Transgenic mice with an R342X mutation in Phf6 have reduced protein levels and behavior deficits yet few prominent features of Börjeson-Forssman-Lehmann Syndrome (BFLS).

The PHF6 mutation, R342X, is a recurrent cause of Börjeson-Forssman-Lehmann Syndrome (BFLS), a neurodevelopmental disorder (MIM#301900). We generated transgenic mice with the identical substitution using CRISPR technology. We show that the R342X mutation causes a reduction in PHF6 protein levels, in both mice and humans, from nonsense mediated decay and nonsense-associated alternative splicing. MRI studies indicated that R342X mice had a reduced brain volume on a mixed genetic background but developed hydrocephaly and a high incidence of postnatal death on a C57BL/6 background. Cortical development proceeded normally while hippocampus and hypothalamus relative brain volumes were reduced. Behavior testing demonstrated deficits in associative learning, spatial memory and an anxiolytic phenotype, although other BFLS clinical features were not observed in the R342X mice. We performed RNA-seq analysis on the cerebral cortices of neonatal R342X mice with the purpose of finding a relationship between gene expression profiles, the behavioral phenotype and the cortical morphology. Overall design: Assess the change in gene expression profiles in mouse cortex due to the R342X mutation in Phf6