A patient derived missense mouse model of Kabuki syndrome 1
Kabuki syndrome (KS) is a rare cause of intellectual disability resulting from heterozygous pathogenic variants in the gene encoding the histone methyltransferase KMT2D. A previously established loss-of-function mouse model of KS exhibits key phenotypic features, and therapeutic trials in this mouse model suggest postnatal malleability of neurological symptoms. However, 15-30% of individuals with KS, carry missense variants. To investigate whether missense variants lead to similar phenotypic presentation in mice, we used CRISPR-Cas9 to introduce the KS patient variant R5230H into C57BL/6NTac. Computational and in vitro testing suggests that the R5230H variant does not impair protein stability or loss of enzyme function of KMT2D. Despite a distinct mechanistic basis, our new mouse model (Kmt2d+/R5230H) recapitulates most phenotypes of our prior loss-of-function model, including growth deficiency, craniofacial anomalies, and IgA deficiency but not altered neurological function. Kmt2d+/R5230Hmice show perinatal lethality and a high frequency of unilateral kidney agenesis, a novel phenotype in KS mouse models. Kmt2d+/R5230H mice provide a unique opportunity to understand the impact of missense variants on KMT2D function and uncover developmental and perinatal abnormalities in KS. Summary statementA novel Kabuki syndrome missense mouse model with intact KMT2D enzymatic function shares most features with prior KS models, except disruption of adult neurogenesis, and exhibits novel unilateral kidney loss.