HOUSTON - (Nov. 8, 2009) - The loss of a gene through deletion of genetic material on chromosome 15 is associated with significant abnormalities in learning and behavior, said a consortium of researchers led by Baylor College of Medicine (www.bcm.edu) in a report that appears online today in the journal Nature Genetics.
"This research goes about 95 percent of the way to pinning these problems in a specific group of individuals to this gene," said Dr. Arthur L. Beaudet (http://www.
Previously, a larger deletion containing more genes had been reported in people with the same constellation of disorders. In this work, Beaudet, Dr. Pawel Stankiewicz (http://www.
"We scanned the genome of about 10,000 people to find this rare but important defect," said Stankiewicz.
"This gene encodes a subunit of a nicotinic receptor," said Beaudet. "It is a gene that mediates the response to nicotine via a receptor whose normal ligand is acetylcholine." The gene encodes a protein called an ion channel, which allows ions to flow in and out of neurons in the brain. Defects in ion channels have previously been associated with forms of epilepsy or seizure disorder.
"If insufficient expression of the nicotinic receptor causes most or all of the problems associated with deletions in this particular area of chromosome 15, then it offers a target for drug treatment," said Stankiewicz. One such drug mentioned in the paper is Chantix, a medicine now used in smoking cessation efforts.
In this study, an international group of researchers identified 10 people from four unrelated families with the same deletion in the chromosome. The area deleted encompasses all of CHRNA7, which encodes a whole subunit of the nicotinic receptor.
Nine of the 10 subjects had developmental delay and/or mental retardation. Four of the 10 had seizure disorders or an abnormal electroencephalogram (EEG).
In two of the families studied, the patients had inherited the deletion from a parent. In one family, researchers found the same deletion in the patient's mother, two siblings, maternal aunt and maternal grandmother. Both the patient's mother and her sister had mental retardation and epilepsy. His both siblings had developmental delay. The patient had severe mental retardation and obesity and mild facial dysmorphism.
A second patient with impaired growth and severe developmental delay inherited her deletion from her mother, who had normal intelligence but had suffered from epilepsy from childhood.
Others who took part in this study include Marwan Shinawi, Christian P. Schaaf, Samarth S. Bhatt, Zhilian Xia, Ankita Patel, Sau Wai Cheung and Jennifer Ruth German, all of BCM; Brendan Lanpher of Vanderbilt University in Nashville, Tenn.; Sandra Nagl and Claudia Nevinny-Stickel of MVZ Humane Genetik in Munich, Germany; Heinrich Stephan Herding of Praxis für Kinder und Jugendmedizin in Meldorf, Germany; LaDonna L Immken and Gayle Simpson Patel of Specially for Children Subspecialty of Clinical Genetics in Austin, Texas. Stankiewicz is also with the Institute of Mother and Child, Warsaw, Poland.
Funding for this work came from the National Institutes of Health; the Mental Retardation and Developmental Disabilities Research Center; the Rare Disease Clinical Research Consortia; and the Polish Ministry of Science and Higher Education.
When the embargo lifts, the report will be available at http://www.