# Investigating the Role of Somatic Mutations in Arteriovenous Malformations

> **NIH NIH F31** · DUKE UNIVERSITY · 2021 · $33,486

## Abstract

PROJECT SUMMARY
 Hereditary Hemorrhagic Telangiectasia (HHT) is a Mendelian disease characterized by the development
of multiple focal vascular malformations (VMs) including large visceral arteriovenous malformations in the brain,
liver, and lungs; and numerous telangiectasia in mucosal and cutaneous tissue. These VMs are tortuous
collections of vessels that result in the direct high-flow shunting of blood between arterial and venous systems.
HHT-related VMs often lead to acute hemorrhage, chronic bleeding, anemia, stroke, heart and liver failure.
Despite the morbidity and mortality associated with HHT, there remains no effective pharmaceutical therapy to
treat HHT-related VMs; the only therapy is surgical embolization or resection. These surgical treatments do not
treat the source of the disease and there are numerous cases of VM regrowth after surgical resection. In addition,
these treatments are reserved for the largest VMs; however, individuals with HHT have a multitude of small VMs
which frequently bleed and remain a significant, yet untreatable, medical problem. Decades of research have
focused on understanding the underlying genetics and vascular biology of HHT-related VMs, however the
molecular events that initiate VMs remain poorly understood. The overall objective of this proposal is to gain a
fundamental understanding of the molecular events that initiate vascular malformation. We have long known that
HHT is caused by autosomal dominant loss-of-function mutations in either ENG, ACVRL1, or SMAD4. These
findings led to the belief that HHT-related VMs results from haploinsufficiency of the mutated gene; however,
this mechanism does not account for why HHT-related VMs are strictly focal lesions despite the systemic
mutation. Counter to the haploinsufficiency hypothesis, I have identified that HHT-related VMs harbor a somatic
mutation in the same gene as the causal germline mutation resulting in biallelic loss-of-function of the gene
product. These mutations are consistent with a Knudsonian two-hit mechanism, strongly supporting a functional
role for somatic mutations in the pathogenesis of HHT-related VMs. The aims of this proposal build on this finding
with the goal of understanding how these somatic mutations impair vascular development to result in vascular
malformation. Successful completion of these specific aims will fill a long-standing critical gap in our
understanding of HHT biology and may identify new molecules/pathways susceptible to therapeutic intervention.
Aim 1: Identify the mutant cell type and determine the extent of mosaicism in the malformation.
Aim 2: Elucidate the functional effects of the somatic mutation on mutant and wild-type cells.
Aim 3: Interrogate the presence of somatic mutations in sporadic and hereditary brain VMs.

## Key facts

- **NIH application ID:** 10410345
- **Project number:** 5F31HL152738-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Daniel Snellings
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,486
- **Award type:** 5
- **Project period:** 2020-06-01 → 2022-04-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10410345

## Citation

> US National Institutes of Health, RePORTER application 10410345, Investigating the Role of Somatic Mutations in Arteriovenous Malformations (5F31HL152738-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10410345. Licensed CC0.

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