Missense variants causing Wiedemann-Steiner syndrome preferentially occur in the KMT2A-CXXC domain and are accurately classified using AlphaFold2.

ABSTRACT: Wiedemann-Steiner syndrome (WDSTS) is a neurodevelopmental disorder caused by de novo variants in KMT2A, which encodes a multi-domain histone methyltransferase. To gain insight into the currently unknown pathogenesis of WDSTS, we examined the spatial distribution of likely WDSTS-causing variants across the 15 different domains of KMT2A. Compared to variants in healthy controls, WDSTS variants exhibit a 61.9-fold overrepresentation within the CXXC domain-which mediates binding to unmethylated CpGs-suggesting a major role for this domain in mediating the phenotype. In contrast, we find no significant overrepresentation within the catalytic SET domain. Corroborating these results, we find that hippocampal neurons from Kmt2a-deficient mice demonstrate disrupted histone methylation (H3K4me1 and

SUBMITTER: Reynisdottir T 

PROVIDER: S-EPMC9249231 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature