image: This is a six-year-old Turkish child with Hamamy syndrome displaying common craniofacial dysmorphisms, including midface prominence, sparse lateral eyebrows, severe telecanthus, and agenesis of lacrimal punctuae. view more
Credit: Reversade Laboratory, Institute of Medical Biology, Agency for Science Technology and Research
Scientists at A*STAR's Institute of Medical Biology (IMB), in collaboration with doctors and scientists in Jordan, Turkey, Switzerland and USA, have identified the genetic cause of a birth defect known as Hamamy syndrome . Their groundbreaking findings were published on May 13th in the prestigious journal Nature Genetics. The work lends new insights into common ailments such as heart disease, osteoporosis, blood disorders and possibly sterility.
Hamamy syndrome is a rare genetic disorder which is marked by abnormal facial features and defects in the heart, bone, blood and reproductive cells. Its exact cause was unknown until now. The international team, led by scientists at IMB, have pinpointed the genetic mistake to be a mutation in a single gene called IRX5.
This is the first time that a mutation in IRX5 (and the family of IRX genes) has ever been discovered in man. IRX5 is part of a family of transcription factors that is highly conserved in all animals, meaning that this gene is present not only in humans but also in mice, fish, frogs, flies and even worms. Using a frog model, the scientists demonstrated that Irx5 orchestrates cell movements in the developing foetus which underlie head and gonad formation.
Carine Bonnard, a final-year PhD student at IMB and the first author of the paper, said, "Because Hamamy syndrome causes a wide range of symptoms, not just in newborn babies but also in the adult, this implies that IRX5 is critical for development in the womb as well as for the function of many organs in our adult body. For example, patients with this disease cannot evacuate tears from their eyes, and they will also go on to experience repetitive bone fractures or progressive myopia as they age. This discovery of the causative gene is a significant finding that will catalyze research efforts into the role of the Irx gene family and greatly increase our understanding of human health, such as bone homeostasis, or gamete formation for instance."
"We believe that this discovery could open up new therapeutic solutions to common diseases like osteoporosis, heart disease, anaemia which affect millions of people worldwide," said Dr Bruno Reversade, Senior Principle Investigator at IMB. "The findings also provide a framework for understanding fascinating evolutionary questions, such as why humans of different ethnicities have distinct facial features and how these are embedded in our genome. IRX genes have been repeatedly co-opted during evolution, and small variation in their activity could underlie fine alterations in the way we look, or perhaps even drastic ones such as the traits seen in an elephant, whale, turtle or frog body pattern."
Only a handful of people in the world have been identified with Hamamy Syndrome making it a very rare genetic disorder. Rare genetic diseases, usually caused by mutations in a single gene, provide a unique opportunity to better understand more common disease processes. These "natural" experiments are similar to carefully controlled knockout animal experiments in which the function of single genes are analyzed and often give major insights into general health issues.
Prof Birgitte Lane, Executive Director of IMB, said, "Understanding how various pathways in the human body function is the foundation for developing new therapeutic targets. This is an important piece of research that I believe will be of great interest to many scientists and clinicians around the world because of the clinical and genetic insights it brings to a large range of diseases."
Notes for editor:
The research findings described in this news release can be found on Nature Genetics's website under the title "Mutations in IRX5 impair craniofacial development and germ cell migration via SDF1" by Carine Bonnard1, Anna C Strobl2, Mohammad Shboul1, Hane Lee3, Barry Merriman3, Stanley F Nelson3, Osama H Ababneh4, Elif Uz5, 6, Tülay Guran7, Hülya Kayserili8, Hanan Hamamy9, 10 & Bruno Reversade1, 11.
1 Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
2 Division of Systems Biology, Medical Research Council National Institute for Medical Research, London, UK
3 Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USA
4 Department of Opthalmology, Faculty of Medicine, University of Jordan, Amman, Jordan
5 Department of Biology, Faculty of Arts and Sciences, Duzce University, Duzce, Turkey
6 Gene Mapping Laboratory, Department of Medical Genetics, Hacettepe University Medical Faculty, Ankara, Turkey
7 Pediatric Endocrinology and Diabetes, Marmara University Hospital, Istanbul, Turkey
8 Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
9 Department of Genetic Medicine and Development, Geneva University Hospital, Geneva, Switzerland
10 National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan
11 Department of Pediatrics, National University of Singapore, Singapore
Correspondence should be addressed to B.R. (Bruno@reversade.com)
The article can be accessed from http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.2259.html.
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About the 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, the 7th and youngest of the BMRC Research Institutes, with a mission to study mechanisms of human disease in order to discover new and effective therapeutic strategies for improved quality of life. From 2011, IMB also hosts the inter-research institute Skin Biology Cluster platform.
IMB has 20 research teams of international excellence in stem cells, genetic diseases, cancer and skin and epithelial biology, and works closely with clinical collaborators to target the challenging interface between basic science and clinical medicine. Its growing portfolio of strategic research topics is targeted at 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 www.imb.a-star.edu.sg.
About the Reversade Laboratory
Dr. Reversade, a human geneticist and embryologist holds a Senior Principal Investigator position at IMB and an adjunct faculty position at the Department of Paediatrics in the National University of Singapore. He is a Fellow of the Branco Weiss Foundation based at ETH in Switzerland and also the first recipient of an A*STAR Investigatorship, a programme which provides competitive and prestigious fellowships to support the next generation of international scientific leaders, offering funding and access to state-of-the-art scientific equipment and facilities at A*STAR.
For more information about Dr. Reversade's laboratory, please visit www.reversade.com.
About the 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 and innovation-driven Singapore. A*STAR oversees 14 biomedical sciences and physical sciences and engineering research institutes, and six consortia & centres, located in Biopolis and Fusionopolis as well as their immediate vicinity.
A*STAR supports Singapore's key economic clusters by providing intellectual, human and industrial capital to its partners in industry. It also supports extramural research in the universities, and with other local and international partners.
For more information about A*STAR, please visit www.a-star.edu.sg.
Journal
Nature Genetics