22 February 2008. A multinational team of researchers has uncovered a chromosomal deletion that is associated with mental retardation and seizures. In the February 17 Nature Genetics online, Evan Eichler of the University of Washington School of Medicine, Seattle, and colleagues report that the 1.5 Mb deletion on chromosome 15 contains six genes, including that for the α7 nicotinic acetylcholine receptor (α7NAChR). The authors suggest that the α7NAChR deletion is most likely responsible for the seizures. The finding may be of interest to Alzheimer disease researchers, since both seizures and the α7NACh receptor have been linked to the disease.
First author Andrew Sharp and colleagues found the deletion when using whole-genome arrays to carry out comparative genomic hybridization studies of 757 individuals with mental retardation or congenital anomalies. They found two people who share the 1.5 Mb deletion at chromosome 15q13.3. Screening a further 1,040 people of European and African-American descent netted a total of nine others with similar deletions. In addition to the mental retardation and seizures, affected individuals can also have mildly abnormal physical features, including facial dysmorphism or skeletal and joint defects. The authors conclude that deletion of this stretch of chromosome 15 accounts for about 0.3 percent of mental retardation of unknown cause, and they suggest that individuals with unexplained mental retardation should be tested for the deletion. Interestingly, it lies close to the breakpoint in chromosome 15 that leads to Prader-Willi and Angelman syndromes. These conditions are also accompanied by developmental problems and learning deficits, suggesting that this region of the chromosome is susceptible to pathological recombination events.
The α7NAChR has long interested some Alzheimer researchers because there is evidence that it binds to amyloid-β (see ARF related news story), is neuroprotective (see Qi et al., 2007), and is upregulated in AD brain (see Counts et al., 2007). Moreover, recent genetic association studies have implicated a polymorphism in the gene (see Alzgene overview).
There is no indication that loss of this gene accounts for the mental retardation in patients with the deletion, but α7NAChR has been recognized as a risk factor for epilepsy. Patients with the chromosomal deletion also have abnormal electrical activity as measured by EEG. This may be related to loss of α7NAChR, as well, since knocking out the gene in mice leads to anomalous EEG recordings.
In fact, it is thought that patients with AD are at increased risk for seizures, and recent EEG recordings of human amyloid precursor protein (hAPP) transgenic mice suggest that they also have electrical activity consistent with non-convulsive seizures (see ARF related news story). All told, there is sufficient evidence to suggest that relationships among AD, the α7NAChR, and seizures deserve a closer look. A workshop ahead of next July’s International Conference on Alzheimer’s Disease may provide some clues.—Tom Fagan.
Sharp AJ, Mefford HC, Li K, Baker C, Skinner C, Stevenson RE, Schroer RJ, Novara F, De Gregori M, Ciccone R, Broomer A, Casuga I, Wang Y, Xiao C, Barbacioru C, Gimelli G, Dalla Bernardina B, Torniero C, Giorda R, Regan R, Murday V, Mansour S, Fichera M, Castiglia L, Failla P, Ventura M, Jiang Z, Cooper GM, Knight SJL, Romano C, Zuffardi O, Chen C, Schwartz CE, Eichler EE. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet. 2008 Feb 17; [Epub ahead of print] Abstract