PRDM15 loss of function links NOTCH and WNT/PCP signaling to patterning defects in holoprosencephaly

PRDM15 loss of function links NOTCH and WNT/PCP signaling to patterning defects in holoprosencephaly
Title:
PRDM15 loss of function links NOTCH and WNT/PCP signaling to patterning defects in holoprosencephaly
Other Titles:
Science Advances
Keywords:
Publication Date:
10 January 2020
Citation:
S. Mzoughi, F. Di Tullio, D. H. P. Low, C.-M. Motofeanu, S. L. M. Ong, H. Wollmann, C. M. Wun, P. Kruszka, M. Muenke, F. Hildebrandt, N. R. Dunn, D. M. Messerschmidt, E. Guccione, PRDM15 loss of function links NOTCH and WNT/PCP signaling to patterning defects in holoprosencephaly. Sci. Adv. 6, eaax9852 (2020).
Abstract:
Holoprosencephaly (HPE) is a congenital forebrain defect often associated with embryonic lethality and lifelong disabilities. Currently, therapeutic and diagnostic options are limited by lack of knowledge of potential disease-causing mutations. We have identified a new mutation in the PRDM15 gene (C844Y) associated with a syndromic form of HPE in multiple families. We demonstrate that C844Y is a loss-of-function mutation impairing PRDM15 transcriptional activity. Genetic deletion of murine Prdm15 causes anterior/posterior (A/P) patterning defects and recapitulates the brain malformations observed in patients. Mechanistically, PRDM15 regulates the transcription of key effectors of the NOTCH and WNT/PCP pathways to preserve early midline structures in the developing embryo. Analysis of a large cohort of patients with HPE revealed potentially damaging mutations in several regulators of both pathways. Our findings uncover an unexpected link between NOTCH and WNT/PCP signaling and A/P patterning and set the stage for the identification of new HPE candidate genes.
License type:
http://creativecommons.org/licenses/by-nc/4.0/
Funding Info:
This work was supported by AGA-SINGA (SINgapore Graduate Award) fellowship to S.M. E.G. is supported by NMRC/OFIRG/0032/2017 and NRF-CRP17-2017-06 grants.
Description:
ISSN:
2375-2548
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