PRDM15 loss of function links NOTCH and WNT/PCP signaling to patterning defects in holoprosencephaly.
Sci Adv
; 6(2): eaax9852, 2020 01.
Article
in En
| MEDLINE
| ID: mdl-31950080
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.
Full text:
1
Database:
MEDLINE
Main subject:
Transcription Factors
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Holoprosencephaly
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Cell Polarity
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DNA-Binding Proteins
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Receptors, Notch
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Wnt Signaling Pathway
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Loss of Function Mutation
Type of study:
Etiology_studies
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Incidence_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limits:
Animals
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Female
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Humans
/
Pregnancy
Language:
En
Journal:
Sci Adv
Year:
2020
Type:
Article
Affiliation country:
Singapore