Spielmann, Malte ORCID: 0000-0002-0583-4683, Kakar, Naseebullah, Tayebi, Naeimeh, Leettola, Catherine, Nuernberg, Gudrun, Sowada, Nadine, Lupianez, Dario G. ORCID: 0000-0002-3165-036X, Harabula, Izabela, Floettmann, Ricarda, Horn, Denise, Chan, Wing Lee, Wittler, Lars, Yilmaz, Ruestem, Altmueller, Janine, Thiele, Holger, van Bokhoven, Hans, Schwartz, Charles E., Nuernberg, Peter, Bowie, James U., Ahmad, Jamil, Kubisch, Christian ORCID: 0000-0003-4220-0978, Mundlos, Stefan and Borck, Guntram (2016). Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice. Genome Res., 26 (2). S. 183 - 192. COLD SPRING HARBOR: COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT. ISSN 1549-5469

Full text not available from this repository.

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Spielmann, MalteUNSPECIFIEDorcid.org/0000-0002-0583-4683UNSPECIFIED
Kakar, NaseebullahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tayebi, NaeimehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leettola, CatherineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sowada, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lupianez, Dario G.UNSPECIFIEDorcid.org/0000-0002-3165-036XUNSPECIFIED
Harabula, IzabelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Floettmann, RicardaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horn, DeniseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chan, Wing LeeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wittler, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yilmaz, RuestemUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Bokhoven, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwartz, Charles E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bowie, James U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahmad, JamilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kubisch, ChristianUNSPECIFIEDorcid.org/0000-0003-4220-0978UNSPECIFIED
Mundlos, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borck, GuntramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-286241
DOI: 10.1101/gr.199430.115
Journal or Publication Title: Genome Res.
Volume: 26
Number: 2
Page Range: S. 183 - 192
Date: 2016
Publisher: COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
Place of Publication: COLD SPRING HARBOR
ISSN: 1549-5469
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HAND/SPLIT-FOOT MALFORMATION; STERILE-ALPHA MOTIF; MOLECULAR CHARACTERIZATION; SAM DOMAIN; ARRAY-CGH; PROTEIN; CELLS; P63; KINASE; TRANSCRIPTIONMultiple languages
Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/28624

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item