2. Academic Validation
  3. PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans

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

  • Nat Med. 2021 Dec;27(12):2165-2175. doi: 10.1038/s41591-021-01572-7.
Tanyeri Barak # 1 2 3 4,  Emma Ristori # 2 5,  A Gulhan Ercan-Sencicek 1 2 3 4,  Danielle F Miyagishima 1 2 3 4,  Carol Nelson-Williams 2,  Weilai Dong 2 6,  Sheng Chih Jin 2 6 7,  Andrew Prendergast 5,  William Armero 2 5,  Octavian Henegariu 1 2 3 4,  E Zeynep Erson-Omay 1 2 3 4,  Akdes Serin Harmancı 1 2 3 4,  Mikhael Guy 8,  Batur Gültekin 1,  Deniz Kilic 1,  Devendra K Rai 1 2 3 4,  Nükte Goc 1,  Stephanie Marie Aguilera 1,  Burcu Gülez 1,  Selin Altinok 1,  Kent Ozcan 1,  Yanki Yarman 1,  Süleyman Coskun 1 2 3 4,  Emily Sempou 9,  Engin Deniz 9,  Jared Hintzen 5,  Andrew Cox 2,  Elena Fomchenko 1,  Su Woong Jung 10,  Ali Kemal Ozturk 11,  Angeliki Louvi 1 4,  Kaya Bilgüvar 2 4 12,  E Sander Connolly Jr 13,  Mustafa K Khokha 2 9,  Kristopher T Kahle 1 14 15 16,  Katsuhito Yasuno 1 2 3 4,  Richard P Lifton 2 6,  Ketu Mishra-Gorur 17 18 19 20,  Stefania Nicoli 21 22 23,  Murat Günel 24 25 26 27
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
  • 2 Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
  • 3 Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA.
  • 4 Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA.
  • 5 Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale School of Medicine, New Haven, CT, USA.
  • 6 Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
  • 7 Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
  • 8 Yale Center for Research Computing, Yale University, New Haven, CT, USA.
  • 9 Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA.
  • 10 Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Korea.
  • 11 Department of Neurosurgery, Pennsylvania Hospital, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA.
  • 12 Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
  • 13 Department of Neurosurgery, Columbia University College of Physicians and Surgeons, New York, NY, USA.
  • 14 Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • 15 Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
  • 16 Broad Institute of MIT and Harvard, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 17 Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA. ketu.mishra@yale.edu.
  • 18 Department of Genetics, Yale School of Medicine, New Haven, CT, USA. ketu.mishra@yale.edu.
  • 19 Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA. ketu.mishra@yale.edu.
  • 20 Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA. ketu.mishra@yale.edu.
  • 21 Department of Genetics, Yale School of Medicine, New Haven, CT, USA. stefania.nicoli@yale.edu.
  • 22 Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale School of Medicine, New Haven, CT, USA. stefania.nicoli@yale.edu.
  • 23 Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA. stefania.nicoli@yale.edu.
  • 24 Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.
  • 25 Department of Genetics, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.
  • 26 Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.
  • 27 Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.
  • # Contributed equally.
PMID: 34887573 DOI: 10.1038/s41591-021-01572-7
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z