Líffræðifélag Íslands - biologia.is
Líffræðiráðstefnan 2021

Erindi/veggspjald / Talk/poster V56

Bioinformatic analysis supports importance of CXXC domain in Wiedemann-Steiner syndrome disease phenotype

Höfundar / Authors: Tinna Reynisdóttir1, Leandros Boukas2, Hans Tómas Björnsson1,2,3

Starfsvettvangur / Affiliations: 1Laboratory of Translational Medicine, Faculty of Medicine, University of Iceland; 2Department of Genetics and Molecular Medicine, Landspítali; 3McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University.

Kynnir / Presenter: Tinna Reynisdóttir

Wiedemann-Steiner syndrome (WSS) is a rare Mendelian disorder of the epigenetic machinery caused by de novo heterozygous loss of function and missense variants (MV) in the KMT2A gene. KMT2A encodes a multi-domain histone-lysine N-methyltransferase that’s post-translationally processed into N- (CpG targeting) and C-terminal (enzymatic) products that subsequently heterodimerize. WSS is characterized by intellectual disability, growth retardation and hypertrichosis, however the mechanistic basis is currently poorly understood although most researchers believe that the enzyme function plays a critical role. In an effort to elucidate the mechanistic basis of WSS, we conducted a systematic analysis of all MVs found in KMT2A in individuals with WSS (ClinVar), cancers (COSMIC) and control population (gnomAD). Our results demonstrate that MVs in WSS are overrepresented in the N-terminal compared to controls. Furthermore, this enrichment appears most striking for the CXXC domain, which plays a role in binding to unmethylated CpG dinucleotides. Within the CXXC domain the MVs appear to preferentially affect well conserved cysteine residues, which play a role in zinc binding of the protein. Finally, when we modelled the structural consequences of individual MVs using AlphaFold and UCSF ChimeraX (1.2.5), we observed that many of the WSS MVs cause disruption of the 3D structure of the domain. Thus, our findings suggest that CXXC domain plays a critical role in WSS pathogenesis.