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Four independent studies have uncovered different autism-associated variants in the gene CNTNAP2 (contactin-associated protein-like 2), making this gene the first to have multiple variants associated with the disorder. The striking pervasiveness and diversity of the variants suggests that CNTNAP2 plays a crucial role in autism, leading Aravinda Chakravarti and his colleagues at The Johns Hopkins University School of Medicine to embark on a detailed study of the gene.
The CNTNAP2 gene encodes a cell adhesion protein that regulates signaling between neurons at a specialized region known as the synapse. As members of the neurexin family, CNTNAP2 proteins organize the synapse on the signal-receiving cell, in part by coordinating the localization of signal receptors to the area. The CNTNAP2 gene is highly expressed in the neurons that control language and language development, difficulties with which are a hallmark of autism. Disrupting the gene?s activity may impair synapse formation in these neurons and potentially affect language abilities.
Chakravarti led one of the recent efforts that linked CNTNAP2 to autism. The four studies together uncovered 13 different variants in this gene?s sequence in people with autism. Chakravarti and his team plan a comprehensive hunt for more variants that are associated with autism and to determine how they affect gene function; this information may be useful in the diagnosis and treatment of autism. Moreover, because CNTNAP2 may be in a fragile region of the genome that is highly susceptible to mutations, the gene may underlie a significant number of autism cases.
The severity of the social, behavioral and language impairments seen in autism varies significantly from person to person, however. For the study that uncovered CNTNAP2, Chakravarti and colleagues limited their examination by gathering DNA samples from a large group of people with autism who share similar abilities and disabilities, such as the age at which they spoke their first word. This pre-selection makes the data set more precisely tuned to uncover genes related to traits of that intensity and improves the statistical analysis to find variants. With collaborator Mark Daly of Harvard Medical School, Chakravarti and colleagues plan to continue to mine this and additional family data, hoping it will prove as fruitful in uncovering novel genes linked to autism as it was for CNTNAP2.
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