Considerations on a mutation in the NOTCH3 gene sparing a cysteine residue: a rare polymorphism rather than a CADASIL variant.
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ABSTRACT:
SUBMITTER: Bersano A
PROVIDER: S-EPMC3861349 | biostudies-literature | 2012 Oct-Dec
REPOSITORIES: biostudies-literature
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Considerations on a mutation in the NOTCH3 gene sparing a cysteine residue: a rare polymorphism rather than a CADASIL variant.
Bersano Anna A Ranieri Michela M Ciammola Andrea A Cinnante Claudia C Lanfranconi Silvia S Dotti Maria Teresa MT Candelise Livia L Baschirotto Cinzaia C Ghione Isabella I Ballabio Elena E Bresolin Nereo N Bassi Maria Teresa MT
Functional neurology 20121001 4
Some missense mutations and small deletions in the NOTCH3 gene, not involving cysteine residues, have been described in patients considered to be affected by paucisymptomatic CADASIL. However, the significance of such molecular variants is still unclear. We describe a 49-year-old woman with a CADASIL-like phenotype, carrying a novel cysteine-sparing mutation in exon 29 of the NOTCH3 gene, and discuss the possible pathogenetic role of this molecular variant. Even though atypical clinical and MRI ...[more]
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Project description:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult onset cerebral small vessel disorder caused by the mutations of the neurogenic locus notch homolog protein 3 (NOTCH3) gene. The extracellular part of NOTCH3 is composed of 34 epidermal growth factor-like (EGF-like) repeat domains. Each EGF-like domain is rich of cysteine and glycine to produce three loops that are essential for high-affinity binding to its ligand. Nearly all reported CADASIL-associated mutations result in gain or loss of a cysteine residue within the EGF-like domains. Only a few cysteine-sparing NOTCH3 mutations have been documented in the patients with CADASIL to date. Here, we reported a Chinese CADASIL family with a cysteine-sparing NOTCH3 mutation. In this family, affected patients had dizziness, memory loss, gait instability, or hemiplegia. Brain magnetic resonance imaging (MRI) showed diffuse leukoencephalopathy with confluent signal abnormalities in the periventricular white matter, basal ganglia, and centrum semiovale bilaterally. By screening the entire coding region of NOTCH3, a novel missense mutation p.G149V (c.446G>T) was found. This mutation was not detected in 400 normal controls. Considering the critical position of glycine within the C-loop of EGF-like domain and its high conservation through evolution, p.G149V mutation could be a potential pathogenic cause for CADASIL.
| S-EPMC4123979 | biostudies-literature
Project description:CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by NOTCH3 mutations affecting the number of cysteines. The pathogenic role of cysteine-sparing NOTCH3 mutations with typical clinical CADASIL syndrome is still debated. This review aimed to characterize NOTCH3 cysteine-sparing mutations in patients with clinical suspicion of CADASIL. Articles on NOTCH3 cysteine-sparing mutations with clinical suspicion of CADASIL were reviewed. Clinical and radiological cerebral phenotypes data were extracted and characterized across regions and compared with phenotypes of typical CADASIL patients. We screened 298 NOTCH3 cysteine-sparing mutation individuals from 20 publications, and mutations in exon 3 were the most frequently reported (21.46%). Gait impairment (76.47%), cognitive impairment (67.47%), and stroke (62.37%) were the three most common clinical phenotypes; the most frequent radiological cerebral phenotypes were lacunes (74.29%) and cerebral microbleeds (72.73%). Compared with CADASIL patients, cognitive impairment and cerebral microbleed frequencies were significantly higher in patients with NOTCH3 cysteine-sparing mutations, while the white matter hyperintensities in anterior temporal polar and external capsule were rarely observed. Compared with Western patients, radiological phenotypes were more common than clinical phenotypes in cysteine-sparing Asian patients. More than half of cysteine-sparing patients had positive granular osmiophilic material deposits. NOTCH3 cysteine-sparing mutations in patients with clinical suspicion of CADASIL mainly manifested with gait and cognitive impairment but rare white matter hyperintensities in anterior temporal pole and external capsule. Further studies are warranted to pay attention to atypical NOTCH3 variants, which could guide specific diagnosis and help unravel underlying mechanisms.
| S-EPMC11354472 | biostudies-literature
Project description:AimsCADASIL, the most prevalent hereditary cerebral small vessel disease, is caused by cysteine-altering NOTCH3 variants (NOTCH3cys ) 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 NOTCH3cys variant position is associated with NOTCH3 protein aggregation load.MethodsWe quantified vascular NOTCH3 aggregation in skin biopsies (n = 25) and brain tissue (n = 7) of CADASIL patients with a NOTCH3cys 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).ResultsPatients with NOTCH3cys EGFr 7-34 variants had lower NOTCH3 scores (P = 1.3·10-5 ) and lower GOM counts (P = 8.2·10-5 ) than patients with NOTCH3cys 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.ConclusionsCADASIL 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 NOTCH3cys EGFr 7-34 and EGFr 1-6 variants.
