Genotype–phenotype correlations and effect of mutation location in Japanese CADASIL patients

Mukai, Makiko; Mizuta, Ikuko; Watanabe-Hosomi, Akiko; Koizumi, Takashi; Matsuura, Jun; Hamano, Ai; Tomimoto, Hidekazu; Mizuno, Toshiki

doi:10.1038/s10038-020-0751-9

Cited by 26 publications

(32 citation statements)

References 29 publications

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“…This finding suggests that there is a difference in aggregation properties between EGFr 1–6 and EGFr 7–34 NOTCH3 cys mutant proteins 3,4,22 . A lower vascular NOTCH3 ECD aggregation load may be one of the factors underlying the later and milder disease onset in CADASIL patients with an EGFr 7–34 variant compared to patients with an EGFr 1–6 variant 9–11 …”

Section: Discussionmentioning

confidence: 98%

“…3,4,22 A lower vascular NOTCH3 ECD aggregation load may be one of the factors underlying the later and milder disease onset in CADASIL patients with an EGFr 7-34 variant compared to patients with an EGFr 1-6 variant. [9][10][11] EGFr domains 1-6 are more exposed to extracellular matrix proteins, some of which have been shown to co-aggregate with NOTCH3 ECD , such as HTRA1, LTBP-1, TIMP3, and vitronectin, [23][24][25] which may explain why mutant EGFr 1-6 proteins are more prone to aggregate. Alternatively, aggregation properties may be related to the distance of the NOTCH3 cys variant from the recently identified nonenzymatic cleavage site between EGFr 1 and 2.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7][8] Recently, we showed that the position of the NOTCH3 cysteinealtering missense variant (NOTCH3 cys ) is an important modifier of disease severity: NOTCH3 cys variants in EGFr domains 7-34 are associated with a later onset of stroke, higher survival and a lower white matter hyperintensity (WMH) MRI lesion load than NOTCH3 cys variants in EGFr domains 1-6. [9][10][11][12] The molecular mechanisms underlying the NOTCH3 EGFr variant position effect are unknown.…”

Section: Introductionmentioning

confidence: 99%

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NOTCH3 variant position is associated with NOTCH3 aggregation load in CADASIL vasculature

Gravesteijn

Hack

Mulder

et al. 2021

Neuropathology Appl Neurobio

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Aims: CADASIL, the most prevalent hereditary cerebral small vessel disease, is caused by cysteine-altering NOTCH3 variants (NOTCH3 cys ) leading to vascular NOTCH3 protein aggregation. It has recently been shown that variants located in one of NOTCH3 protein epidermal growth-factor like repeat (EGFr) domains 1-6, are associated with a more severe phenotype than variants located in one of the EGFr domains 7-34. The underlying mechanism for this genotype-phenotype correlation is unknown. The aim of this study was to analyse whether NOTCH3 cys variant position is associated with NOTCH3 protein aggregation load.Methods: We quantified vascular NOTCH3 aggregation in skin biopsies (n = 25) and brain tissue (n = 7) of CADASIL patients with a NOTCH3 cys EGFr 1-6 variant or a EGFr 7-34 variant, using NOTCH3 immunohistochemistry (NOTCH3 score) and ultrastructural analysis of granular osmiophilic material (GOM count). Disease severity was assessed by neuroimaging (lacune count and white matter hyperintensity volume) and disability (modified Rankin scale).Results: Patients with NOTCH3 cys EGFr 7-34 variants had lower NOTCH3 scores (P = 1.3Á10 À5 ) and lower GOM counts (P = 8.2Á10 À5 ) than patients with NOTCH3 cys EGFr 1-6 variants in skin vessels. A similar trend was observed in brain vasculature. In the EGFr 7-34 group, NOTCH3 aggregation levels were associated with lacune count (P = 0.03) and white matter hyperintensity volume (P = 0.02), but not with disability.Conclusions: CADASIL patients with an EGFr 7-34 variant have significantly less vascular NOTCH3 aggregation than patients with an EGFr 1-6 variant. This may be one of the factors underlying the difference in disease severity between NOTCH3 cys EGFr 7-34 and EGFr 1-6 variants.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NOTCH3 variant position is associated with NOTCH3 aggregation load in CADASIL vasculature

