PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans

Tanyeri Barak, Emma Ristori, A. Gulhan Ercan-Sencicek, Danielle F. Miyagishima, Carol Nelson-Williams, Weilai Dong, Sheng Chih Jin, Andrew Prendergast, William Armero, Octavian Henegariu, E. Zeynep Erson-Omay, Akdes Serin Harmancı, Mikhael Guy, Batur Gültekin, Deniz Kilic, Devendra K. Rai, Nükte Goc, Stephanie Marie Aguilera, Burcu Gülez, Selin AltinokKent Ozcan, Yanki Yarman, Süleyman Coskun, Emily Sempou, Engin Deniz, Jared Hintzen, Andrew Cox, Elena Fomchenko, Su Woong Jung, Ali Kemal Ozturk, Angeliki Louvi, Kaya Bilgüvar, E. Sander Connolly, Mustafa K. Khokha, Kristopher T. Kahle, Katsuhito Yasuno, Richard P. Lifton, Ketu Mishra-Gorur, Stefania Nicoli, Murat Günel

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)2165-2175
Number of pages11
JournalNature medicine
Volume27
Issue number12
DOIs
StatePublished - Dec 2021

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