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ATP7B Variant c.1934T>G p.Met645Arg Causes Wilson Disease by Promoting Exon 6 Skipping

View ORCID ProfileDaniele Merico, Carl Spickett, Matthew O’Hara, Boyko Kakaradov, Amit G. Deshwar, Phil Fradkin, Shreshth Gandhi, Jiexin Gao, Solomon Grant, Ken Kron, Frank W. Schmitges, Zvi Shalev, Mark Sun, Marta Verby, Matthew Cahill, James J. Dowling, Johan Fransson, Erno Wienholds, Brendan J. Frey
doi: https://doi.org/10.1101/693572
Daniele Merico
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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  • ORCID record for Daniele Merico
  • For correspondence: daniele@deepgenomics.com daniele.merico@gmail.com frey@deepgenomics.com
Carl Spickett
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Matthew O’Hara
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Boyko Kakaradov
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Amit G. Deshwar
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Phil Fradkin
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Shreshth Gandhi
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Jiexin Gao
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Solomon Grant
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Ken Kron
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Frank W. Schmitges
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, CanadaWuXi AppTec, NJ, USA
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Zvi Shalev
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Mark Sun
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Marta Verby
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Matthew Cahill
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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James J. Dowling
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Johan Fransson
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Erno Wienholds
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, CanadaTesseraqt Optimization Inc., 222 College Street, Toronto, ON M5J 3J1, Canada
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Brendan J. Frey
Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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  • For correspondence: daniele@deepgenomics.com daniele.merico@gmail.com frey@deepgenomics.com
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ABSTRACT

Wilson Disease is a recessive genetic disorder caused by pathogenic loss-of-function variants in the ATP7B gene. It is characterized by disrupted copper homeostasis resulting in liver disease and/or neurological abnormalities. The variant NM_000053.3:c.1934T>G (Met645Arg) has been reported as compound heterozygous and is highly prevalent among Wilson Disease patients of Spanish descent. Accordingly, it is classified as pathogenic by leading molecular diagnostic centers. However, functional studies suggest that the amino acid change does not alter protein function, leading one ClinVar submitter to question its pathogenicity. Here we used a minigene system and gene-edited HepG2 cells to demonstrate that c.1934T>G causes approximately 70% skipping of exon 6. Exon 6 skipping results in frameshift and stop gain, which is expected to cause loss of ATP7B function. The elucidation of the mechanistic effect for this variant resolves any doubt about its pathogenicity and enables the development of genetic medicines for restoring correct splicing.

Footnotes

  • ↵* equal contribution

  • Added results for two homozygous HepG2 clones; moved some material to supplement.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 17, 2019.
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ATP7B Variant c.1934T>G p.Met645Arg Causes Wilson Disease by Promoting Exon 6 Skipping
Daniele Merico, Carl Spickett, Matthew O’Hara, Boyko Kakaradov, Amit G. Deshwar, Phil Fradkin, Shreshth Gandhi, Jiexin Gao, Solomon Grant, Ken Kron, Frank W. Schmitges, Zvi Shalev, Mark Sun, Marta Verby, Matthew Cahill, James J. Dowling, Johan Fransson, Erno Wienholds, Brendan J. Frey
bioRxiv 693572; doi: https://doi.org/10.1101/693572
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ATP7B Variant c.1934T>G p.Met645Arg Causes Wilson Disease by Promoting Exon 6 Skipping
Daniele Merico, Carl Spickett, Matthew O’Hara, Boyko Kakaradov, Amit G. Deshwar, Phil Fradkin, Shreshth Gandhi, Jiexin Gao, Solomon Grant, Ken Kron, Frank W. Schmitges, Zvi Shalev, Mark Sun, Marta Verby, Matthew Cahill, James J. Dowling, Johan Fransson, Erno Wienholds, Brendan J. Frey
bioRxiv 693572; doi: https://doi.org/10.1101/693572

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