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Accepted (AM)Open Access (License Unspecified), Open
Journal article
PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans
Nature medicine, v 27(12), pp 2165-2175
01 Dec 2021
PMID: 34887573
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans
- Creators
- Tanyeri Barak - Yale UniversityEmma Ristori - Yale UniversityA Gulhan Ercan-Sencicek - Yale UniversityDanielle F Miyagishima - Yale UniversityCarol Nelson-Williams - Yale UniversityWeilai Dong - Yale UniversitySheng Chih Jin - Yale UniversityAndrew Prendergast - Yale UniversityWilliam Armero - Yale UniversityOctavian Henegariu - Yale UniversityE Zeynep Erson-Omay - Yale UniversityAkdes Serin Harmancı - Yale UniversityMikhael Guy - Yale UniversityBatur Gültekin - Yale UniversityDeniz Kilic - Yale School of MedicineDevendra K Rai - Yale School of MedicineNükte Goc - Yale UniversityStephanie Marie Aguilera - Yale UniversityBurcu Gülez - Yale UniversitySelin Altinok - Yale School of MedicineKent Ozcan - Yale UniversityYanki Yarman - Yale UniversitySüleyman Coskun - Yale UniversityEmily Sempou - Yale UniversityEngin Deniz - Yale UniversityJared Hintzen - Yale UniversityAndrew Cox - Yale School of MedicineElena Fomchenko - Yale UniversitySu Woong Jung - Kyung Hee University Hospital at GangdongAli Kemal Ozturk - University of Pennsylvania Health SystemAngeliki Louvi - Yale UniversityKaya Bilgüvar - Yale UniversityE Sander Connolly, Jr - Columbia UniversityMustafa K Khokha - Yale UniversityKristopher T Kahle - Yale UniversityKatsuhito Yasuno - Yale UniversityRichard P Lifton - Yale UniversityKetu Mishra-Gorur - Yale UniversityStefania Nicoli - Yale UniversityMurat Günel - Yale University
- Publication Details
- Nature medicine, v 27(12), pp 2165-2175
- Publisher
- Springer Nature
- Grant note
- R00 HL143036 / NHLBI NIH HHS R01 NS127879 / NINDS NIH HHS R01 NS109160 / NINDS NIH HHS R21 NS116484 / NINDS NIH HHS R01 NS111935 / NINDS NIH HHS R01 NS057756 / NINDS NIH HHS R01 HL130246 / NHLBI NIH HHS UL1 TR001863 / NCATS NIH HHS R01 NS111029 / NINDS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurology
- Web of Science ID
- WOS:000728466100004
- Scopus ID
- 2-s2.0-85120978725
- Other Identifier
- 991022004951904721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology
- Medicine, Research & Experimental