| S-EPMC9291091 | biostudies-literature
Project description:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited vascular dementia characterised by recurrent ischemic strokes in the deep white matter. Mutations in the gene encoding the cell surface receptor, Notch3, have been identified in CADASIL patients, and accumulation of the extracellular domain of Notch3 has been demonstrated in affected vessels. Almost all CADASIL mutations alter the number of cysteine residues in the epidermal growth factor (EGF)-like repeats in the extracellular domain of the protein.To understand the functional consequences of a recurrent CADASIL mutation on furin processing, cell surface expression, ligand binding, and activation of a downstream effector CBF1 by the Notch3 receptor.We expressed wild type and mutant Notch3 receptors in cultured cells and examined cell surface expression of the proteins. We also applied a new flow cytometry based approach to semi-quantitatively measure binding to three Notch ligands. Additionally, we used a well characterised co-culture system to examine ligand dependent activation of transcription from a CBF1-luciferase reporter construct.These studies revealed subtle abnormalities in furin processing of the mutant receptor, although both heterodimeric and full length receptors are present on the cell surface, are capable of interacting with soluble forms of three ligands, Delta1, Delta4, and Jagged1, and retain the ability to activate CBF1 in a ligand dependent manner.By comparison with other mutant forms of Notch3, these data indicate that individual CADASIL mutations can have disparate effects on Notch3 expression and function.
| S-EPMC1739793 | biostudies-other
Project description:BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by mutations in NOTCH3 gene with remarkable phenotypic heterogeneity. Cases of CADASIL associated with homozygous NOTCH3 mutations are rare and subsequently understudied. In this study, we investigate the genetic and phenotypic features within patients of CADASIL with homozygous NOTCH3 mutations.Case presentationWe recruited two affected individuals with CADASIL from a mainland Chinese family. The proband (Patient 1), a 60-year-old male, presented with slow progressive gait instability, severe cognitive impairment, and emotional disorder for more than 2 years with a history of ischemic stroke and hypertension. His younger brother (Patient 2) presented with apparent gait difficulties, dysarthria as well as cognitive decline at 59 years old. Brain magnetic resonance imaging (MRI) showed diffused white matter lesions involving bilateral periventricular white matter, semioval center region, and anterior temporal lobes. Molecular genetic testing identified a homozygous variant, c.1759C > T (p.R587C), in NOTCH3 gene in both patients. Pathological analysis revealed granular osmiophilic material (GOM) deposits in small arterial walls of skin from the proband. The diagnosis of CADASIL was confirmed.ConclusionsOur cases of CADASIL with homozygous mutation c.1759C > T (p.R587C) in NOTCH3 share similar manifestation to the patients with heterozygous same mutation reported previously. Other than genetic factors, vascular risk factors or environmental factors might contribute to the phenotypic variation of CADASIL.
| S-EPMC7053106 | biostudies-literature
Project description:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke caused by mutations in NOTCH3 gene. We report the first case of CADASIL in an indigenous Rungus (Kadazan-Dusun) family in Kudat, Sabah, Malaysia confirmed by a R54C (c.160C>T, p.Arg54Cys) mutation in the NOTCH3. This mutation was previously reported in a Caucasian and two Korean cases of CADASIL. We recruited two generations of the affected Rungus family (n = 9) and found a missense mutation (c.160C>T) in exon 2 of NOTCH3 in three siblings. Two of the three siblings had severe white matter abnormalities in their brain MRI (Scheltens score 33 and 50 respectively), one of whom had a young stroke at the age of 38. The remaining sibling, however, did not show any clinical features of CADASIL and had only minimal changes in her brain MRI (Scheltens score 17). This further emphasized the phenotype variability among family members with the same mutation in CADASIL. This is the first reported family with CADASIL in Rungus subtribe of Kadazan-Dusun ethnicity with a known mutation at exon 2 of NOTCH3. The penetrance of this mutation was not complete during the course of this study.
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Project description:ObjectiveTo determine the small vessel disease spectrum associated with cysteine-altering NOTCH3 variants in community-dwelling individuals by analyzing the clinical and neuroimaging features of UK Biobank participants harboring such variants.MethodsThe exome and genome sequencing datasets of the UK Biobank (n = 50,000) and cohorts of cognitively healthy elderly (n = 751) were queried for cysteine-altering NOTCH3 variants. Brain MRIs of individuals harboring such variants were scored according to Standards for Reporting Vascular Changes on Neuroimaging criteria, and clinical information was extracted with ICD-10 codes. Clinical and neuroimaging data were compared to age- and sex-matched UK Biobank controls and clinically diagnosed patients from the Dutch cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) registry.ResultsWe identified 108 individuals harboring a cysteine-altering NOTCH3 variant (2.2 of 1,000), of whom 75% have a variant that has previously been reported in CADASIL pedigrees. Almost all variants were located in 1 of the NOTCH3 protein epidermal growth factor-like repeat domains 7 to 34. White matter hyperintensity lesion load was higher in individuals with NOTCH3 variants than in controls (p = 0.006) but lower than in patients with CADASIL with the same variants (p < 0.001). Almost half of the 24 individuals with brain MRI had a Fazekas score of 0 or 1 up to age 70 years. There was no increased risk of stroke.ConclusionsAlthough community-dwelling individuals harboring a cysteine-altering NOTCH3 variant have a higher small vessel disease MRI burden than controls, almost half have no MRI abnormalities up to age 70 years. This shows that NOTCH3 cysteine altering variants are associated with an extremely broad phenotypic spectrum, ranging from CADASIL to nonpenetrance.
