Identification of a rare BMP pathway mutation in a non-syndromic human brain arteriovenous malformation via exome sequencing

Authors

Brian P. Walcott, Department of Neurological Surgery, University of Southern California, Los Angeles, CA, USA.
Ethan A. Winkler, Center for Cerebrovascular Research, University of California, San Francisco, CA, USA.
Sirui Zhou, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Harjus Birk, Center for Cerebrovascular Research, University of California, San Francisco, CA, USA.
Diana Guo, Center for Cerebrovascular Research, University of California, San Francisco, CA, USA.
Matthew J. Koch, Department of Neurological Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA.
Christopher J. Stapleton, Department of Neurological Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA.
Dan Spiegelman, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Alexandre Dionne-Laporte, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Patrick A. Dion, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Kristopher T. Kahle, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT USA.
Guy A. Rouleau, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Michael T. Lawton, Center for Cerebrovascular Research, University of California, San Francisco, CA, USA.Follow

Document Type

Article

Abstract

Brain arteriovenous malformations (AVMs) are abnormal connections between arteries and veins that can result in hemorrhagic stroke. A genetic basis for AVMs is suspected, and we investigated potential mutations in a 14-year-old girl who developed a recurrent brain AVM. Whole-exome sequencing (WES) of AVM lesion tissue and blood was performed accompanied by modeling, protein expression observation in lesion tissue and zebrafish modeling. A stop-gain mutation (c.C739T:p.R247X) in the gene SMAD family member 9 () was discovered. In the human brain tissue, immunofluorescent staining demonstrated a vascular predominance of SMAD9 at the protein level. Vascular SMAD9 was markedly reduced in AVM peri-nidal blood vessels, which was accompanied by a decrease in phosphorylated SMAD4, a downstream effector protein of the bone morphogenic protein signaling pathway. Zebrafish modeling () of the morpholino splice site and translation-blocking knockdown of resulted in abnormal cerebral artery-to-vein connections with morphologic similarities to human AVMs. Orthogonal trajectories of evidence established a relationship between the candidate mutation discovered in via WES and the clinical phenotype. Replication in similar rare cases of recurrent AVM, or even more broadly sporadic AVM, may be informative in building a more comprehensive understanding of AVM pathogenesis.

Publication Date

5-31-2018

Publication Title

Human genome variation

ISSN

2054-345X

Volume

5

First Page

18001

PubMed ID

29844917

Digital Object Identifier (DOI)

10.1038/hgv.2018.1

Recommended Citation

Walcott, Brian P.; Winkler, Ethan A.; Zhou, Sirui; Birk, Harjus; Guo, Diana; Koch, Matthew J.; Stapleton, Christopher J.; Spiegelman, Dan; Dionne-Laporte, Alexandre; Dion, Patrick A.; Kahle, Kristopher T.; Rouleau, Guy A.; and Lawton, Michael T., "Identification of a rare BMP pathway mutation in a non-syndromic human brain arteriovenous malformation via exome sequencing" (2018). Neurosurgery. 1293.
https://scholar.barrowneuro.org/neurosurgery/1293