TY - JOUR
T1 - PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans
AU - Barak, Tanyeri
AU - Ristori, Emma
AU - Ercan-Sencicek, A. Gulhan
AU - Miyagishima, Danielle F.
AU - Nelson-Williams, Carol
AU - Dong, Weilai
AU - Jin, Sheng Chih
AU - Prendergast, Andrew
AU - Armero, William
AU - Henegariu, Octavian
AU - Erson-Omay, E. Zeynep
AU - Harmancı, Akdes Serin
AU - Guy, Mikhael
AU - Gültekin, Batur
AU - Kilic, Deniz
AU - Rai, Devendra K.
AU - Goc, Nükte
AU - Aguilera, Stephanie Marie
AU - Gülez, Burcu
AU - Altinok, Selin
AU - Ozcan, Kent
AU - Yarman, Yanki
AU - Coskun, Süleyman
AU - Sempou, Emily
AU - Deniz, Engin
AU - Hintzen, Jared
AU - Cox, Andrew
AU - Fomchenko, Elena
AU - Jung, Su Woong
AU - Ozturk, Ali Kemal
AU - Louvi, Angeliki
AU - Bilgüvar, Kaya
AU - Connolly, E. Sander
AU - Khokha, Mustafa K.
AU - Kahle, Kristopher T.
AU - Yasuno, Katsuhito
AU - Lifton, Richard P.
AU - Mishra-Gorur, Ketu
AU - Nicoli, Stefania
AU - Günel, Murat
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85120978725&partnerID=8YFLogxK
U2 - 10.1038/s41591-021-01572-7
DO - 10.1038/s41591-021-01572-7
M3 - Article
C2 - 34887573
AN - SCOPUS:85120978725
SN - 1078-8956
VL - 27
SP - 2165
EP - 2175
JO - Nature medicine
JF - Nature medicine
IS - 12
ER -