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

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dc.contributor.author Reynisdóttir, Tinna
dc.contributor.author Anderson, Kimberley Jade
dc.contributor.author Boukas, Leandros
dc.contributor.author Björnsson, Hans Tómas
dc.date.accessioned 2022-09-22T01:02:00Z
dc.date.available 2022-09-22T01:02:00Z
dc.date.issued 2022-06-21
dc.identifier.citation Reynisdóttir , T , Anderson , K J , Boukas , L & Björnsson , H T 2022 , ' Missense variants causing Wiedemann-Steiner syndrome preferentially occur in the KMT2A-CXXC domain and are accurately classified using AlphaFold2 ' , PLoS Genetics , vol. 18 , no. 6 , e1010278 , pp. e1010278 . https://doi.org/10.1371/journal.pgen.1010278
dc.identifier.issn 1553-7390
dc.identifier.other 59757623
dc.identifier.other f58224a9-e1a8-41e9-aa67-9bd94e5866ab
dc.identifier.other 85133097120
dc.identifier.other 35727845
dc.identifier.uri https://hdl.handle.net/20.500.11815/3474
dc.description Funding Information: This work was supported by a grant from the Wiedemann-Steiner Foundation to HTB (salary coverage of TR). HTB is also supported by the Louma G. Foundation, the Icelandic Research Fund (#217988, #195835, #206806) and the Icelandic Technology Development Fund (#2010588). Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health (#R01GM121459 to LB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2022 Reynisdottir et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.description.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 H3K4me3) preferentially at CpG-rich regions, but this has no systematic impact on gene expression. Motivated by these results, we combine accurate prediction of the CXXC domain structure by AlphaFold2 with prior biological knowledge to develop a classification scheme for missense variants in the CXXC domain. Our classifier achieved 92.6% positive and 92.9% negative predictive value on a hold-out test set. This classification performance enabled us to subsequently perform an in silico saturation mutagenesis and classify a total of 445 variants according to their functional effects. Our results yield a novel insight into the mechanistic basis of WDSTS and provide an example of how AlphaFold2 can contribute to the in silico characterization of variant effects with very high accuracy, suggesting a paradigm potentially applicable to many other Mendelian disorders.
dc.format.extent 1826810
dc.format.extent e1010278
dc.language.iso en
dc.relation.ispartofseries PLoS Genetics; 18(6)
dc.rights info:eu-repo/semantics/openAccess
dc.subject Lífefna- og sameindalíffræði
dc.subject Abnormalities, Multiple
dc.subject Craniofacial Abnormalities
dc.subject Growth Disorders
dc.subject Hypertrichosis
dc.subject Intellectual Disability
dc.subject Myeloid-Lymphoid Leukemia Protein
dc.subject Myeloid-Lymphoid Leukemia Protein/genetics
dc.subject Abnormalities, Multiple/genetics
dc.subject Hypertrichosis/genetics
dc.subject Growth Disorders/genetics
dc.subject Histone-Lysine N-Methyltransferase/genetics
dc.subject Mutation, Missense
dc.subject Protein Folding
dc.subject Syndrome
dc.subject Intellectual Disability/genetics
dc.subject Animals
dc.subject Protein Domains
dc.subject Mice
dc.subject Genetics (clinical)
dc.subject Genetics
dc.subject Ecology, Evolution, Behavior and Systematics
dc.subject Molecular Biology
dc.subject Cancer Research
dc.title Missense variants causing Wiedemann-Steiner syndrome preferentially occur in the KMT2A-CXXC domain and are accurately classified using AlphaFold2
dc.type /dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article
dc.description.version Peer reviewed
dc.identifier.doi 10.1371/journal.pgen.1010278
dc.relation.url http://www.scopus.com/inward/record.url?scp=85133097120&partnerID=8YFLogxK
dc.contributor.department Faculty of Medicine
dc.contributor.department Other departments
dc.contributor.department Clinical Laboratory Services, Diagnostics and Blood Bank

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