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Results for “Receptor, Notch3”

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PubMed2001

Two cases of Japanese CADASIL with corpus callosum lesion.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a rare hereditary stroke disease. In the present study, a Japanese CADASIL family was first reported with missense mutation of Arg141Cys of Notch3 and a unique lesion of corpus callosum. Upon neuropsychological examination, our case 1 showed only right-handed constructional apraxia associated with corpus callosum lesion. No other callosal disconnection signs were present. Sagittal T2 weighted image of case 1 showed multiple small lesions along with the pericallosal branches from the truncus to the posterior part of the splenium in the corpus callosum. Although detailed mapping of the corpus callosum for functional fractionation in humans remains incomplete, the constructional apraxia on the right may be related to callosal dysfunction from the truncus to the posterior part of the splenium in the corpus callosum.

Corpus Callosum↗

PubMed2001

NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL.

Mutations in NOTCH3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary angiopathy causing stroke and vascular dementia. All CADASIL mutations identified so far result in the loss or gain of one cysteine residue within epidermal growth factor (EGF)-like repeat domains. Here an in-frame deletion causing a loss of three cysteine residues within EGF repeat 6 is reported. These data are consistent with the hypothesis that the change toward an odd number of cysteine residues within a given EGF repeat and therefore an unpaired, reactive cysteine residue is the common and critical molecular event in CADASIL.

Adult↗

PubMed2006

Unexpected features of acute T lymphoblastic lymphomas in Notch1IC transgenic rats.

Dysregulated Notch signaling accounts for the majority of acute T lymphoblastic leukemia/lymphoma (T-ALL) cases in humans. Here, we characterize lymphomas from Notch1IC transgenic rats, which develop T-ALL shortly after weaning, and show that they display a number of previously undocumented features. Starting from monoclonal thymic tumors, the CD4(+)CD8alphaalpha(+) lymphoma cells infiltrate the bone marrow and then spread to secondary lymphoid and non-lymphoid organs. However, major hallmarks of T-ALL cells in other murine models and human patients, such as constitutive NF-kappaB activity and increased levels of anti-apoptotic proteins, are remarkably absent in Notch1IC lymphomas. In contrast, CD30, a classic marker of Hodgkin lymphomas, is overexpressed in these tumors. Intriguingly, enforced Notch1 signaling up-regulates expression of Notch3, which has also been implicated in the pathogenesis of T-ALL. By blocking endogenous Notch signaling, we could demonstrate that Notch1IC is sufficient to induce sustained preTCR expression in transgenic thymocytes but not for their progression to the double-positive stage. This suggests that other Notch activities may also contribute to the phenotype of the transgenic rats. In summary, we anticipate this new animal model will help to further elucidate the role of Notch1 in the pathogenesis of T-ALL.

Acute Disease↗

PubMed2006

A novel mutation (C271F) in the Notch3 gene in a Chinese man with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult-onset hereditary condition caused by mutations in the Notch3 gene. A Chinese man was studied. METHOD: Electronic microscopy examination of skin biopsy. The Notch3 gene was screened for mutations by polymerase chain reaction and direct DNA sequencing. RESULTS: Electronic microscopy showed the presence of deposits of granular osmiophilic material in dermal capillaries in the index patient. A novel heterozygous C271F in exon 6 was detected in the index patient. This heterozygous C271F mutation was also detected in the asymptomatic elder son but was not detected in the asymptomatic wife of the patient. Allele specific amplification showed that C271F was not detected in 100 normal subjects. CONCLUSION: We established the molecular basis of CADASIL in a Chinese man. Mutation detection assay provides a reliable method for confirming the diagnosis of CADASIL.

Asian People↗

PubMed2001

A novel mutation in the Notch3 gene in an Italian family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: genetic and magnetic resonance spectroscopic findings.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary syndrome caused by mutations of the Notch3 gene, usually localized to exons 3 and 4. OBJECTIVES: To report a novel pathogenetic mutation occurring in exon 6 of the Notch3 gene, a location not previously recognized in patients with CADASIL, and to report the results of magnetic resonance spectroscopy in CADASIL. METHODS: Mutation analysis of the Notch3 gene was performed in 2 patients belonging to a large kindred manifesting CADASIL, as well as in 7 clinically unaffected members of the family and 200 control chromosomes. Proton magnetic resonance spectroscopy was used to estimate metabolite resonance intensities in the 2 affected subjects. RESULTS: Sequence analysis of the Notch3 gene showed a new missense mutation CGC-->TGC in codon 332 of exon 6, resulting in the replacement of an arginine residue with a cysteine. This mutation was never observed in the 7 unaffected members of the family and the 200 control chromosomes examined. Proton magnetic resonance spectroscopy showed a diffuse decrease in cerebral N-acetylaspartate, indicating the presence of widespread axonal damage. CONCLUSIONS: Our findings emphasize the role of direct DNA sequence analysis for the diagnosis of CADASIL. Moreover, the results of proton magnetic resonance spectroscopy suggest that widespread axonal damage may be an early finding of the disease.

