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

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 lar

SUBMITTER: Mzoughi S 

PROVIDER: S-EPMC6954057 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature