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

Wiedemann-Steiner syndrome (WDSTS) is a rare genetic 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 Rett, Rubinstein-Taybi and Kabuki syndromes, related Mendelian disorders of the epigenetic machinery. 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. The neurological phenotypes show rescue upon restoration of KMT2A in-utero following breeding to a nestin-Cre. 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.