Genetic study of the NOTCH3 gene in CADASIL patients

Tarzjani, Seyedeh Parisa Chavoshi; Fazeli, Seyed Abolhassan Shahzadeh; Sanati, Mohammad Hossein; Mirzayee, Zahra

doi:10.1016/j.ejmhg.2018.05.001

Cited by 4 publications

(2 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Five small deletions (four in non-frame [47,62,63] and one frameshift), one splice site mutation [64], and a small deletion of a non-cysteine related residue were reported [52]. Further, p.Ala1020Pro, p.Arg213Lys, p.Tyr1098Ser, and p.Arg75Pro variants were found in diagnosed patients with CADASIL (Table 2) [65,66,67,68,69,70,71,72,73,74,75,76,77,78], in whom exons 2–24 were sequenced from skin biopsy for confirmation [79,80,81,82]. Recently, a three-nucleotide insertion was reported as the first pathogenic insertion in the NOTCH3 gene [83].…”

Section: Cerebral Autosomal-dominant Arteriopathy With Subcorticalmentioning

confidence: 99%

Genetic Factors of Cerebral Small Vessel Disease and Their Potential Clinical Outcome

Giau

Bagyinszky

Youn

et al. 2019

IJMS

View full text Add to dashboard Cite

Cerebral small vessel diseases (SVD) have been causally correlated with ischemic strokes, leading to cognitive decline and vascular dementia. Neuroimaging and molecular genetic tests could improve diagnostic accuracy in patients with potential SVD. Several types of monogenic, hereditary cerebral SVD have been identified: cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL), hereditary diffuse leukoencephalopathy with spheroids (HDLS), COL4A1/2-related disorders, and Fabry disease. These disorders can be distinguished based on their genetics, pathological and imaging findings, clinical manifestation, and diagnosis. Genetic studies of sporadic cerebral SVD have demonstrated a high degree of heritability, particularly among patients with young-onset stroke. Common genetic variants in monogenic disease may contribute to pathological progress in several cerebral SVD subtypes, revealing distinct genetic mechanisms in different subtype of SVD. Hence, genetic molecular analysis should be used as the final gold standard of diagnosis. The purpose of this review was to summarize the recent discoveries made surrounding the genetics of cerebral SVD and their clinical significance, to provide new insights into the pathogenesis of cerebral SVD, and to highlight the possible convergence of disease mechanisms in monogenic and sporadic cerebral SVD.

show abstract

Section: Cerebral Autosomal-dominant Arteriopathy With Subcorticalmentioning

confidence: 99%

Genetic Factors of Cerebral Small Vessel Disease and Their Potential Clinical Outcome

Giau

Bagyinszky

Youn

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…CADASIL-associated mutations mainly occur in epidermal growth factor (EGF)-like repeats in the ECD, which causes an odd number of cysteine residues, resulting in the formation of an unpaired cysteine sulfhydryl group that may interact with adjacent NOTCH3 receptors or other proteins 8,9. Therefore, mutated NOTCH3 code for a misfolded protein that causes pathological features of CADASIL, accumulation of NOTCH3, formation of granular and osmiophilic material (GOM), followed by degeneration of vascular smooth muscle cells (VSMCs), suggesting the deleterious role of mutant NOTCH3 7,10,11. Protein misfolding and accumulation are the main etiologies of many other neurodegenerative diseases, including Parkinson's, Alzheimer's, and Huntington's diseases 12. In case of CADASIL, NOTCH3 ECD accumulation and GOM deposits cause VSMC degeneration and vascular wall thickening 10,13,14.…”

Section: Introductionmentioning

confidence: 99%

Cellular and Molecular Characterization of CADASIL Using In Vitro Models of Vascular Smooth Muscle Cells and Blood Vessel Organoids

Do,

Lee,

Nam

et al. 2023

Preprint

View full text Add to dashboard Cite

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common inherited form of stroke, characterized by a NOTCH3 mutation on chromosome 19. Despite many genetic and functional studies, the exact mechanisms and pathologies have not been fully elucidated. Herein, the cellular and molecular characteristics of vascular smooth muscle cells (VSMCs) and constituent cells of blood vessel organoids are investigated. Fibroblasts derived from a patient with CADASIL are reprogrammed into iPSCs and differentiated into VSMCs, cerebral organoids, and blood vessel organoids. In CADASIL iPSC-derived VSMCs, NOTCH3 extracellular domain antibody is detected. In CADASIL-blood vessel organoids, significant differences in the blood vessel related parameters between CADASIL and control blood vessel organoids are found. Additionally, cerebral organoids by CADASIL-iPSCs are distinct from those by control-iPSCs. Furthermore, based on RNA sequencing, differentially expressed genes between control and CADASIL samples are associated with proliferation rate, cell cycle, and nuclear division in VSMCs and angiogenesis and vasculogenesis in blood vessel organoids. Six distinct clusters in blood vessel organoids and cell proportion differences between control and CADASIL are identified using single-cell RNA sequencing. This study highlights CADASIL VSMCs and 3D organoids may facilitate investigating molecular and cellular mechanisms underlying CADASIL pathogenesis.

show abstract

A Chinese CADASIL Family with a Novel Mutation on Exon 10 of Notch3 Gene

Liu

Huang

et al. 2021

Journal of Stroke and Cerebrovascular Diseases

View full text Add to dashboard Cite

Genetic study of the NOTCH3 gene in CADASIL patients

Cited by 4 publications

References 36 publications

Genetic Factors of Cerebral Small Vessel Disease and Their Potential Clinical Outcome

Genetic Factors of Cerebral Small Vessel Disease and Their Potential Clinical Outcome

Cellular and Molecular Characterization of CADASIL Using In Vitro Models of Vascular Smooth Muscle Cells and Blood Vessel Organoids

A Chinese CADASIL Family with a Novel Mutation on Exon 10 of Notch3 Gene

Contact Info

Product

Resources

About