A genetic variant that disrupts MET transcription is associated with autism

 Authored by Campbell, DB, Sutcliffe JS, Ebert PJ, Militerni R., Bravaccio C., Trillo S., Elia M., Schneider C., Melmed R., Sacco R., et al. in Proc Natl Acad Sci U S A. (epub), Volume 103, Issue 45, p. 16834-16839, (2006).

This article describes a study showing that many children with autism have a mutation in a gene involved in brain development, immune system function, and digestion.

The authors describe how previous research into the genetics of autism has focused on genes involved only in brain function. In this study, they take a different approach, and focus on a gene that is also involved in the immune system and digestion. Previous studies have shown that many children with autism seem to have problems in their immune system and digestive system. After analyzing the genes of 1,231 individuals with autism, they found that this gene was significantly more likely to be altered than in the general population. Because this gene is involved in brain development as well as the function of the immune and digestive systems, the result suggests that more than one system may be affected in autism

Abstract

There is strong evidence for a genetic predisposition to autism and an intense interest in discovering heritable risk factors that disrupt gene function. Based on neurobiological findings and location within a chromosome 7q31 autism candidate gene region, we analyzed the gene encoding the pleiotropic MET receptor tyrosine kinase in a family based study of autism including 1,231 cases. MET signaling participates in neocortical and cerebellar growth and maturation, immune function, and gastrointestinal repair, consistent with reported medical complications in some children with autism. Here, we show genetic association (P = 0.0005) of a common C allele in the promoter region of the MET gene in 204 autism families. The allelic association at this MET variant was confirmed in a replication sample of 539 autism families (P = 0.001) and in the combined sample (P = 0.000005). Multiplex families, in which more than one child has autism, exhibited the strongest allelic association (P = 0.000007). In case-control analyses, the autism diagnosis relative risk was 2.27 (95% confidence interval: 1.41-3.65; P = 0.0006) for the CC genotype and 1.67 (95% confidence interval: 1.11-2.49; P = 0.012) for the CG genotype compared with the GG genotype. Functional assays showed that the C allele results in a 2-fold decrease in MET promoter activity and altered binding of specific transcription factor complexes. These data implicate reduced MET gene expression in autism susceptibility, providing evidence of a previously undescribed pathophysiological basis for this behaviorally and medically complex disorder

This entry was posted on 6. February 2011 at 00:09 and is filed under Genetic. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response or trackback from your own site.