Page 50 - EJMO-9-3

Eurasian Journal of
Medicine and Oncology NOTCH3 in CSVD and breast cancer

severe CSVD. Indeed, examinations of tissues samples mutations that modify cysteine to be between 2.2 and
from members of these families revealed distinct brain 3.4 cases/1000 individuals. This prevalence is nearly
pathology, characterised by degenerative alterations in the 100 times higher than the earlier estimates available for
walls of cerebral arteries. Therefore, it became evident CADASIL. The evident disparity in the estimates of
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that while most cases of CSVD are sporadic or involve disease and mutation occurrence lacks a comprehensive
multiple genes, a certain portion is probably attributed to understanding but probably stems from variations in
monogenic genetic variations. the extent of penetrance or the severity linked to these
Subsequently, an acronym was coined for the most genetic mutations. This explanation aligns with evidence
prevalent monogenic autosomal-dominant form of CSVD, suggesting that not all individuals carrying NOTCH3 gene
which is CADASIL. An analysis of numerous extensive mutations, whether altering cysteine or sparing cysteine,
and well-documented CADASIL families established a or those with legitimate NOTCH3 loss-of-function
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genetic linkage to a single disease locus on chromosome mutations, exhibit symptoms. Hence, some individuals
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19q12. The defining pathological feature of CADASIL can be asymptomatic, which reflects the typical nature of
is the existence of granular osmophilic material (GOM) CSVD.
within the basement membrane of VSMCs. Common 7.3. Impact of aberrant NOTCH3 signalling in
clinical manifestations in CADASIL patients encompass CADASIL and NOTCH3-related CSVD
migraine with aura, transient ischemic attacks or ischemic
strokes, intracranial haemorrhage, cognitive deficits, and The pathophysiological mechanisms underlying CADASIL
psychiatric disturbances. Patients may exhibit one or involve NOTCH3 receptor activation by its ligands, leading
more of these symptoms. Neuroimaging, typically MRI, to proteolytic cleavages and release of the NICD. The
frequently reveals WMHs, lacune infarcts and cerebral NICD then translocate to the nucleus, where it influences
microbleeds. Anomalies in periventricular regions gene transcription and cellular processes. However, in
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appear as initial findings on fluid-attenuated inversion CADASIL, the aberrant receptor structure disrupts this
recovery and T2-weighted imaging. Over time, these signalling cascade, promoting VSMC apoptosis and
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anomalies spread symmetrically to affect other regions, impairing vascular function.
including distinctive areas, such as the anterior temporal Moreover, recent findings highlight a significant baseline
pole and the external capsule. 138 of ligand-independent NOTCH3 signalling, which could
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The NOTCH3 gene encodes a single-pass transmembrane be relevant in both normal and pathological contexts.
NOTCH3 receptor. It has been pinpointed as the causative This signalling variability underscores the complexity of
gene for CADASIL. Exons 2 – 24 of the NOTCH3 gene NOTCH3-related diseases and suggests potential targets
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encode 34 epidermal growth factor-like repeats (EGFRs) for therapeutic intervention. Understanding the precise
within the extracellular domain of the NOTCH3 protein. molecular mechanisms and cellular effects of NOTCH3
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Each EGFR contains six cysteine residues that form three mutations is essential for developing targeted treatments
disulphide bonds, contributing to the receptor’s structural for CADASIL and NOTCH3-related CSVD.
stability. However, mutations that alter in the number In conclusion, aberrant NOTCH3 signalling plays
of cysteine residues, changing from an even to an odd a critical role in the pathogenesis of CADASIL and
number, result in a structural change in the extracellular NOTCH3-related CSVD. Advances in genetic and
domain of the NOTCH3 receptor. This structural change molecular research continue to unravel the complexities of
leads to misfolding and the aggregation of the extracellular this signalling pathway, offering hope for novel therapeutic
domain. Consequently, this misfolding and aggregation strategies aimed at mitigating the clinical burden of these
can give rise to the formation of GOM deposits, which are debilitating conditions.
a distinctive characteristic of CADASIL. Furthermore, this
process can also lead to the deterioration of VSMCs. 141 8. NOTCH3 as a potential link between the
CADASIL is a rare condition, and its estimated BC and CSVD
occurrence in the general population ranges from 1.98 The interplay between BC and CSVD through aberrant
to 4.6 cases/100,000. Nonetheless, recent research NOTCH3 signalling presents a compelling narrative that
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indicates that NOTCH3 gene mutations, which alter underscores the intricate pathophysiological mechanisms
cysteine, are considerably more common than previously linking these two seemingly distinct conditions. This
documented. As an illustration, utilising exome manuscript has delineated the critical role of NOTCH3
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databases that are publicly accessible, recent investigations in both oncogenesis and vasculogenesis, particularly
have approximated the prevalence of NOTCH3 gene highlighting its involvement in CADASIL and BC

Volume 9 Issue 3 (2025) 42 doi: 10.36922/EJMO025150095