Functional characterization of a FRMPD4 mutation in a UDP family

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DESCRIPTION (provided by applicant): Abstract The NIH-undiagnosed disease program (UDP) focuses on defining the molecular basis and mechanisms of rare genetic disorders. A large fraction of patients applying for the UPD program suffer from unknown neurological disorders (43%), which underscores the importance to develop novel diagnostic workup and therapies through close collaborations between clinical and basic investigators. A missense mutation in an X-linked gene, FRMPD4 (also termed Preso1), was recently identified in two male sibs who exhibited global developmental delays, cognitive regression, seizure disorders, and a constellation of other clinical findings. Here, we will examine the hypothesis that human Preso1-K195E is causal for these symptoms. In our previous work, we have identified Preso1 as a co-functional protein with the group 1 metabotropic glutamate receptors (mGluR). Genetic modifications of group 1 mGluR signaling are known to result in various developmental and degenerative phenotypes in mouse models (Niswender and Conn, 2010). Preso1 encodes a multi-domain protein that binds mGluR5 and controls its phosphorylation state, and thereby provides important regulation of mGluR5 function. We propose to utilize in vitro and neuron- based assays, and to generate transgenic mouse models to examine the hypothesis that the K187E mouse mutation of Preso1 results in altered mGluR5 functions that are crucial for synapse formation, synaptic plasticity, and behavioral responses in social interaction and to rewarding stimuli that are important for learning and memory. We will examine convergent mechanisms with other genetic causes of developmental brain disease that impact mGluR5 function including Fragile X Mental Retardation Syndrome. We will also screen for mutations in the Preso gene family members in additional patients with X-linked intellectual disability and/or epilepsy. These studies will determine if Preso1 (K195E) is causal for the neurological defects in the UDP family and if the Preso gene family represents a novel cause for developmental brain disorders. The results will provide mechanistic insights into pathogenesis that will be important for the establishment of rational therapies.