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

Human Genome Variation
Brian P WalcottMichael T Lawton

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 in silico 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 (SMAD9) 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 (Tg kdrl:eGFP) of the morpholino splice site and translation-blocking knockdown of SMAD9 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 SMAD9 via WES and the clinical phenotype. Replica...Continue Reading

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Citations

Jun 28, 2019·Current Opinion in Pediatrics·Miguel Zúñiga-CastilloJoyce M C Teng
Sep 17, 2019·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Celia L GregsonEmma L Duncan
Feb 7, 2020·Interventional Neuroradiology : Journal of Peritherapeutic Neuroradiology, Surgical Procedures and Related Neurosciences·Takahiro Ota, Masaki Komiyama
Jun 25, 2021·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Peipei PanHua Su

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Methods Mentioned

BETA
surgical resection
transgenic

Software Mentioned

PhyloP
DepthOfCoverage
MutationTaster
ANNOVAR
HaplotypeCaller
Genome Analysis Toolkit
ImageJ

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