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Gene & Protein in Disease Genetics of arteriovenous malformations

The most common cause of CM-AVM is loss-of- mostly caused by somatic activating R183Q GNAQ
function mutations in the RASA1 and EPHB4 genes mutations, emerging evidence has implicated somatic
with a penetrance of 89–95% [41,54] . Similar to HTT, mutations in GNA11 and GNB2 in the pathogenesis
CM-AVM can also be subdivided based on which gene of SWS . SWS is associated abnormal vasculature in
[85]
has been mutated. CM-AVM1 is caused by a heterozygous the brain, skin, and eye resulting in characteristic facial
loss-of-function mutation in the RASA1 gene [41,54] . capillary malformations (port wine stain), glaucoma, and
RASA1 encodes RASp21, which is a protein that acts leptomeningeal angiomatosis [83-85] . The leptomeningeal
as a suppressor of RAS function by boosting the RAS angiomatosis is characterized by an increased number of
proteins’ poor intrinsic GTPase activity, which results capillaries with a reduced number and size of veins in the
in the inactive GDP-bound form of RAS and permits pia mater and cerebral cortical surface. While rare, bAVM
control over cellular proliferation and differentiation . has been reported with SWS, occurring primarily among
[93]
Typically, the inherited mutation is non-sense, frameshift, infants [83,86-88] . The underlying mechanism of bAVM in
or a splice-site mutation resulting in a premature stop SWS remains unknown, but it has been posited that the
codon [54,92,94] . Conversely, loss-of-function mutation of the vessel malformation occurring in such cases happens at
EPHB4 gene results in CM-AVM2 variant [54,61,95] . EPHB4 a different stage than would otherwise occur in classic
encodes EphB4, a tyrosine kinase receptor that, along with SWS .
[83]
its ligand, ephrinB2, is a key mediator in angiogenesis [96,97] .
Contrary to CM-AVM1, 50% of the mutations associated In the realm of precision medicine, a thorough
with EPHB4 are loss-of-function mutations associated foundation of genetic basis for disease can prove especially
with null alleles, while the remaining 50% are missense useful for more innovative treatment approaches. Next,
mutations [54,95,98] . These missense mutations typically we discuss the ongoing research on and the emerging
affect the extracellular domain or the intracellular protein treatment options for AVM both in its sporadic form and
tyrosine kinase domain [54,95] . Clinically, CM-AVM1 and its associated genetic conditions as well as the impact
CM-AVM2 have similar presentations. However, fast- of varying genotypes and its related targeted therapies
flow vascular malformations are typically associated less (Table 2).
with CM-AVM2 compared to CM-AVM1. Of patients 7. New advances and emerging treatments
with CM-AVM2, an estimated 18% present with fast-flow
vascular malformations, of which only 3% occur in the The management of AVM typically calls for a
brain [54,95] . multidisciplinary approach. New and emerging
treatments for AVM have been developed due to recent
6.3. Parkes Weber syndrome and Sturge Weber developments in the field of study. This section will
syndrome discuss some of the most exciting recent discoveries
Parkes Weber syndrome (PWS) is characterized by a and cutting-edge AVM therapies. Due to the risk and
triad of limb hypertrophy, port-wine stain, and high- controversies associated with surgical, endovascular, and
flow AVM [99,100] . PWS is a congenital vascular disorder radiotherapeutic procedures, there has been an increase
associated with mutations in RASA1 [100,101] . The prevalence in the demand for pharmacological treatment modalities.
of this condition is not well described, and it does not Pharmacological therapies targeting various critical
appear to have a predilection for race or gender. The
most severe feature of this disease is the high-flow AVM Table 2. An overview of syndrome associated with AVM,
that commonly cause secondary symptoms, such as inheritance pattern, and associated genes
venous hypertension, pain, limb fatigue, and high-output Conditions Inheritance Common
heart failure [100] . One systematic review on the clinical, pattern associated genes
diagnostic, and treatment modalities of PWS concluded HHT Autosomal Endoglin, ACVRL1
that a diagnosis of PWS should be made based on the dominant
presence of capillary, venous, lymphatic malformation, Capillary malformation- Autosomal RASA1, EPHB4
and AVM in an overgrowth extremity. However, it is the arteriovenous malformation dominant
latter finding—that is, the presence of high-flow AVM — Lymphatic malformation Sporadic PIK3CA, AKT1
that distinguishes PWS from other congenital vascular
disorders [101] . Sturge Weber syndrome Sporadic GNAQ
Parkes Weber syndrome Autosomal RASA1
Sturge Weber syndrome (SWS) is a sporadic dominant
neurocutaneous congenital disorder that affects one Abbreviations: AVM: Arteriovenous malformations; HHT: Hereditary
in 20,000 to 50,000 live births [83-85] . Although SWS is hemorrhagic telangiectasia.

Volume 2 Issue 2 (2023) 9 https://doi.org/10.36922/gpd.0312