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 that is primarily caused by heterozygous loss-of-function variants in the gene encoding the histone lysine methyltransferase 2A (KMT2A). Prior studies have shown successful postnatal amelioration of disease phenotypes for Rett, Rubinstein-Taybi, and Kabuki syndromes, which are related Mendelian disorders of the epigenetic machinery. To explore whether the neurological phenotype in WDSTS is treatable in utero, we created a mouse model carrying a loss-of-function variant placed between 2 loxP sites. Kmt2a+/LSL mice demonstrated core features of WDSTS including growth retardation, craniofacial abnormalities, and hypertrichosis as well as hippocampal memory defects. The neurological phenotypes were rescued upon restoration of KMT2A in utero following breeding to a nestin-Cre. Together, our data provide a mouse model to explore the potential therapeutic window in WDSTS. Our work suggests that WDSTS has a window of opportunity extending at least until the midpoint of in utero development, making WDSTS an ideal candidate for future therapeutic strategies.