AUTISM AND AMPS LYASE MUTATIONS: CELL AND MOUSE MODELS

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DESCRIPTION (provided by applicant): Adenylosuccinate lyase (ADSL) catalyzes two steps of de novo purine biosynthesis. In 1984, a genetic syndrome was described in which a deficiency in ADSL leads to profound developmental delay and, in up to 30% of cases, autistic features (5). Currently, over 30 mutations in ADSL are known to cause ADSL deficiency. The clinical picture in these individuals can vary widely. Interestingly, in 2000 an ADSL deficiency patient was reported with minimal developmental delay and autistic features. (6) In 1987, we mapped the gene for ADSL to human chromosome 22 (29). The precise location of the ADSL gene is now known to be in the 22q13 region. Chromosomal anomalies in this region are also associated with autism. This data suggests that ADSL deficiency is a contributing factor to autism as well as to psychomotor delay and mental retardation. Autism affects approximately 1 in 2000 individuals. Defining features are impaired sociability, language and communication, and range of interests and activities. Mental deficiency may or may not be present, and the cognitive profile is narrow, occasionally with superior but narrow talent. Perseveration, concreteness, affective blunting, and lack of insight into other persons' thinking may be present. We have isolated and extensively characterized a Chinese hamster ovary cell (CHO-K1) cell mutant, Adel, completely lacking in ADSL activity. We now propose to create and characterize a mouse model of ADSL deficiency. For this purpose, we will inactivate the mouse ADSL gene by targeted mutagenesis. We will then introduce the wild type and selected mutant human ADSL genes into different lines of transgenic mice and by appropriate breeding create mice carrying only the wild type or mutant forms of human ADSL. We will produce mice with the R426H mutation that leads to severe developmental delay, often with autistic features, and the R303C mutation that leads to mild disease. These mice will then be analyzed neuroanatomically, biochemically, physiologically, and behaviorally to understand the consequences of ADSL mutations. We will then attempt to intervene with appropriate pharmacological agents to reverse the effects of ADSL deficiency, and, we hope, to other forms of autism.