Early developmental gene can cause deadly aneurysms

Date:
December 9, 2021
Source:
Yale University
Summary:
Mutations of a gene that regulates formation of blood vessels in
the brain of vertebrates can lead to potentially deadly aneurysms
in adults.

Saccular brain aneurysms affect nearly 3% of the human
population. If they rupture, it can cause subarachnoid hemorrhage,
the deadliest type of intracranial hemorrhage. Approximately
500,000 hemorrhagic strokes are reported annually worldwide;
nearly one in four victims die before reaching the hospital.



FULL STORY ========================================================================== Mutations of a gene that regulates formation of blood vessels in the
brain of vertebrates can lead to potentially deadly aneurysms in adults,
Yale School of Medicine researchers report in the December issue of
Nature Medicine.


========================================================================== Saccular brain aneurysms affect nearly 3% of the human population. If
they rupture, it can cause subarachnoid hemorrhage, the deadliest type
of intracranial hemorrhage. Approximately 500,000 hemorrhagic strokes
are reported annually worldwide; nearly one in four victims die before
reaching the hospital.

Predicting who might be vulnerable to such inherited forms of intracranial aneurysms, however, has been notoriously difficult. And until now,
researchers have had difficulty identifying the genes that might trigger
an increased risk of aneurysms in adults.

In the new study, researchers from the Yale's departments of neurosurgery, genetics, and cardiovascular medicine identified the role of a gene,
named PPIL4, in intracranial aneurysms. The gene is known to play a
crucial role in creating blood vessels in the developing vertebrate brain.

For the study, the group analyzed the genomes of more than 300 patients
with intracranial aneurysms and found significant increase of PPIL4
mutations compared with the general population.

The Yale team was led by three co-corresponding authors: Murat Gunel,
the Nixdorf German Professor and chair of the Department of Neurosurgery; Stefania Nicoli, an associate professor of internal medicine and genetics
and co- director of the Yale Cardiovascular Research Center in Cardiology;
and Ketu Mishra-Gorur, a research scientist.

"Identifying inherited forms of intracranial aneurysms that have large
effect sizes have been difficult to identify," Gunel said. "We are very
excited to report such mutations in the PPIL4 gene, providing a unique
insight on how these deadly lesions form." Unruptured aneursyms cause no symptoms and are hard to detect in normal clinical exams, which makes it difficult to identify individuals who could benefit from early treatment.

"The disease has never been associated with a developmental defect and
this gene is like a time machine that allows us to look back and find
the origins of the aneurysms," said Nicoli. "It is only one piece of the puzzle, but one that dramatically changes how we look at the disease."
In addition to the genetic discovery of PPIL4, the group demonstrated
that a novel PPIL4-Wnt signaling pathway is essential for brain vessel development and integrity.

"Studies like ours not only provide a genetic and mechanistic window into disease pathogenesis but present a remarkable potential for new pathways
in IA screening, early diagnosis, and treatment," Mishra-Gorur said.

Tanyeri Barak, an associate research scientist in neurosurgery in Gunel's
lab, and Emma Ristori, a postdoctoral fellow at the Yale Cardiovascular Research Center in Cardiology, are co-first authors. Other Yale authors
include Gulhan Adife Ercan-Sencicek and Andrew Prendergast.

========================================================================== Story Source: Materials provided by Yale_University. Original written
by Bill Hathaway. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. 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 Gu"ltekin,
Deniz Kilic, Devendra K. Rai, Nu"kte Goc, Stephanie Marie Aguilera,
Burcu Gu"lez, Selin Altinok, Kent Ozcan, Yanki Yarman, Su"leyman
Coskun, Emily Sempou, Engin Deniz, Jared Hintzen, Andrew Cox,
Elena Fomchenko, Su Woong Jung, Ali Kemal Ozturk, Angeliki Louvi,
Kaya Bilgu"var, E. Sander Connolly, Mustafa K. Khokha, Kristopher
T. Kahle, Katsuhito Yasuno, Richard P.

Lifton, Ketu Mishra-Gorur, Stefania Nicoli, Murat Gu"nel. PPIL4
is essential for brain angiogenesis and implicated in
intracranial aneurysms in humans. Nature Medicine, 2021; DOI:
10.1038/s41591-021-01572-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211209123702.htm

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