Study Sheds Light on Mental Retardation, Birth Defects

Study Sheds Light on Mental Retardation, Birth Defects

Jul 20, 2009 3:00 PM

(SALT LAKE CITY) - Studying a small group of humans with rare genetic make-ups, researchers have produced a high-resolution genetic map of Down Syndrome (DS) that may determine the direction of future research and clinical applications in a wide range of birth defects treatments. Researchers at the University of Utah's Brain Institute and their colleagues at Yale University, working with a consortium of national and international institutions, have published their findings in the July 21, 2009 issue of Proceedings of the National Academy of Sciences.

A key finding revealed a specific gene that plays a significant role in the formation of the human heart and may unlock the causes of congenital heart disease, the most common cause of hospital days in children. Moreover, their work provides a direct link from the human genome to the debilitating illnesses faced by those with Down Syndrome. 

DS - three copies of chromosome 21 - is a major cause of mental retardation and congenital anomalies, affecting the welfare of more than 400,000 individuals and their families in the USA and millions worldwide. Down's individuals typically have a myriad of problems including intellectual disabilities, heart defects, and Alzheimers. Despite decades of research, there are no genes or chromosomal regions linked to any specific disease and no successful treatment for the cognitive deficits. This study dramatically advances the understanding of those links. 

"Understanding the genetic origins of the diseases apparent in patients with Down Syndrome is crucial for ultimately designing treatments for this disease," says Julie R. Korenberg, MD, PhD, USTAR Professor and Professor of Pediatric Genetics at the University of Utah's Brain Institute. "Surprisingly, none of these malformations or diseases are clearly understood and their increased risk in trisomy 21 is proof positive that there is a gene or genes on this smallest chromosome, that can disturb and identify disease pathways for human development as well as for major adult diseases - cardiovascular, cancer, mental illness and dementia."

Although overwhelmingly caused by an extra entire copy of chromosome 21, rare people exist in whom DS features are associated with rearranged chromosomes that result in duplications of only parts of chromosome 21 containing only a few of the genes. These individuals provide the critical human models for examining the underlying mechanisms for malformations, neural, and cognitive features in DS and in the normal population.  Korenberg led a team of researchers that have established a unique cohort of 31 individuals with partial trisomy for chromosome 21, associated with subsets of characteristic features of DS.  "This is the world's largest collection of partial trisomies, and these individuals provide a unique opportunity to relate small numbers of chromosome 21 genes to the defects of development and function in DS," Korenberg said.

Using advanced microarray methods, which can identify the duplicated regions down to single exon/gene level, Korenberg of the University of Utah, Michael Snyder of Yale University, and their teams performed high-resolution genetic mapping of DS with this unique subject cohort. "The microarrays we designed allow mapping of breakpoints at unprecedented resolution" says Snyder. The study, representing more than 20 years of Korenberg's research, identifies discrete sections of chromosomes that are involved in serious birth defects of DS, as well as the leukemia of DS.
  
"This is the highest resolution Down syndrome phenotype map to date and it lets us identify distinct genomic regions that likely contribute to the manifestation of eight Down syndrome features," Korenberg said. "These features include acute megakaryocytic leukemia, some intestinal conditions such as Hirchsprung disease, severe mental retardation, and Down syndrome-specific congenital heart disease."

Korenberg's work has shown that mapping with partial trisomies is a uniquely human and powerful approach to studying DS. This map also enables researchers to focus on the critical genes in the critical regions of the human genome.  "In particular, our map focuses in on an essential role for several genes," Korenberg said. Korenberg and Snyder agree, "These findings powerfully point the way to the mechanisms underlying birth defects, heart disease, and leukemia, the critical knowledge for drug discovery and new treatments."

The paper, ""The Genetic Architecture of DS Phenotypes Revealed by High Resolution Analysis of Human Segmental Trisomies," is senior authored by Korenberg and Snyder, and represents the efforts of their teams of researchers from the University of Utah, Yale University, and numerous national and international institutions.  Korenberg is a USTAR Professor at The Brain Institute and the Department of Pediatrics, Genetics, and Director of the Center for Integrated Neuroscience and Human Behavior at the University of Utah, School of Medicine. Michael Snyder was formerly Lewis B. Cullman Professor of Molecular and Cellular Biology and Professor of Molecular Biophysics and Biochemistry at Yale University and is currently Professor and Chair of Genetics and Director of the Center for Genomics and Personalized Medicine, Stanford University. The success of this work paves the way to unravel the fundamental causes of intellectual disabilities and impaired brain development in Down Syndrome.

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