Adult↗

PubMed2004

Positron emission tomography examination of cerebral blood flow and glucose metabolism in young CADASIL patients.

BACKGROUND AND PURPOSE: CADASIL causes repeated ischemic strokes leading to subcortical vascular dementia. The purpose of this study was to assess whether cerebral blood flow (CBF) and regional cerebral metabolic rates of glucose (rCMR(gluc)) in CADASIL patients are affected in early adulthood. METHODS: CBF and rCMR(gluc) were examined with positron emission tomography in correlation with magnetic resonance imaging (MRI) in 14 adult (19 to 41 years) CADASIL patients with the Notch3 R133C mutation. Seven patients had experienced transient ischemic attack and 3 had experienced > or =1 strokes. RESULTS: The mean CBF in the CADASIL patients was significantly lower in both frontal (P=0.019) and occipital (P=0.009) white matter (WM) than those in the controls. CBF decreased significantly with increased severity of the disease. The patients had lower mean rCMR(gluc) values than the controls, although differences were not statistically significant. Sum scores of semiquantitative MRI rating scale (Scheltens) correlated significantly with WM CBF but not with rCMR(gluc). CONCLUSIONS: In CADASIL, there is an early and significant decrease in the CBF of WM associated with simultaneous MRI changes. These are obviously caused by the arteriopathy in long penetrating arteries and indicate early tissue damage, also expressed as impaired rCMR(gluc) in the WM.

Adult↗

PubMed2004

Detection of the founder effect in Finnish CADASIL families.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease characterized by brain infarcts, cognitive decline and dementia. The disease is caused by at least 91 missense mutations, four deletions and one splice site mutation in the NOTCH3 gene, which maps to 19p13.1. In 18 out of the 21 Finnish CADASIL families so far identified, the causative mutation is an arginine to cysteine substitution in position 133 (R133C). Most of the families carrying this mutation originate from the western coast of Finland, thus suggesting a founder effect. No previous reports of a founder effect in CADASIL have been published. We haplotyped 60 patients from these 18 families for 10 microsatellite markers in order to determine whether the families descend from a common ancestor. We found a similar haplotype linked to the mutation in all 18 pedigrees, which indicates a single common ancestor for all the Finnish R133C families. The age analysis of the founder mutation places the introduction of the mutation in the late 1600s or early 1700s.

Amino Acid Substitution↗

PubMed2006

Notch signalling and voltage-gated Na+ channel activity in human prostate cancer cells: independent modulation of in vitro motility.

This study tested the possible functional relationship of two signalling mechanisms shown previously to be involved in human prostate cancer (PCa), Notch and voltage-gated sodium channel. Notch1 and Notch2 were differentially expressed in PCa cell lines of varying metastatic potential (LNCaP, PC-3, PC-3M) in comparison to a normal prostate cell line (PNT2), whereas Notch3 and Notch4 were not expressed. The Notch ligand Jagged1, but not Jagged2, was increased in all cell lines, whereas the Notch downstream target Deltex was not expressed. In comparison to the LNCaP cell line, Hes1, another downstream target, showed elevated expression in the metastatic PC-3 and PC-3M cells and promoted lateral motility. In contrast, the Notch ligand Delta-like1 (Dll1) levels were higher in LNCaP compared with PC-3 and PC-3M cells. Importantly, decreasing Dll1 expression increased the lateral motility of PC-3 cells, whereas blocking voltage-gated Na(+) channel activity with tetrodotoxin decreased motility. However, the effect of Dll1 was independent of Notch signalling through Hes1 and voltage-gated Na(+) channel expression/activity.

