A novel cysteine-sparing G73A mutation of NOTCH3 in a Chinese CADASIL family

Huang, Liyan; Li, Wei; Li, Yang; Song, ChaoYuan; Wang, Pin; Wang, Hongchun; Sun, Xiulian

doi:10.1007/s10048-019-00592-3

Cited by 8 publications

(4 citation statements)

References 35 publications

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“…GOM deposits were observed in patients carrying cysteine-sparing mutations (Santa et al, 2003;Scheid et al, 2008;Brass et al, 2009;Wang et al, 2011;Wollenweber et al, 2015). In vitro studies showed that the aggregation behavior of cysteinesparing mutants was similar to cysteine-affecting mutants (Wollenweber et al, 2015;Huang et al, 2020). We identified six cysteine-sparing variants in EGFr region, all of them has been reported in previous studies.…”

Section: Discussionsupporting

confidence: 56%

NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients

Sun

Zhou

et al. 2021

Front. Genet.

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. Archetypal disease-causing mutations are cysteine-affecting variants within the 34 epidermal growth factor-like repeat (EGFr) region of the Notch3 extracellular subunit. Cysteine-sparing variants and variants outside the EGFr coding region associated with CADASIL phenotype have been reported. However, the linkage between untypical variants and CADASIL is unclear. In this study, we investigated the spectrum of NOTCH3 variants in a cohort of 38 probands from unrelated families diagnosed as CADASIL. All coding exons of the NOTCH3 gene were analyzed, and clinical data were retrospectively studied. We identified 23 different NOTCH3 variants including 14 cysteine-affecting pathogenic variants, five cysteine-sparing pathogenic variants, two reported cysteine-sparing variants of unknown significance (VUS), and two novel VUS outside EGFr region. In retrospective studies of clinical data, we found that patients carrying cysteine-sparing pathogenic variants showed later symptom onset (51.36 ± 7.06 vs. 44.96 ± 8.82, p = 0.023) and milder temporal lobe involvement (1.50 ± 1.74 vs. 3.11 ± 2.32, p = 0.027) than patients carrying cysteine-affecting pathogenic variants. Our findings suggested that untypical variants comprise a significant part of NOTCH3 variants and may be associated with a distinctive phenotype.

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Section: Discussionsupporting

confidence: 56%

NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients

Sun

Zhou

et al. 2021

Front. Genet.

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“…For a systematic review of these variants see Muiño et al ( Muiño et al, 2017 ). Recently, the effects of two cysteine-sparing mutations that are not present in gnomAD (p.Gly73Ala and p.Arg75Pro) and one known CADASIL mutation (p.Arg133Cys), were tested in cells and shown to follow the same trend on cell survival, suggesting that mutations not involving cysteines but located in the EGF-like repeats domain might have a role in CADASIL ( Huang et al, 2020 ). Interestingly, loss of function mutations do not appear to cause CADASIL ( Rutten et al, 2013 ).…”

Section: Genetics Of Vascular Dementiamentioning

confidence: 99%

Genetic architecture of common non-Alzheimer’s disease dementias

Guerreiro

Gibbons

Tábuas‐Pereira

et al. 2020

Neurobiology of Disease

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Frontotemporal dementia (FTD), dementia with Lewy bodies (DLB) and vascular dementia (VaD) are the most common forms of dementia after Alzheimer’s disease (AD). The heterogeneity of these disorders and/or the clinical overlap with other diseases hinder the study of their genetic components. Even though Mendelian dementias are rare, the study of these forms of disease can have a significant impact in the lives of patients and families and have successfully brought to the fore many of the genes currently known to be involved in FTD and VaD, starting to give us a glimpse of the molecular mechanisms underlying these phenotypes. More recently, genome-wide association studies have also pointed to disease risk-associated loci. This has been particularly important for DLB where familial forms of disease are very rarely described. In this review we systematically describe the Mendelian and risk genes involved in these non-AD dementias in an effort to contribute to a better understanding of their genetic architecture, find differences and commonalities between different dementia phenotypes, and uncover areas that would benefit from more intense research endeavors.

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“…Some cysteine-involving mutations (Duering et al, 2011) and also p.Arg75Pro and p.Asp80Gly (Wollenweber et al, 2015) was reported to be prone to aggregation by using a single-particle aggregation assay. In the very recent report of the patient with p.Gly73Ala, unfortunately, skin biopsy was declined, cellular and in vitro experiments showed pro-aggregatory property of the mutation (Huang et al, 2020).…”

Section: Cysteine-sparing Mutationsmentioning

confidence: 99%

Clinical and Genetic Aspects of CADASIL

Mizuno

Mizuta

Watanabe-Hosomi

et al. 2020

Front. Aging Neurosci.

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebral small vessel disease caused by mutations in NOTCH3, is characterized by recurrent stroke without vascular risk factors, mood disturbances, and dementia. MRI imaging shows cerebral white matter (WM) hyperintensity, particularly in the external capsule and temporal pole. Missense mutations related to a cysteine residue in the 34 EGFr on the NOTCH3 extracellular domain (N3ECD) are a typical mutation of CADASIL. On the other hand, atypical mutations including cysteine sparing mutation, null mutation, homozygous mutation, and other associate genes are also reported. From the viewpoint of gain of function apart from Notch signaling or loss of function of Notch signaling, we review the research article about CADASIL and summarized the pathogenesis of small vessel, stroke, and dementia in this disease.

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A novel cysteine-sparing G73A mutation of NOTCH3 in a Chinese CADASIL family

Cited by 8 publications

References 35 publications

NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients

NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients

Genetic architecture of common non-Alzheimer’s disease dementias

Clinical and Genetic Aspects of CADASIL

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