Dataset Information

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 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.

SUBMITTER: Mzoughi S

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

REPOSITORIES: biostudies-literature

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

Mzoughi Slim S Di Tullio Federico F Low Diana H P DHP Motofeanu Corina-Mihaela CM Ong Sheena L M SLM Wollmann Heike H Wun Cheng Mun CM Kruszka Paul P Muenke Maximilian M Hildebrandt Friedhelm F Dunn N Ray NR Messerschmidt Daniel M DM Guccione Ernesto E

Science advances 20200110 2

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 <i>PRDM15</i> 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 murin ...[more]

PMID: 31950080

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Dataset Information

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

Publications

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

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