PhD Student McGill University Montreal, Quebec, Canada
Abstract: Kleefstra syndrome is a rare, neurodevelopmental disorder characterized by intellectual disability, childhood hypotonia, craniofacial anomalies, and psychiatric regression. Genetically, Kleefstra syndrome arises from either a heterozygous deletion in the 9q34.3 chromosomal region (including the EHMT1 gene) or an intragenic pathogenic variant in EHMT1, in either case leading to haploinsufficiency of EHMT1. EHMT1 encodes a lysine methyltransferase protein, critically tasked with methylating histone 3 to regulate gene expression. The c.2712+1866G>A is a newly identified pathogenic variant in Kleefstra syndrome, an intronic splice variant in EHMT1 that activates a cryptic acceptor site. Using human-derived pluripotent stem cells as a model, we have demonstrated that this variant leads to the expression of an alternate transcript, which contains a retained portion of an intron, and reduced EHMT1 protein on western blot. Antisense oligonucleotides (ASOs) are a powerful emerging class of drugs that can target disease at the level of pre-mRNA. We have designed ASOs that sterically block the cryptic acceptor site, in order to restrict access to the spliceosome and encourage skipping of the cryptic exon. Given the heterozygous nature of this disorder, a steric-blocking ASO approach aims to promote functional EHMT1 protein from the pathogenic allele. This study utilizes human-derived stem cells as a model to demonstrate a novel use for ASOs in this rare disorder.
Funding Source: Canadian Institutes of Health Research (CIHR) Doctoral Scholarship
