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. Epub 2021 Dec 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / blood supply*
  • Cyclophilins / genetics*
  • Cyclophilins / physiology
  • Exome Sequencing
  • Humans
  • Intracranial Aneurysm / genetics*
  • Mutation
  • Neovascularization, Pathologic / genetics*
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / physiology
  • Wnt Signaling Pathway / physiology


  • RNA-Binding Proteins
  • Cyclophilins
  • PPIL4 protein, human