By sequencing the genome of individuals of normal height but with a very small head size, the international team revealed that these individuals had mutations in the KATNB1 gene, indicating that this gene is important for proper human brain development. Microcephaly (literally meaning "small head" in Latin) is a condition often associated with neurodevelopmental disorders. Measured at birth by calculating the baby's head circumference, a diagnosis of microcephaly is given if it is smaller than average.
Microcephaly may stem from a variety of conditions that cause abnormal growth of the brain during gestation or degenerative processes after birth, all resulting in a small head circumference. In general, individuals with microcephaly have a reduced life expectancy due to reduced brain function which is often associated with mental retardation.
The team also carried out further experiments to determine the function of KATNB1, whose exact mode of action was previously unknown in humans. Using organisms specifically designed to lack this gene, they realised that KATNB1 is crucial for the brain to reach its correct size. Zebrafish and mice embryos without this gene could not live past a certain stage and showed dramatic reduction in brain and head size, similar to the human patients. Their results were published in the 17 December 2014 online issue of Neuron, the most influential journal in the field of Neuroscience.
Sequencing and screening for this particular gene before birth or at birth might also help to detect future neurocognitive problems in the general population. Dr Reversade said, "We will continue to search for other genes important for brain development as they may unlock some of the secrets explaining how we, humans, have evolved such cognitive abilities."
Prof Birgit Lane, Executive Director of IMB, said, "This is one of a small number of genes that scientists have found to be vital for brain development. The work is therefore an important advance in understanding the human brain. The team's findings provide a new platform from which to look further into whether - and how - this gene can be used for targeted therapeutic applications."
Prof Hong Wanjin, Executive Director of IMCB, said, "This coordinated effort shows the increasingly collaborative nature of science. As the complexity and interdisciplinary nature of research evolves, so do the networks of collaborations between research institutes at A*STAR and across continents."
INFORMATION:
Notes for Editor:
The research findings described in this media release can be found in the 17 December online issue of Neuron, Cell Press under the title, "Katanin p80 Regulates Human Cortical Development by Limiting Centriole and Cilia Number" by Wen F. Hu,1,2,3,5,6 Oz Pomp,19 Tawfeg Ben-Omran,12 Andrew Kodani,18 Katrin Henke,4,9
Ganeshwaran H. Mochida,1,2,7,10 Timothy W. Yu,1,7,11 Mollie B. Woodworth,1,2,3,7 Carine Bonnard,19 Grace Selva Raj,19Thong Teck Tan,19 Hanan Hamamy,21 Amira Masri,23 Mohammad Shboul,19 Muna Al Saffar,1,2,13 Jennifer N. Partlow,1,2,3 Mohammed Al-Dosari,17 Anas Alazami,14 Mohammed Alowain,15,16 Fowzan S. Alkuraya,14,16 Jeremy F. Reiter,18 Matthew P. Harris,4,9,24,* Bruno Reversade,19,20,22,24 and Christopher A. Walsh1,2,3,5,6,7,8,24.
1Division of Genetics and Genomics, Department of Medicine
2Manton Center for Orphan Disease Research
3Howard Hughes Medical Institute
4Department of Orthopedic Research
Boston Children's Hospital, Boston, MA 02115, USA
5Program in Neuroscience
6Harvard MD-PhD MSTP Program
7Department of Pediatrics
8Department of Neurology
9Department of Genetics
Harvard Medical School, Boston, MA 02115, USA
10Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
11Program in Medical and Population Genetics, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA
12Clinical and Metabolic Genetics Division, Department of Pediatrics, Hamad Medical Corporation, Doha 3050, Qatar
13Department of Pediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
14Department of Genetics
15Department of Medical Genetics
King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
16Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
17Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
18Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco,
CA 94158, USA
19Institute of Medical Biology, Human Genetics and Embryology Laboratory
20Institute of Molecular and Cellular Biology, A*STAR, Singapore 138648, Singapore
21Department of Genetic Medicine and Development, Geneva University, Geneva 1211, Switzerland
22Department of Paediatrics, National University of Singapore, Singapore 119260, Singapore
23Department of Paediatrics, Faculty of Medicine, University of Jordan, Amman 11942, Jordan
*Correspondence should be addressed to: Bruno Reversade (bruno.reversade@imb.a-star.edu.sg)
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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 http://www.imb.a-star.edu.sg.
About A*STAR's Institute of Molecular and Cell Biology (IMCB)
The Institute of Molecular and Cell Biology (IMCB) was established in 1987 at the National University of Singapore (NUS) before becoming an autonomous research institute (RI) of A*STAR and moving to Biopolis in 2004. IMCB strives to maintain the scientific excellence of PI-driven research and at the same time aims to promote collaborative team-based projects of medical and industrial relevance.
Funded primarily by the Biomedical Research Council (BMRC) of A*STAR, IMCB's research activities focus on four major fields: Animal Models of Development and Disease, Cancer Genetics and Therapeutics, Cell Biology in Health and Disease, and Structural Biology and Drug Discovery.
For more information about IMCB, please visit http://www.imcb.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 fosters world-class scientific research and talent to drive economic growth and transform Singapore into a vibrant knowledge-based and innovation driven economy.
In line with its mission-oriented mandate, A*STAR spearheads research and development in fields that are essential to growing Singapore's manufacturing sector and catalysing new growth industries. A*STAR supports these economic clusters by providing intellectual, human and industrial capital to its partners in industry.
A*STAR oversees 18 biomedical sciences and physical sciences and engineering research entities, located in Biopolis and Fusionopolis, as well as their vicinity. These two R&D hubs house a bustling and diverse community of local and international research scientists and engineers from A*STAR's research entities as well as a growing number of corporate laboratories.
For more information on A*STAR, please visit http://www.a-star.edu.sg
