Genomic imbalances at the 22q11 locus and predisposition to autism

Joseph Gogos, M.D., Ph.D.
Columbia University

Autism has been linked to small genomic rearrangements such as deletions, insertions and duplications, but how these aberrations lead to the disorder is unclear. Joseph Gogos of Columbia University and his colleagues aim to address this question by studying mice with a deletion similar to one frequently seen in people with autism.

Copy-number variations (CNV), or the gain or loss of a chunk of DNA, can change cell physiology by altering the dosage of genes in that region. The technological advances of the past few years have made it possible to systematically detect small genomic rearrangements (~1Mb) and identify their high frequency in neurological disorders such as autism and schizophrenia. These CNVs can be found at many sites in the genome, but some locations, such as the human chromosomal region 22q11, appear to be rearranged in several cases of autism.

Gogos and colleagues have generated a mouse with a small deletion in the chromosomal region equivalent to the human 22q11 region, and found that the deletion disrupts two cellular processes: the production of microRNAs — small RNAs that regulate gene expression — and the addition of palmitoyl groups to proteins. In the absence of microRNAs, cells have abnormal gene expression; without protein palmitoylation, important signaling proteins are improperly distributed within the cell. Either malfunction can lead to deficits in neuronal communication and function, the researchers reported in 2008.

Gogos and colleagues now plan to more thoroughly characterize these mice and determine whether miRNAs or protein palmitoylation may underlie the neurobiological abnormalities in autism. Signaling complexes between neurons, called synapses, tend to be sparse and weaker in autistic brains. The researchers plan to look at neuronal morphology in these mice, following synapse formation through initial construction to maturation. They also plan to measure the electrical activity of the mouse neurons to determine how the abnormal development affects neuronal function and how these cellular phenotypes manifest in terms of cognition and social behavior. Their exploration of this deletion may show how other CNVs interfere with neural development, and perhaps uncover new targets for autism therapies or diagnostic tests.