@article{Spielmann01022016,
author = {Spielmann, Malte and Kakar, Naseebullah and Tayebi, Naeimeh and Leettola, Catherine and Nürnberg, Gudrun and Sowada, Nadine and Lupiáñez, Darío G. and Harabula, Izabela and Flöttmann, Ricarda and Horn, Denise and Chan, Wing Lee and Wittler, Lars and Yilmaz, Rüstem and Altmüller, Janine and Thiele, Holger and van Bokhoven, Hans and Schwartz, Charles E. and Nürnberg, Peter and Bowie, James U. and Ahmad, Jamil and Kubisch, Christian and Mundlos, Stefan and Borck, Guntram}, 
title = {Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice},
volume = {26}, 
number = {2}, 
pages = {183-191}, 
year = {2016}, 
doi = {10.1101/gr.199430.115}, 
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.}, 
URL = {http://genome.cshlp.org/content/26/2/183.abstract}, 
eprint = {http://genome.cshlp.org/content/26/2/183.full.pdf+html}, 
journal = {Genome Research} 
}