RNA expression studies in autism spectrum disorders
Louis Kunkel, Ph.D.
Children’s Hospital Boston
There are several factors that raise the risk of autism, including sequence variants of some genes, advanced paternal age and viral infection during pregnancy. Louis Kunkel of the Children’s Hospital in Boston and his colleagues aim to discern whether these diverse factors trigger a common gene expression profile in children with autism.
The initial conditions that disrupted neural development are difficult to identify after autism has been diagnosed, but hints might be found in the patterns of gene expression that those conditions leave behind. For example, several risk factors may spark brain growth by inducing proliferation pathways, albeit each in a different way: one may increase the production of growth factors, which promote mitosis, whereas another may reduce the levels of PTEN, a protein that represses cell growth. But both effects would stimulate cell division in the brain and may create a similar gene expression profile.
Kunkel and his team plan to compare the expression profiles in blood samples from families affected by autism with those from healthy controls, to search for differences that might indicate a gene expression ‘signature’ for the disorder; many genes expressed in the brain are also expressed in blood cells. The researchers then hope to associate some cases of autism with these patterns of gene expression. For example, they may be able to correlate a specific gene expression signature to the severity of the disorder, such as age at first word spoken. This information may help researchers group cases of autism to look for common genetic causes or to develop individualized therapies.
Patterns of gene expression do not always reflect the final protein composition, however, in part because primary transcripts can be alternatively spliced into several, distinct mRNA sequences called isoforms. Kunkel and colleagues propose that atypical patterns of mRNA isoforms expressed in neurons may lead to the abnormal brain development seen in autistic brains. To search for these patterns, they plan to analyze patterns of mRNA isoforms in blood and autopsy brain samples from people with the disorder, focusing on the transcripts expressed in late neuronal development, around the time of autism onset. These studies may lead to a simple test for diagnosing the disorder and may implicate new cellular pathways in autism, opening up new avenues for research.