Splice site mutation causing a seven amino acid
            <i>Notch3</i>
            in-frame deletion in CADASIL

Joutel, Anne; Chabriat, Hugues; Vahedi, Katayoun; Domenga, Valérie; Vayssière, Céline; Mm, Ruchoux; Lucas, Christian M; Leys, Didier; Bousser, Marie Germaine; Tournier‐Lasserve, Elisabeth

doi:10.1212/wnl.54.9.1874

Cited by 81 publications

(40 citation statements)

References 7 publications

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“…113 The molecular explanations for these cellular outcomes are still under investigation; however, the current model suggests that unpaired cysteine residues in the mutated epidermal growth factor repeats of Notch3 result in abnormal conformation and accumulation of the ectodomain of the receptor at the cell surface. 115 This is consistent with immunocytochemical findings demonstrating high levels of Notch3 extracellular domain in the granular deposits, also referred to as "GOMs" (granular osmiophilic materials), located in the cytosol of smooth muscle cells in small arteries. 80,116 Recently, a mouse model for CADASIL has been developed.…”

Section: The Notch Pathway and Hereditary Cardiovascular Pathologiessupporting

confidence: 88%

Notch Signaling in Blood Vessels

Hofmann

Iruela‐Arispe

2007

Circulation Research

197

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Abstract-It has become increasingly clear that the Notch signaling pathway plays a critical role in the development and homeostasis of the cardiovascular system. This notion has emerged from loss-and gain-of-function analysis and from the realization that several hereditary cardiovascular disorders originate from gene mutations that have a direct impact on Notch signaling. Current research efforts are focused on determining the specific cellular and molecular effects of Notch signaling. The rationale for this has stemmed from the clinical importance and therapeutic potential of modulating vascular formation during various disease states. A more complete appreciation of Notch signaling, as it relates to vascular morphogenesis, requires an in-depth knowledge of expression patterns of the various signaling components and a comprehensive understanding of downstream targets. The goal of this review is to summarize current knowledge regarding Notch signaling during vascular development and within the adult vascular wall. Our focus is on the genetic analysis and cellular experiments that have been performed with Notch ligands, receptors, and downstream targets. We also highlight questions and controversies regarding the contribution of this pathway to vascular development. (Circ Res. 2007;100:1556-1568.)

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Section: The Notch Pathway and Hereditary Cardiovascular Pathologiessupporting

confidence: 88%

Notch Signaling in Blood Vessels

Hofmann

Iruela‐Arispe

2007

Circulation Research

197

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“…CADASIL is caused by single missense mutations (2)(3)(4)(5), small in-frame deletions (6,7), or splice site mutations (8) in the Notch3 gene. Most previously reported mutations have resulted in an odd number of cysteine residues within the first five EGF-like repeats (4,9).…”

Section: Notch3 Which Consists Of 33 Exons Encoding a Protein Of 232mentioning

confidence: 99%

Two Japanese CADASIL Families Exhibiting Notch3 Mutation R75P Not Involving Cysteine Residue

et al. 2008

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“…Currently, more than 230 different CADASIL‐causing mutations in the NOTCH3 gene have been detected,19 which are either missense mutations or small in‐frame deletions in the epidermal growth factor repeats of NOTCH3 . These mutations affect the number of cysteine residues, leading to an unpaired cysteine residue 20, 21, 23, 24…”

Section: Introductionmentioning

confidence: 99%

Differences in proliferation rate between CADASIL and control vascular smooth muscle cells are related to increased TGFβ expression

Panahi

Mesri

Samuelsson

et al. 2018

J Cellular Molecular Medi

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Cerebral autosomal‐dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial fatal progressive degenerative disorder. One of the pathological hallmarks of CADASIL is a dramatic reduction of vascular smooth muscle cells (VSMCs) in cerebral arteries. Using VSMCs from the vasculature of the human umbilical cord, placenta and cerebrum of CADASIL patients, we found that CADASIL VSMCs had a lower proliferation rate compared to control VSMCs. Exposure of control VSMCs and endothelial cells (ECs) to media derived from CADASIL VSMCs lowered the proliferation rate of all cells examined. By quantitative RT‐PCR analysis, we observed increased Transforming growth factor‐β (TGFβ) gene expression in CADASIL VSMCs. Adding TGFβ‐neutralizing antibody restored the proliferation rate of CADASIL VSMCs. We assessed proliferation differences in the presence or absence of TGFβ‐neutralizing antibody in ECs co‐cultured with VSMCs. ECs co‐cultured with CADASIL VSMCs exhibited a lower proliferation rate than those co‐cultured with control VSMCs, and neutralization of TGFβ normalized the proliferation rate of ECs co‐cultured with CADASIL VSMCs. We suggest that increased TGFβ expression in CADASIL VSMCs is involved in the reduced VSMC proliferation in CADASIL and may play a role in situ in altered proliferation of neighbouring cells in the vasculature.

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Splice site mutation causing a seven amino acid Notch3 in-frame deletion in CADASIL

Cited by 81 publications

References 7 publications

Notch Signaling in Blood Vessels

Notch Signaling in Blood Vessels

Two Japanese CADASIL Families Exhibiting Notch3 Mutation R75P Not Involving Cysteine Residue

Differences in proliferation rate between CADASIL and control vascular smooth muscle cells are related to increased TGFβ expression

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