Gravesteijn

Hack

Mulder

et al. 2021

Neuropathology Appl Neurobio

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“…The NOTCH3 protein is mainly located in vascular smooth muscle cells and pericytes [1]. All CADASIL pathogenic variants are reported to be located in EGFRs, and most of them are missense variants that lead to an amino acid substitution at cysteine residues located at odd-number positions [2,7]. Such mutations may lead to disruption of disulfide bonds between cysteines which, in turn, may result in a conformational change that could alter the NOTCH3 protein aggregation pattern [2,7].…”

Section: Discussionmentioning

confidence: 99%

A case of mild CADASIL patient with a novel heterozygous NOTCH3 variant

2022

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single-gene disease caused by mutations in the neurogenic locus notch homolog protein 3 (NOTCH3) gene. The spectrum of clinical manifestations is broad, ranging from asymptomatic to typical ischemic stroke, and mainly depends on the location of the mutations. We describe the case of a 76-year-old female without apparent neurological deficits. However, brain magnetic resonance imaging revealed confluent lesions in the white matter. Direct sequencing of the NOTCH3 gene revealed a novel pathogenic mutation, c.811T>A, which results in a mild phenotype. Therefore, this report will expand the current knowledge in regards to the mutations that can cause CADASIL.

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“…Cysteine-sparing mutations should be further studied to confirm their pathological role in CADASIL (Rutten et al, 2014;Coupland et al, 2018 of 14; 42.9%; Mukai et al, 2020). p.R75P presents as clinical symptoms that resemble sporadic lacunar infarcts, and head MRI often shows external capsule lesions and white matter lesions without temporal pole lesions (Kim et al, 2014;Ueda et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Atypical Clinical Characteristics of NOTCH3 Mutations Among Patients Admitted for Acute Lacunar Infarctions

Okada

Washida

Irie

et al. 2020

Front. Aging Neurosci.

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Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary small vessel disease, with reported frequencies of 2-5/100,000 individuals. Recently, it has been reported that some patients with NOTCH3 gene mutations show atypical clinical symptoms of CADASIL. Assuming that CADASIL is underdiagnosed in some cases of lacunar infarction, this study was designed to examine the prevalence of NOTCH3 gene mutations in the patients at highest risk who were admitted for lacunar infarctions.Methods: From January 2011 to April 2018, 1,094 patients with lacunar infarctions were admitted to our hospital, of whom 31 patients without hypertension but with white matter disease (Fazekas scale 2 or 3) were selected and genetically analyzed for NOTCH3 gene mutations (Phase 1). Furthermore, 54 patients, who were 60 years or younger, were analyzed for NOTCH3 mutations (Phase 2). NOTCH3 exons 2-24, which encode the epidermal growth factor-like repeat domain of the NOTCH3 receptor, were analyzed for mutations by direct sequencing of genomic DNA.Results: Three patients presented NOTCH3 p.R75P mutations: two in the Phase 1 and one in the Phase 2 cohort. Among patients aged 60 years or younger and those without hypertension but with moderate-to-severe white matter lesions, the carrier frequency of p.R75P was 3.5% (3/85), which was significantly higher than that in the Japanese general population (4.7KJPN) (odds ratio [95% CI] = 58. 2 [11.6-292.5]). All three patients with NOTCH3 mutations had family histories of stroke, and the average patient age was 51.3 years. All three patients also showed white matter lesions in the external capsule but not in the temporal pole. The CADASIL and CADASIL scale-J scores of the three patients were 6, 17, 7 (mean, 10.0) and 13, 20, 10 (mean, 14.3), respectively. Conclusion:Among patients hospitalized for lacunar infarctions, the p.R75P prevalence may be higher than previously estimated. The NOTCH3 p.R75P mutation may be Okada et al.NOTCH3 Mutations Among Lacunar Infarctions underdiagnosed in patients with early-onset lacunar infarctions due to the atypical clinical and neuroimaging features of CADASIL. Early-onset, presence of family history of stroke, external capsule lesions, and absence of hypertension may help predict underlying NOTCH3 mutations despite no temporal white matter lesions.

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Genotype–phenotype correlations and effect of mutation location in Japanese CADASIL patients

Cited by 26 publications

References 29 publications

NOTCH3 variant position is associated with NOTCH3 aggregation load in CADASIL vasculature

NOTCH3 variant position is associated with NOTCH3 aggregation load in CADASIL vasculature

A case of mild CADASIL patient with a novel heterozygous NOTCH3 variant

Prevalence and Atypical Clinical Characteristics of NOTCH3 Mutations Among Patients Admitted for Acute Lacunar Infarctions

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