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.

中文翻译：

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PRDM15的功能丧失将NOTCH和WNT / PCP信号转导与全脑前突的形态缺陷联系在一起。

头前脑畸形（HPE）是先天性前脑缺陷，通常与胚胎致死率和终身残疾相关。当前，由于缺乏对潜在的致病突变的认识，治疗和诊断选择受到限制。我们在多个家族中发现了与HPE综合征形式相关的PRDM15基因（C844Y）中的新突变。我们证明C844Y是功能受损的突变，损害PRDM15转录活性。鼠Prdm15的基因缺失会导致前/后（A / P）模式缺陷，并重述患者中观察到的脑畸形。从机理上讲，PRDM15调节NOTCH和WNT / PCP途径的关键效应子的转录，以在发育中的胚胎中保留早期中线结构。对一大批患有HPE的患者进行的分析显示，这两种途径的多个调节剂均具有潜在的破坏性突变。我们的发现揭示了NOTCH与WNT / PCP信号传导和A / P模式之间的意外联系，并为鉴定新的HPE候选基因奠定了基础。