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

Spielmann, Malte; Kakar, Naseebullah; Tayebi, Naeimeh; Leettola, Catherine; Nürnberg, Gudrun; Sowada, Nadine; Lupiáñez, Darío G.; Harabula, Izabela; Flöttmann, Ricarda; Horn, Denise; Chan, Wing Lee; Wittler, Lars; Yilmaz, Rüstem; Altmüller, Janine; Thiele, Holger; van Bokhoven,, Hans; Schwartz, Charles E.; Nürnberg, Peter; Bowie, James U.; Ahmad, Jamil; Kubisch, Christian; Mundlos, Stefan

doi:10.1101/gr.199430.115

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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.

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Spielmann, Malte
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;
Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin.;
International Graduate School in Molecular Medicine Ulm, University of Ulm.;

Tayebi, Naeimeh
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

Lupiáñez, Darío G.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;
Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin.;

Harabula, Izabela
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

Chan, Wing Lee
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;
Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin.;

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Wittler, Lars
Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Mundlos, Stefan
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;
Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin.;

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Citation

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.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002D-431F-D

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.