In-utero rescue of neurological dysfunction in a mouse model of Wiedemann-Steiner syndrome

Wiedemann-Steiner syndrome (WDSTS) is a rare genetically determined cause of intellectual disability primarily caused by heterozygous loss of function variants in the gene encoding the histone methyltransferase KMT2A. Prior studies have shown successful postnatal amelioration of disease phenotypes for several related Mendelian disorders of the epigenetic machinery, including Rett, Rubinstein-Taybi and Kabuki syndromes. To explore whether the neurological phenotype in WDSTS is treatable in-utero, we created a novel mouse model carrying a loss of function variant in between two LoxP sites. Kmt2a+/LSL mice demonstrate core features of WDSTS including growth retardation, craniofacial abnormalities, and hypertrichosis as well as hippocampal memory defects. This mouse model offers a strategy to systematically explore the therapeutic window in WDSTS. The neurological phenotypes show rescue upon breeding to a nestin-Cre, which restores KMT2A levels in-utero. Together, our data provide a novel mouse model to explore the therapeutic window in WDSTS. Our work suggests that WDSTS has a window of opportunity extending at least until the mid-point of in-utero development, making WDSTS an ideal candidate for future therapeutic strategies. Overall design: To evaluate rescue of transcriptional abnormalities caused by heterozygous Kmt2a-deficiency and in-utero rescue of the effect in a homogenous cell population, we dissected the hippocampus from newborn pups (P0) and cultured mouse neuronal progenitor cells (mNPCs). We performed RNA-sequencing to identify gene expression changes between Kmt2a+/+ and Kmt2a+/LSL NPCs and the reversal in Nes-Cre+/-Kmt2a+/LSL.