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Gene & Protein in Disease Genetics of arteriovenous malformations

Previous studies focused on somatic mutations and factor binding protein 7 (IGFBP7), slit guidance ligand 2
genetic abnormalities have revealed promising findings (SLIT2), CD109 molecule (CD109), tenascin XB (TNXB),
allowing for a better understanding of the development of chondroitin sulfate proteoglycan 4 (CSPG4), amine oxidase
bAVM. Mukhtarova et al. identified a pathogenic sirtuin copper containing 3 (AOC3), NEDD4 like E3 ubiquitin
1 (SIRT1) variant that could be linked to a molecular protein ligase (NEDD4L), serine/threonine kinase 4 (STK4),
mechanism in bAVM development . According to and fibronectin leucine rich transmembrane protein 3
[31]
Mukhtarova et al., SIRT1 is expressed in the blood vessels (FLRT3). The major classification categories of these
during development and is important for angiogenesis . variants were defined by their involvement in transforming
[31]
They found that when SIRT1 was impaired in mice and growth factor beta 1-suppressor of mothers against
[31]
zebrafish, it led to abnormal blood vessel formation . decapentaplegic (TGF-β/SMAD) transduction pathway,
In another study, Yan et al. found that the mammalian and the regulation of angiogenetic process and arterial
target of rapamycin - fatty acid-binding protein 4 (mTOR- and venous differentiation. While most of their discovered
FABP4) signal was activated in bAVM . They noted variants have yet to be associated with clinical significance
[32]
that the mTOR-FABP4 pathway plays a role in several in the literature, they proposed that the de novo c.569G > A
endothelial cell processes such as proliferation, apoptosis, (p.Trp190Ter) nonsense mutation affecting the STK4 gene
migration, and vascular tube formation. Finding mTOR- could be involved in the AVM phenotype development.
FABP4 pathway activation in bAVM indicates that mTOR This variant was uniquely found in their AVM patient and
pathway inhibitors could potentially be implicated in not in the familial cohort who were also tested. In addition,
future treatment . Other gene mutations found in bAVM in the literature, STK4 has been implicated in blood vessel
[32]
include the Kirsten rat sarcoma virus (KRAS) and v-raf branching and morphogenesis [35,36] . Thus, continued NGS
murine sarcoma viral oncogene homolog B1 (BRAF) studies have helped identify unique genetic markers
mutations. Bameri et al. found in a systematic literature associated with AVM which can later be correlated with
review that in 1726 patients with bAVM, 55% had KRAS their role in pathogenesis.
mutations and 7.5% had BRAF mutations . Both the
[33]
KRAS and BRAF mutations are associated with cancers bAVM has also been reported to overexpress genes
and tumor growth, but in bAVM, they may be linked to which play a regulatory role in essential processes of
endothelial proliferation, angiogenic signaling, or vascular angiogenesis and lymphogenesis. In a study examining
remodeling process . human AVM tissue, Shoemaker et al. identified these set of
[33]
AVM unique genes, including COUP transcription factor
3.2. Genetics of molecular mechanism of 2 (COUP-TFII), SRY-box transcription factor 18 (SOX18),
pathogenesis prospero homeobox 1 (PROX1), nuclear factor of activated
More recently, next generation sequencing (NGS) T cells 1 (NFATC1), forkhead box C2 (FOXC2), T-box
technologies have allowed for multiple studies to examine transcription factor 1 (TBX1), lymphatic vessel endothelial
the genetic basis of AVM pathogenesis. While our hyaluronan receptor 1 (LYVE1), Podoplanin, and VEGFC.
understanding at this level is still limited, we will discuss In addition, these expressed genes were correlated with
[37]
the current literature on the molecular mechanisms of clinical edema and acute hemorrhage . This assembly of
AVM angiogenesis. The two greatest areas of attention for complex genes implies that the signaling pathway of AVM
research have focused on (i) the family linkage analysis in formation and proliferation is also complex, and future
patients with AVM and (ii) the analysis of the defective studies are needed to more definitively define the specific
genes using post-operative specimens . role of these genes in AVM pathogenesis. The authors also
[34]
propose that these genes highlight the ability of endothelial
Scimone et al. conducted a study using whole exome cells of AVM to lose their arterial/venous specificity and
sequencing on a young boy with sporadic bAVM to acquire a partial lymphatic molecular phenotype . The
[37]
identify a set of novel gene-disrupting variants implicated significance of these findings is that these markers may
in vascular differentiation . They proposed a set of 20 help clinicians to predict hemorrhage risk, given their
[35]
gene-disrupting variants, which are potentially involved in association with inflammatory and hemorrhagic processes
AVM pathogenesis, of which 1 is non-sense mutation, 2 are
splice-affecting variants, and 17 are missense mutations. at the molecular level.
The list of candidate loci they proposed for future study in In understanding the genetic basis of AVM development,
AVM pathogenesis included: NBPF member 10 (NBPF10), it is also important to discuss our genetic understanding of
Ephrin A4 (EFNA4), NAD(P)HX epimerase (NAXE), the vascular stability of these lesions. Deficient expression
tetratricopeptide repeat domain 21B (TTC21B), bone of platelet-derived growth factor subunit B (PDGFB) and its
morphogenetic protein 3 (BMP3), insulin like growth linked PDGF receptor beta can result in weakened vessels

Volume 2 Issue 2 (2023) 4 https://doi.org/10.36922/gpd.0312