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  Exome Sequencing and CRISPR/Cas Genome Editing Identify Mutations of ZAK as a Cause of Limb Defects in Humans and Mice.

Spielmann, M., Kakar, N., Tayebi, N., Leettola, C., Nürnberg, G., Sowada, N., et al. (2016). Exome Sequencing and CRISPR/Cas Genome Editing Identify Mutations of ZAK as a Cause of Limb Defects in Humans and Mice. Genome Research, 26(2), 183-191. doi:10.1101/gr.199430.115.

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© 2016 Spielmann et al. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at




Spielmann, Malte1, 2, 3, Author              
Kakar, Naseebullah 3, 4, Author
Tayebi, Naeimeh 1, Author
Leettola, Catherine5, Author
Nürnberg, Gudrun 4, Author
Sowada, Nadine 4, Author
Lupiáñez, Darío G. 1, 2, Author
Harabula, Izabela 1, Author
Flöttmann, Ricarda 2, Author
Horn, Denise 2, Author
Chan, Wing Lee1, 2, Author
Wittler, Lars6, Author              
Yilmaz, Rüstem 3, 4, Author
Altmüller, Janine7, Author
Thiele, Holger7, Author
van Bokhoven,, Hans8, Author
Schwartz, Charles E. 9, Author
Nürnberg, Peter 7, 10, 11, Author
Bowie, James U. 5, Author
Ahmad, Jamil12, Author
Kubisch, Christian13, AuthorMundlos, Stefan1, 2, Author               more..
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin., 13353 Berlin, Germany., ou_persistent22              
3International Graduate School in Molecular Medicine Ulm, University of Ulm., 89081 Ulm, Germany., ou_persistent22              
4Institute of Human Genetics, University of Ulm., 89081 Ulm, Germany., ou_persistent22              
5Department of Chemistry and Biochemistry, UCLA-DOE Institute of Genomics and Proteomics, University of California, Los Angeles., Los Angeles, California 90095, USA., ou_persistent22              
6Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              
7Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany, ou_persistent22              
8Department of Human Genetics, Radboud University Medical Center., 6525 GA Nijmegen, The Netherlands., ou_persistent22              
9J.C. Self Research Institute, Greenwood Genetic Center, Greenwood., South Carolina 29646, USA., ou_persistent22              
10Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne., 50931 Cologne, Germany., ou_persistent22              
11Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany;, 50931 Cologne, Germany., ou_persistent22              
126Department of Biotechnology and Informatics, BUITEMS, , Quetta, 57789 Pakistan., ou_persistent22              
13Institute of Human Genetics, University Medical Center Hamburg-Eppendorf., 20246 Hamburg, Germany., ou_persistent22              


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 Abstract: The CRISPR/Cas technology enables targeted genome editing and the rapid generation of transgenic animal models for the study of human genetic disorders. Here we describe an autosomal recessive human disease in two unrelated families characterized by a split-foot defect, nail abnormalities of the hands, and hearing loss, due to mutations disrupting the SAM domain of the protein kinase ZAK. ZAK is a member of the MAPKKK family with no known role in limb development. We show that Zak is expressed in the developing limbs and that a CRISPR/Cas-mediated knockout of the two Zak isoforms is embryonically lethal in mice. In contrast, a deletion of the SAM domain induces a complex hindlimb defect associated with down-regulation of Trp63, a known split-hand/split-foot malformation disease gene. Our results identify ZAK as a key player in mammalian limb patterning and demonstrate the rapid utility of CRISPR/Cas genome editing to assign causality to human mutations in the mouse in <10 wk.


Language(s): eng - English
 Dates: 2015-12-072015-09-112015-12-072016-01-112016-02-01
 Publication Status: Published in print
 Pages: 9
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1101/gr.199430.115
 Degree: -



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Project name : M.S. was supported by a fellowship of the Berlin- Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany.
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Source 1

Title: Genome Research
Source Genre: Journal
Publ. Info: Cold Spring Harbor, N.Y. : Cold Spring Harbor Laboratory Press
Pages: - Volume / Issue: 26 (2) Sequence Number: - Start / End Page: 183 - 191 Identifier: ISSN: 1088-9051
CoNE: https://pure.mpg.de/cone/journals/resource/954926997202