele d'Annunzio University, Chieti, Italy.
9. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles.
10. Max Planck Institute for Molecular Genetics, Berlin, Germany.
11. Departments of Pediatrics, Obstetrics and Gynecology, Faculty of Medicine, The University of Jordan, Amman, Jordan.
12. Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
13. Department of Pediatrics, University of Modena and Reggio Emilia, Modena, Italy.
14. As'ad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait City, Kuwait.
15. Genetic Unit, Directorate General of Health Affairs, Ministry of Health, Muscat, Sultanate of Oman.
16. Department of Pathology, University of Otago, Dunedin, New Zealand.
17. Genetic Services of Western Australia, King Edward Memorial Hospital for Women, Perth, Australia.
18. The Permanente Medical Group, Sacramento, California.
19. The Ohio State University College of Medicine and Nationwide Children's Hospital, Molecular and Human Genetics, Columbus, Ohio.
20. University of Melbourne, Murdoch Childrens Research Institute, Royal Children's Hospital, and Genetic Health Services Victoria, Parkville, Victoria, Australia.
21. Division of Clinical Genetics, Innsbruck Medical University, Innsbruck, Austria.
22. Klinik fuer Kinder- und Jugendheilkunde, Universitaet Innsbruck, Innsbruck, Austria.
23. Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
24. Universitaets-Hautklinik Heidelberg, Heidelberg, Germany.
25. Cologne Center for Genomics, Universität zu Köln, Germany.
26. Berlin-Brandenburg Center for Regenerative Therapies, Charité Universitaetsmedizin Berlin, Germany.
27. Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
28. Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitaetsmedizin Berlin, Germany.
29. Department of Paediatrics and Child Health, University of Otago, Dunedin, New Zealand.
30. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
31. Institute of Human Genetics, University of Cologne, Cologne, Germany.
32. Centre de Génétique Humaine, Centre Hospitalier Universitaire du Sart-Tilman, Université de Liège, Liège, Belgium.
33. These authors contributed equally to this work.

* Corresponding authors: Bruno Reversade, email: or Stefan Mundlos, email:

Institute of Medical Biology (IMB):

The Institute of Medical Biology is a member of the Agency for Science, Technology and Research (A*STAR). With its roots in the Centre for Molecular Medicine since 2004, it became the Institute of Medical Biology 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 is developing internationally excellent research programmes working closely with clinical collaborators, targeting the challenging interface between basic science and clinical medicine, and aiming to promote increased and effective throughput of research from bench to bedside. Its growing portfolio of strategic research topics aims to promote translational research on the mechanisms of human diseases with a cell to tissue emphasis that can help identify new therapeutic strategies for disease amelioration, cure and eradication. For more information about IMB, please visit

Agency for Science, Technology and Research (A*STAR):

The Agency for Science, Technology and Research (A*STAR) is the lead agency for fostering world-class scientific research and talent for a vibrant knowledge-based Singapore. A*STAR actively nurtures public sector research and development in Biomedical Sciences, and Physical Sciences and Engineering, and supports Singapore's key economic clusters by providing intellectual, human and industrial capital to our partners in industry and the healthcare sector. It oversees 23 research institutes, consortia and centres located in Biopolis and Fusionopolis, and the area in their vicinity, and supports extramural research in the universities, hospitals, research centres, and with other local and international partners.

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