January 13, 2009

Specific Nervous System Abnormalities Caused By Genomic Duplications

The lack of the important brain protein LIS1 results in lissencephaly, a devastating condition in which the brain appears smooth and does not develop normally.

This occurs when a gene called PAFAH1B1 is deleted. If a nearby gene called YWHAE is deleted in combination with PAFAH1B1, a condition called Miller-Dieker syndrome characterized by severe brain abnormalities and other findings.

Now a consortium of researchers led by Baylor College of Medicine (www.bmc.edu) in Houston and the Weizmann Institute of Science in Rehovot, Israel, have found that tiny duplications of the area of chromosome 17 that contains the gene responsible for the production of LIS1 and the gene related to Miller-Dieker syndrome slightly increases levels of LIS1, causing abnormalities in the developing brains of human and mice. Their report appears online in the journal Nature Genetics.

"This continues a two-decade theme of my laboratory that duplications of genes can give subtle gene dosage changes and convey clinical disease traits that here involve brain development," said Dr. James R. Lupski (http://www.bcm.edu/genetics/facultyaz/lupski.html), vice chair of molecular and human genetics at BCM and a senior author of the report. The other senior author is Dr. Orly Reiner of the Weizmann Institute.

In studies of seven unrelated people with minute duplications (not visible by a microscope) involving the gene PAFAH1BI as well as YWAHE on a portion of chromosome 17, the researchers found that higher levels of the first gene caused mild abnormalities in brain structure along with moderate to severe developmental delay. These subjects also had a condition called "failure to thrive," which encompasses slow weight gain and other physical and developmental traits. Those who had duplications of the gene YWAHE were abnormally heavy as infants, had mild developmental delay and pervasive developmental disorders with symptoms similar to those of autism in which the child does not socialize or communicate normally. These children also have facial abnormalities.

In parallel studies of mice that have too much LIS1 in the developing brain, Reiner's group found a decreased brain size, more dying brain cells and problems with the organization of cells in the brain.

"These studies demonstrate the importance of "Ëœgenomotype'/phenotype correlations," said Lupski, who is also a professor of pediatrics  at BCM. "Our findings increase the repertoire of known genomic disorders (a field of study initiated by the Lupski laboratory: http://www.bcm.edu/solutions/v4i1/lupski.html) near the area associated with Miller-Dieker syndrome."

Combining the information from the human patients with that derived from the mouse studies enabled the researchers to attribute the detectable signs of disease (called phenotype) to copy number variations of crucial genes. (Copy number variation refers to differences in the usual number of copies (i.e. two, one from each parent) of stretches of DNA found among different genomes).

Others who took part in this research include Weimin Bi, Oleg A. Shchelochkov, Feng Zhang, Marjorie A. Withers, Xin-Yan Lu, Trilochan Sahoo, Arthur L. Beaudet and Sau Wai Cheung, all of BCM, Tamar Sapir, Talia Levy, and Vera Shinder, all of the Weizmann Institute; Jill V. Hunter of Texas Children's Hospital, Daniel A. Peiffer and Kevin L. Gunderson of Illumina Inc., in San Diego, California; Marjan M. Nezarat of North York General Hospital in Toronto, Ontario; Vern Ann Shotts of Arkansas Children's Hospital in Little Rock; Stephen S. Amato and Sarah K. Savage of Eastern Maine Medical Center in Bangor; David J. Harris of Children's Hospital, Boston, Massachusetts; Debra-Lynn Day-Salvatore and Michele Horner of Saint Peters University Hospital in New Brunswick New Jersey, and  Salvador Martinez of Instituto de Neurociencias, UMNH-CSIS, San Juan de Alicante, Alicante, Spain.

Funding for this work came from the Israeli Science Foundation, the Foundation Jerome Lejeune, the Minerva Foundation with funding from  the Federal German Ministry for Education and Research, German-Israeli collaboration grant, the Paul Godfrey Research Foundation Children's Diseases, the Benoziyo Center for Neurological Diseases, the Kekst Center, the Forcheimer Center, a Weizmann-Pasteur collaborative grant, the Michigan Women of Wisdom Fund to support Weizmann Women Scientists, support from Maurice Janin, the Jewish Communal Fund, Albert Einstein College of Medicine Yeshiva University, the David and Fela Shapell Family Center Research Grant for Genetic Disorders Research, the European Union, Baylor Medical Genetics Laboratories, the Mental Retardation Developmental Disabilities Research Center at BCM and the National Institute of Child Health and Human Development and the National Institutes of Health.

The article is available at http://www.nature.com/ng/index.html