Grosz, Bianca R;
Tisch, Stephen;
Tchan, Michel C;
Fung, Victor SC;
Darveniza, Paul;
Fellner, Avi;
Kurian, Manju A;
... Kumar, Kishore R; + view all
(2022)
A novel synonymous KMT2B variant in a patient with dystonia causes aberrant splicing.
Molecular Genetics and Genomic Medicine
, 10
(5)
, Article e1923. 10.1002/mgg3.1923.
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Kurian_Molec Gen Gen Med - 2022 - Grosz - A novel synonymous KMT2B variant in a patient with dystonia causes aberrant splicing.pdf Download (1MB) | Preview |
Abstract
BACKGROUND: Heterozygous KMT2B variants are a common cause of dystonia. A novel synonymous KMT2B variant, c.5073C>T (p.Gly1691=) was identified in an individual with childhood-onset progressive dystonia. METHODS: The splicing impact of c.5073C>T was assessed using an in vitro exon-trapping assay. The genomic region of KMT2B exons 23-26 was cloned into the pSpliceExpress plasmid between exon 2 and 3 of the rat Ins2 gene. The c.5073C>T variant was then introduced through site-directed mutagenesis. The KMT2B wild-type and c.5073C>T plasmids were transfected separately into HeLa cells and RNA was extracted 48 hours after transfection. The RNA was reverse transcribed to produce cDNA, which was PCR amplified using primers annealing to the flanking rat Ins2 sequences. RESULTS: Sanger sequencing of the PCR products revealed that c.5073C>T caused a novel splice donor site and therefore a 5-bp deletion of KMT2B exon 23 in mature mRNA, leading to a coding frameshift and premature stop codon (p.Lys1692AsnfsTer7). CONCLUSION: To our knowledge, this is the first report of a KMT2B synonymous variant associated with dystonia. Reassessment of synonymous variants may increase diagnostic yield for inherited disorders including monogenic dystonia. This is of clinical importance, given the generally favourable response to deep brain stimulation for KMT2B-related dystonia.
| Type: | Article |
|---|---|
| Title: | A novel synonymous KMT2B variant in a patient with dystonia causes aberrant splicing |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/mgg3.1923 |
| Publisher version: | https://doi.org/10.1002/mgg3.1923 |
| Language: | English |
| Additional information: | © 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
| Keywords: | KMT2B, deep brain stimulation, dystonia, splicing, synonymous |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10145616 |
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