"This is going to change the way we approach single-gene disorders," said lead investigator Murat Gunel, M.D., who is chief of the Neurovascular Surgery Program and co-director of the Program on Neurogenetics at Yale University in New Haven, Conn. Whole exome sequencing can be applied to dozens of other rare genetic disorders where the culprit genes have so far evaded discovery, he said.
Such information can help couples assess the risk of passing on genetic disorders to their children. It can also offer insights into disease mechanisms and treatments.
The research is funded in part by a $2.9 million stimulus grant from NIH's National Institute of Neurological Disorders and Stroke (NINDS) made possible by the American Recovery and Reinvestment Act.
"This study demonstrates a powerful new tool for discovering the cause of tough-to-crack genetic disorders," said NINDS director Story Landis, Ph.D. "It also exemplifies how Recovery Act support to the NIH community is successfully driving biomedical technology and innovation."
The study appears today in Nature, and focuses on children with malformations of cortical development (MCD). These are severe abnormalities of the cerebral cortex, the brain's outermost layer, which normally contains complex folds that are densely packed with brain cells. In MCD, the cortex is smaller and its folds are less complex. Affected children have severe intellectual disabilities and may not reach developmental milestones.
Different types of MCD are recognized based on anatomy. They carry names like microcephaly (small brain and head), schizencephaly (fluid filled clefts in the brain), pachygyria (a cortex with thicker, fewer folds) and polymicrogyria (cortex with many small folds). These conditions reflect a failure of brain cells to grow and reach their proper places during development. They can result from prenatal exposure to alcohol, drugs and some viruses. In many cases, the cause is genetic, but the specific genetic lesion is often unknown.
Through whole exome sequencing, the new study found a single gene at the root of seemingly distinct types of MCD in children from multiple families. Rather than scanning a person's entire genome for mutations, this technique focuses on the protein-coding bits of DNA, or exome, which makes up about 1.5 percent of the genome.
Genetic forms of MCD occur worldwide and in all kinds of families, but the highest incidence is among children born to parents who are related. Dr. Gunel and his colleagues at Yale teamed up with investigators in Turkey to study Turkish families with MCD. The country has a tradition of first- and second-cousin marriages, and thus a relatively high incidence of MCD.
The study began by focusing on two related children who were diagnosed with microcephaly. Whole exome sequencing revealed that both children had mutations in a gene called WDR62. As the study grew to include children from other families with microcephaly, many of the children were found to have mutations in the same gene. Unexpectedly, brain imaging revealed that the children also tended to have other types of MCD, superimposed with microcephaly. In all, the investigators found 6 unique mutations in the WDR62 gene among 30 families.
Those results show that a single gene "is required for strikingly diverse aspects of human cortical brain development," said Dr. Gunel.
No one knows precisely what WDR62 does, but related proteins are known to regulate the processing of RNA (the intermediate between DNA and protein). The researchers found that in the developing mouse and human brain, WDR62 is enriched in a band of brain tissue that contains neural stem cells. They plan to explore the exact functions of WDR62 in mouse studies. Meanwhile, they will use their Recovery Act grant to extend whole exome sequencing to hundreds of additional families with MCD.
The technology should prove to be quick and cost effective for identifying the roots of other rare genetic disorders too, according to Dr. Gunel. In his laboratory, whole genome sequencing takes several weeks and costs about $50,000, while whole exome sequencing takes 9 days and costs about $3,500, he said.
In addition to NINDS, other support for the study came from a Clinical and Translational Science Award from NIH's National Center for Research Resources, and from NIH's National Institute of Mental Health.
NINDS (www.ninds.nih.gov) is the nation's leading funder of research on the brain and nervous system. The mission of NIMH (www.nimh.nih.gov) is to reduce the burden of mental and behavioral disorders through research on mind, brain and behavior. NCRR (www.ncrr.nih.gov) provides laboratory scientists and clinical researchers with the resources and training they need to understand, detect, treat and prevent a wide range of diseases.
The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
The activities described in this release are being funded through the American Recovery and Reinvestment Act. More information about NIH's Recovery Act grant funding opportunities can be found at http://grants.nih.gov/recovery/. To track the progress of HHS activities funded through the Recovery Act, visit www.hhs.gov/recovery. To track all federal funds provided through the Recovery Act, visit www.recovery.gov.
Reference: Bilguvar K, Ozturk AK et al. "Whole exome sequencing identifies WDR62 mutations in severe brain cortical malformations." Nature, published online August 22, 2010.
Daniel Stimson | EurekAlert!
Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory
How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
24.03.2017 | Materials Sciences
24.03.2017 | Physics and Astronomy
24.03.2017 | Physics and Astronomy