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Project description:Introduction: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal-dominant systemic vascular disease that primarily involves small arteries. Patients with CADASIL experience migraines, recurrent ischemic strokes, cognitive decline, and dementia. The NOTCH3 gene, which is located on chromosome 19p13.12, is one of the disease-causing genes in CADASIL. Herein, we investigate the genetic and phenotypic features in a Chinese CADASIL family with heterozygous NOTCH3 mutation. Methods and Results: In the family, the proband suffered from dizziness, stroke, and cognitive deficits. Brain magnetic resonance imaging (MRI) demonstrated symmetrical white matter lesions in the temporal lobe, outer capsule, lateral ventricle, and deep brain. Whole-exome sequencing identified a known missense mutation in the proband, c.397C>T (p.Arg133Cys), which was identified in his son and granddaughter using Sanger sequencing. The proband's younger brother and younger sister also have a history of cognitive impairment or cerebral infarction, but do not have this genetic mutation, which may highlight the impact of lifestyle on this neurological disease. Conclusion: We identified a known CADASIL-causing mutation NOTCH3 (c.397C>T, p.Arg133Cys) in a Chinese family. The clinical manifestations of mutation carriers in this family are highly heterogeneous, which is likely a common feature for the etiology of different mutations in CADASIL. Molecular genetic analyses are critical for accurate diagnosis, as well as the provision of genetic counselling for CADASIL.
| S-EPMC9756437 | biostudies-literature
Project description:Background and objectiveCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microvascular disease characterized by the development of vascular dementia and lacunar infarctions. This study aimed to identify the genetic and clinical features of CADASIL in Japan.MethodsWe conducted genetic analysis on a case series of patients clinically diagnosed with CADASIL. Clinical and imaging analyses were performed on 32 patients with pathogenic mutations in the NOTCH3 gene. To assess the presence of cerebral microbleeds (CMBs), we utilized several established rating scales including the Fazekas scale, Scheltens rating scale, and Microbleed Anatomical Rating Scale, based on brain MRI images.ResultsAmong the 32 CADASIL patients, 24 cases were found carrying the R75P mutation in NOTCH3, whereas the remaining eight cases had other NOTCH3 mutations (R75Q, R110C, C134F, C144F, R169C, and R607C). The haplotype analysis of the R75P mutation uncovered the presence of a founder effect. A brain MRI analysis revealed that cases with the R75P mutation had a significantly higher total number of CMBs, particularly in the thalamus when compared to patients with other NOTCH3 mutations. Among 15 out of 24 cases with the R75P mutation, we observed a notable clustering of CMBs in the thalamus, termed microbleed clustering in thalamus sign (MCT sign).ConclusionWe propose that the MCT sign observed in NOTCH3 R75P-related CADASIL patients may serve as a potentially characteristic imaging feature. This finding offers further insights into the interactions between genotypes and phenotypes between NOTCH3 and CADASIL.
| S-EPMC10480842 | biostudies-literature
Project description:Notch3 is a member of the Notch family and its mutations are known to cause a hereditary human disorder called cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, the specific function and signaling cascade initiated by CADASIL mutants remain unknown. To gain further insight into mechanism of action of CADASIL mutants, the present study conducted several experiments on the effects of Notch3 mutants in multiple cell lines. The protein levels of Notch3, fibronectin, collagen, inducible nitric oxide synthase and DNA (cytosine-5)-methyltransferase 1 (DNMT1) were determined by western blotting. The mRNA levels of IL-1? and TNF-? were measured by reverse transcription semi-quantitative PCR and DNMT1 mRNA levels were determined by quantitative PCR. Trypan blue staining was used for proliferation analysis and wound healing assays were performed to determine cell migration capability. The present study reported that R90C and R169C Notch3 mutants, and wild-type Notch3 had different effects on several cell lines. In T/GHA-VSMC cells, following the transfection of the two mutants, collagen and fibronectin expression increased, whereas expression decreased in IMR-90 cells. In BV2 cells, the two mutants resulted in decreased nitric oxide and iNOS production. In HeLa cells, proliferation and migration increased significantly following the transfection of the two mutants, whereas in the MCF-7 and HCC1937 cell lines, cell proliferation and migration decreased. In addition, the two mutants suppressed the expression of DNMT1 in HeLa and IMR-90 cells. Overall, the present study provided novel insights that further explored the underlying mechanisms of CADASIL.
| S-EPMC7739825 | biostudies-literature