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Researchers at Duke University Medical Center transplanted a set ofhuman genes into a zebrafish and then used it to identify genesresponsible for head size at birth. Head size in human babies is a feature that is related to autism, acondition that recent figures have shown to be more common thanpreviously reported, 1 in 88 children in a March 2012 study. Headsize is also a feature of other major neurological disorders, suchas schizophrenia. "In medical research, we need to dissect events in biology sowe can understand the precise mechanisms that give rise toneurodevelopmental traits," said senior author NicholasKatsanis, Ph.D., Jean and George Brumley Jr., MD, Professor ofDevelopmental Biology, and Professor of Pediatrics and CellBiology. "We need expert scientists to work side by side withclinicians who see such anatomic and other problems in patients, ifwe are to effectively solve many of our medical problems." The study was published online in Nature journal on May 16. Katsanis knew that a region on chromosome 16 was one of the largestgenetic contributors to autism and schizophrenia, but aconversation at a European medical meeting pointed him toinformation that changes within that same region of the genome alsowere related to changes in a newborn's head size. The problem was difficult to address because the region had largedeletions and duplications in DNA, which are the most commonmutational mechanisms in humans. "Interpretation isharrowingly hard," said Katsanis, who is also director of theDuke Center for Human Disease Modeling. The reason is that a duplication of DNA or missing DNA usuallyinvolves several genes. "It is very difficult to go from 'hereis a region with many genes, sometimes over 50' to 'these are thegenes that are driving this pathology,'" Katsanis said. "There was a light bulb moment," Katsanis said. "Thearea of the genome we were exploring gave rise to reciprocal(opposite) defects in terms of brain cell growth, so we realizedthat overexpressing a gene in question might give one phenotype --a smaller head, while shutting down the same gene might yield theother, a larger head." The researchers transplanted a common duplication area of humanchromosome 16 known to contain 29 genes into zebrafish embryos andthen systematically turned up the activity of each transplantedhuman gene to find which might cause a small head (microcephaly) inthe fish. They then suppressed the same gene set and asked whetherany of them caused the reciprocal defect: larger heads(macrocephaly). The researchers knew that deletion of the region that containedthese 29 genes occurred in 1.7% of children with autism. It took the team a few months to dissect such a "copy numbervariant" -- an alteration of the genome that results in anabnormal number of one or more sections of chromosomal DNA. "Now we can go from a genetic finding that is dosage-sensitiveand start asking reasonable questions about this gene as itpertains to neurocognitive traits, which is a big leap,"Katsanis said. Neurocognitive refers to the ability to think,concentrate, reason, remember, process information, learn,understand and speak. Many human conditions have anatomical features that are alsorelated to genetics, he said. "There are major limitations instudying autistic or schizophrenic behavior in zebrafish, but wecan measure head size, jaw size, or facial abnormalities." The single gene in question, KCTD13, is responsible for drivinghead size in zebrafish by regulating the creation and destructionof new neurons (brain cells). This discovery let the team focus onthe analogous gene in humans. "This gene contributes to autismcases, and probably is associated with schizophrenia and alsochildhood obesity," Katsanis said. Once the gene has been uncovered, researchers can examine theprotein it produces. "Once you have the protein, you can startasking valuable functional questions and learning what the genedoes in the animal or human," Katsanis said. Copy number variants, such as the ones this team found onchromosome 16, are now thought to be one of the most common sourcesof genetic mutations. Hundreds, if not thousands, of suchchromosomal deletions and duplications have been found in patientswith a broad range of clinical problems, particularlyneurodevelopmental disorders. "Now we may have an efficient tool for dissecting them, whichgives us the ability to improve both diagnosis and understanding ofdisease mechanisms," Katsanis said. The current study suggests that KCTD13 is a major contributor tosome cases of autism, but also points to the synergistic action ofthis gene with two other genes in the region, named MVP and MAPK3,Katsanis said. Other authors include lead author Christelle Golzio, Jason Willerand Edwin Oh of the Duke Center for Human Disease Modeling andDepartment of Cell Biology; Mike Talkowski, Mei Sun and Jim Guzellafrom the Molecular Neurogenetics Unit, Center for Human GeneticResearch, Massachusetts General Hospital in Boston; SebastienJacquemont, Alexandre Reymond and Jacques Beckmann from the Servicede Génétique Médicale, Centre HospitalierUniversitaire Vaudois, in Lausanne, Switzerland; and Yu Taniguchi,Akira Sawa and Atsushi Kamiya from the Department of Psychiatry,Johns Hopkins University School of Medicine in Baltimore. Funding is from a Silvio O. Conte Center grant from the NationalInstitute of Mental Health (NIMH), National Institutes of Healthgrants, the Simons Foundation, the Autism Consortium of Boston, theLeenaards Foundation Prize, the Swiss National Science Foundation,a National Science Foundation Sinergia grant, an NIMH NationalResearch Service Award, and an academic study award from theUniversity of Lausanne. The e-commerce company in China offers quality products such as Apple Iphone car holder , China Cell Phone Bike Holder, and more. For more , please visit Car Cellphone Holder today!
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