Systemic abnormalities of immune system function in patients with autism spectrum disorders (ASD) have been noted for more than 35 years. Indeed, disrupted immune system function has been proposed as a causative factor of ASD. In this Concept Award application, we propose that disrupted immune function might be correlative, but not causative of ASD. Rather, we propose that there might be a gene mutation in common. Such a gene would have important functions both for the development and/or function of the immune system as well as important functions for the development and/or function of the brain. Disruption of the function of such a gene would, therefore, independently affect both systems.
We recently discovered that the transcription factor Promyelocytic Leukemia Zinc Finger (PLZF) is critical for the function of several cell types that are part of the innate immune system. PLZF is also expressed in the brain, where it has been proposed to influence forebrain organization. Importantly, forebrain abnormalities have been noted in children with autism. We will explore the possibility that mutation of PLZF represents a commonality between immune system disruption and altered brain functions associated with ASD. A two-tier approach will be carried out. First, mice that have the PLZF gene disrupted by gene targeting will be studied for behavior abnormalities. Both PLZF deficient and haploinsufficient mice will be examined. Second, databases of human genetic variations associated with ASD will be explored to determine if allelic variations of PLZF can be correlated with ASD.