FMRP in Psychiatric Disease

Fragile X Syndrome

• Caused by loss of expression of FMR1
• FMRP is an RNA-binding protein which stalls target transcript translation at postsynaptic sites in the brain
• Found to regulate a broad range of psychiatric disease genes

Symptoms: Elongated face, Broad forehead, low IQ, developmental delays, autism, ADD, seizures

Role in Human psychiatric disease

• FMRP found to regulate a large number of autism and schizophrenia disease genes

Unanswered questions

• Schizophrenia and Autism disease genes are expressed at different developmental timepoints--do the targets of FMRP change over time?
• Can we uncover new disease genes by reanalyzing genetic data w/ an FMRP filter?

8PCW

40 YO

FMR1 expression

Aim 1

Perform CLIP-seq on fetal and adult mice frontal cortex neurons to determine differential regulation by FMRP

Fetal

Old

Sequencing

Sequencing

Aim 2

A) Filter regulated transcripts for disease significance and possible impact

gene list

psychiatric disease genetic studies

B) Test for morphological changes in human neuronal cell lines (KO/overexpression models)

gene list

PGC GWAS, TDT & recurrent DN:LOF w/ SSC

KO gene X