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.
journal_name
Sci Advjournal_title
Science advancesauthors
Mzoughi S,Di Tullio F,Low DHP,Motofeanu CM,Ong SLM,Wollmann H,Wun CM,Kruszka P,Muenke M,Hildebrandt F,Dunn NR,Messerschmidt DM,Guccione Edoi
10.1126/sciadv.aax9852subject
Has Abstractpub_date
2020-01-10 00:00:00pages
eaax9852issue
2issn
2375-2548pii
aax9852journal_volume
6pub_type
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