Intracranial aneurysm (IA) rupture leads to subarachnoid hemorrhage, a sudden-onset disease that often causes death or severe disability. Although genome-wide association studies have identified common genetic variants that increase IA risk moderately, the contribution of variants with large effect remains poorly defined. Using whole-exome sequencing, we identified significant enrichment of rare, deleterious mutations in PPIL4, encoding peptidyl-prolyl cis-trans isomerase-like 4, in both familial and index IA cases. Ppil4 depletion in vertebrate models causes intracerebral hemorrhage, defects in cerebrovascular morphology and impaired Wnt signaling. Wild-type, but not IA-mutant, PPIL4 potentiates Wnt signaling by binding JMJD6, a known angiogenesis regulator and Wnt activator. These findings identify a novel PPIL4-dependent Wnt signaling mechanism involved in brain-specific angiogenesis and maintenance of cerebrovascular integrity and implicate PPIL4 gene mutations in the pathogenesis of IA.

颅内动脉瘤（IA）破裂会导致蛛网膜下腔出血，这是一种突发性疾病，常常导致死亡或严重残疾。尽管全基因组关联研究已经确定了可适度增加 IA 风险的常见遗传变异，但具有较大影响的变异的贡献仍然不明确。使用全外显子组测序，我们在家族性和索引 IA 病例中发现了编码肽基脯氨酰顺反异构酶样 4 的PPIL4中罕见的有害突变的显着富集。脊椎动物模型中Ppil4缺失会导致脑出血、脑血管形态缺陷和 Wnt 信号传导受损。野生型（而非 IA 突变型）PPIL4 通过结合 JMJD6（一种已知的血管生成调节剂和 Wnt 激活剂）来增强 Wnt 信号传导。这些发现确定了一种新的 PPIL4 依赖性 Wnt 信号传导机制，参与大脑特异性血管生成和脑血管完整性的维持，并暗示PPIL4基因突变与 IA 的发病机制有关。