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Gene & Protein in Disease Genetics of arteriovenous malformations

part of the MAP kinase signal transduction pathway. increased risk for fast-flow vascular malformations, but
Studies have shown that most sporadic extracranial AVM clinical features differ, and CM-AVM2 is inherited as an
has an endothelial cell-specific MAP2K1 mutation [50,51] . autosomal-dominant disorder .
[52]
More specifically, the most common mutation associated Choi et al. used mouse models to show that
with AVM is MAP2K1-K57N, and it over-activates the homozygous deletion of ENG in endothelial cells is
RAS/MPK pathway in endothelial cells . It has been vital for the development of HHT Type 1 (HHT1) brain
[51]
hypothesized that the aberrant coordination of artery- with AVM phenotype . Activin-like kinase 1(ALK-1
[59]
capillary-vein development may result from the activation or ACVLR1) is a transmembrane kinase that encodes
of RAS/MAPK signaling by mutant endothelial cells. TGF-β Type 1 receptor and its proteins are also expressed
MAP2K1 mutant endothelial cells that interfere with on endothelial cells . Loss-of-function mutation in
[60]
normal vascular development may result in abnormal ACVRL1 leads to dysregulation of TGF-β/BMP signaling,
attachment of arteries and veins .
[51]
which would negatively impact proliferation, migration,
The RAS P21 protein activator 1 (RASA1) gene and recruitment of cells . Kim et al. stated that BMP-9
[54]
produces a cytoplasmic protein that belongs to the GAP1 may be a physiologically significant endothelial signaling
family of GTPase-activating proteins. Furthermore, channel for HHT development, according to studies that
RASA1 regulates Ras GDP and GTP and is involved in reveal that ALK-1 may instead signal through it and that
a myriad of physiologic processes, such as angiogenesis, endoglin can strengthen the signal . Although only
[30]
cell proliferation, and apoptosis. The gene product contributing < 1% to HHT etiology, mutations in an
increases the GTPase activity of normal RAS p21. The additional causative gene called growth differentiation
protein acts as a suppressor of RAS function by boosting factor 2 (GDF2) can cause rare vascular abnormality
the RAS proteins’ poor intrinsic GTPase activity, syndromes that resemble HHT . Assorted studies have
[61]
which results in the inactive GDP-bound form of RAS reported missense, homozygous, and in some cases, a
and permits control over cellular proliferation and complete deletion of the entire GDF2 region in people with
differentiation [52] . Heterozygous mutation of the RASA1 HHT [62-64] . Another causative gene for AVM pathogenesis
gene causes capillary malformation AVM (CM-AVM) in relation to HHT is the SMAD4 gene, which encodes
1 disorder [53] . Hongo et al. states that the majority of the downstream effector for both TGF-β and BMP
inherited RASA1 mutations in CM-AVM1 are nonsense, signaling . SMAD4 mutations include missense, non-
[30]
frameshift, or splice-site mutations [54] . Some studies sense, and frameshift mutations and they cause juvenile
have also shown that complete inactivation of RASA1 polyposis HHT (JP-HHT) in patients [65,66] .
may arise because of a second-hit somatic mutation in KRAS mutations were found in endothelial cell-
endothelial cells [54,55] . enriched cultures obtained from sporadic brain
Numerous developmental processes, particularly those AVMs [67,68] . Nikolaev et al. found that in vitro activation of
involving the nervous system, are mediated by ephrin mutant KRAS in endothelial cells increased extracellular
receptors and their ligands, the ephrins. The largest subset signal-regulated kinase (ERK) activity, angiogenesis and
of the receptor tyrosine kinase (RTK) family is ephrin Notch signaling gene expression, and enhanced migratory
receptors . The ephrin-A (EFNA) class, which is tethered behavior . More precisely, bAVM can be caused by
[68]
[56]
to the membrane by a glycosylphosphatidylinositol bond, endothelial-specific gain-of-function mutations in KRAS
and the ephrin-B (EFNB) class, which are transmembrane (G12D or G12V), as demonstrated in mice and zebrafish by
proteins, are separated from one another based on their Fish et al. Although studies have shown that constitutive
[69]
structures and sequence correlations . In addition to being activation of the MAPK/MEK/ERK signaling pathway by
[57]
important axon guidance regulators during nervous system somatic mutations in the KRAS gene is the most known
development, erythropoietin-producing hepatocellular cause of sporadic brain AVM, the mechanism is still
(Eph) receptor tyrosine kinase receptors and their ligands, poorly understood [68-73] . Active KRAS signaling caused
ephrins, also play a significant role in many aspects of ectopic sprouting, increased arterial lumen diameter,
blood vessel morphogenesis . Approximately half of the altered endothelial cell morphogenesis, increased cell size,
[58]
patients with CM-AVM exhibit heterozygous mutations and direct linkages between arteries and veins . As one
[69]
in the RASA1 gene. The EPHB4 gene is the second gene of the RAF proteins, BRAF (encoded by BRAF gene) also
mutated in patients with CM-AVM that does not exhibit activates the RAF/MEK/ERK (MAPK/ERK) signaling
any mutations in the RASA1 gene . CM-AVM resulting pathway . These pathways regulate crucial cellular
[56]
[54]
[74]
from mutated EPHB4 and RASA1 genes is characterized growth, survival, and senescence . Bameri et al. showed
by small multifocal capillary malformations (CM) and that there was significant prevalence of BRAF mutations
Volume 2 Issue 2 (2023) 6 https://doi.org/10.36922/gpd.0312