Loss of nicotinic receptor could cause developmental delay
By Ruth SoRelle, M.P.H.
Using sophisticated genetic technology, a consortium of researchers led by Baylor College of Medicine has narrowed down the reason for abnormalities in learning and behavior inherited in some families to loss of a specific gene called a nictotinic receptor.
Finding the defect required scanning the genomes of more than 10,000 people, said Dr. Pawel Stankiewicz, assistant professor of molecular and human genetics at BCM and an author on the report in Nature Genetics.
Links problems to a particular gene
"This research goes about 95 percent of the way to pinning these problems in a specific group of individuals to this gene (CHRNA7)," said Dr. Arthur L. Beaudet, chair of molecular and human genetics at BCM and a senior author of the report. He believes that the deletion will be identified in other people with behavioral problems as well as schizophrenia, developmental delay and epilepsy. The gene's role in schizophrenia has been under study for some time.
Previously, a larger deletion containing more genes had been reported in people with the same constellation of disorders. In this work, Beaudet, Stankiewicz and colleagues found that a smaller deletion of genetic material – the whole of the gene in question, CHRNA7, and a part of another – was associated with similar problems in 10 members of four families.
Nicotinic receptor
"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.
Study involved four families
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).
Inherited deletion
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. Both of his siblings had developmental delay. The patient had severe mental retardation and obesity and mild facial dysmorphism or a difference in the usual facial structure.
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.
Other authors
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.
