Málstofa Lífvísindaseturs - Neurological dysfunction in Wiedemann-Steiner mouse model

Málstofa Lífvísindaseturs fimmtudaginn 22. janúar kl. 12:30 - 13:10 í Árnagarði, stofu 306

Fyrirlesari: Dr. Kimberley J. Anderson, Department of Genetics and Molecular Medicine, Landspítali University Hospital; Louma G. Laboratory of Epigenetic Research, Faculty of Medicine, University of Iceland.

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

Abstract: Wiedemann–Steiner syndrome (WDSTS) is a neurodevelopmental disorder resulting from heterozygous loss-of-function variants in KMT2A, which encodes a histone methyltransferase. Although WDSTS is clinically defined by postnatal cognitive and developmental impairments, the developmental timing at which KMT2A function is required for normal brain development remains unclear. Prior studies in related chromatin-associated neurodevelopmental disorders have demonstrated phenotypic improvement following either restoration of gene function or modulation of chromatin state.

To directly test this possibility in WDSTS, we engineered a conditionally reversible Kmt2a loss-of-function mouse model that allows restoration of gene expression in vivo. Mice carrying the Kmt2a loss-of-function allele (Kmt2a+/LSL) display multiple phenotypes consistent with WDSTS, including impaired growth, craniofacial abnormalities, excess hair growth, and deficits in hippocampal-dependent learning and memory. Targeted restoration of Kmt2a expression in neural progenitors during mid-gestation via Nestin-Cre rescued the observed neurological phenotypes.

Together, these findings indicate that the neurological consequences of early Kmt2a loss remain developmentally malleable. This work establishes a mouse model for defining the developmental timing of KMT2A requirement in WDSTS and demonstrates that disease-relevant neurological phenotypes are not fixed prior to the midpoint of embryonic development. Collectively, these results reposition WDSTS as a neurodevelopmental disorder with a meaningful therapeutic window, supporting its potential as a treatable cause of intellectual disability.