Amyloid Precursor Protein Secretases↗

PubMed2002

Diagnostic strategies in CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited autosomal dominant condition characterized by migraine, recurrent stroke, and dementia. It results from mutations in the notch3 gene but mutations may occur at multiple sites making molecular diagnosis time consuming. It has been suggested that the presence of granular osmiophilic material (GOM) on skin biopsy and involvement of the anterior temporal lobe and external capsule on MRI may help in diagnosis. METHODS: The authors identified 83 potential index cases from the British population and screened exons 2 to 23 of notch3. MRI scans were scored using a modified Scheltens scale. Skin biopsy was performed in a subgroup. RESULTS: Fifteen different point mutations were identified in 48 families, 73% of which were in exon 4, 8% in exon 3, and 6% in each of exons 5 and 6. Moderate or severe involvement of the anterior temporal pole on MRI had a sensitivity of 89% and specificity of 86% for diagnosis of CADASIL, whereas external capsule involvement had a high sensitivity of 93% but a low specificity of 45%. Skin biopsy, performed in 18 cases, had a sensitivity of 45% and specificity of 100%. CONCLUSIONS: The spectrum of mutations in this study can be used to plan appropriate screening protocols; a suggested protocol is to screen exon 4, and proceed to exons 3, 5, and 6 where indicated. GOM on skin biopsy is diagnostic but can be negative. Anterior temporal pole involvement on MRI is a useful diagnostic marker.

Adult↗

PubMed2004

Fibrosis and stenosis of the long penetrating cerebral arteries: the cause of the white matter pathology in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) the vascular smooth muscle cells are destroyed and granular osmiophilic material is deposited followed by fibrosis of the arterial wall. To verify whether true stenosis of the fibrotic white matter arteries is a key pathogenic event in CADASIL, we analyzed the thickness of walls (expressed as sclerotic index) and luminal diameters of penetrating arterioles in both grey matter and white matter of four CADASIL patients due to the C475T (R133C) mutation in the Notch3 gene and in 9 age-matched controls. We also reconstructed 9 arterioles from 1000 serial sections in two CADASIL patients. The thickness of the arteriolar walls in both grey matter and white matter was significantly increased in the CADASIL patients compared with controls. Furthermore, in CADASIL patients the arteriolar walls were significantly thicker in the white matter than in the grey matter. The distribution curve of arteriolar internal diameters in CADASIL patients shifted towards smaller sizes. In serial sections, the marked increase in the thickness of the white matter penetrating arterioles or their branches did not occur until the internal diameters had decreased to about 20 to 30 pm and external diameters to about 100 to 130 microm. In conclusion, long penetrating arterioles and their branches supplying subcortical structures in CADASIL are stenosed and their walls are thickened. This conforms to the abundance of infarcts and primary ischemic damage in CADASIL patients' white matter.

Actins↗

PubMed2006

Cortical neuronal apoptosis in CADASIL.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations of the NOTCH3 gene and is a model of pure vascular dementia. Cortical atrophy has been reported to be associated with cognitive decline in the disease, although the underlying mechanism is unknown. We postulated that apoptosis may be involved in this process. METHODS: We report the clinical history, magnetic resonance imaging findings, and pathologic examinations of 4 patients (2 of whom were demented) who died from complications of the disease. Apoptosis was evaluated in brain tissue using antibodies against activated caspase3 and in situ end labeling assays for DNA fragmentation. RESULTS: Widespread neuronal apoptosis in the cerebral cortex (predominantly in layers 3 and 5) was observed in all patients. This was not seen in 3 non-CADASIL controls. Semiquantitative analysis suggested that apoptosis was more extensive in the presence of larger load of subcortical ischemic lesions and smaller brain volumes. CONCLUSIONS: Neuronal apoptosis may be involved in cortical atrophy in CADASIL and appears related to the burden of subcortical ischemic lesions. These findings may have important implications in other small vessel diseases and may provide a potential target for future therapeutic interventions.

Adult↗

PubMed2004

Insidious cognitive decline in CADASIL.

BACKGROUND AND PURPOSE: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) causes repeated ischemic attacks leading to subcortical vascular dementia. The aim of this study was to characterize cognitive function in subjects with a C475T (R133C) mutation in the Notch3 gene, leading to CADASIL. METHODS: Prestroke (n=13) and poststroke (n=13) mutation carriers and mutation carriers with dementia (n=8) were compared with healthy noncarriers from the same families using a comprehensive set of neuropsychological tests. RESULTS: Changes in working memory and executive function were observed in the very early phase of the disease before transient ischemic attack (TIA) or stroke. Later, in the poststroke phase, the cognitive impairment concerned also mental speed and visuospatial ability. Finally, the subjects with dementia had multiple cognitive deficits, which engaged even verbal functions, verbal episodic memory, and motor speed. The 2 mutation carrier groups without dementia and the controls could be reliably distinguished using 3 tests that assessed working memory/attention, executive function, and mental speed. Episodic memory was relatively well-preserved late in the disease. CONCLUSIONS: A deterioration of working memory and executive function was already observed in the prestroke phase, which means that cognitive decline may start insidiously before the first onset of symptomatic ischemic episodes.

Adult↗

PubMed2003

A novel mutation (C67Y)in the NOTCH3 gene in a Korean CADASIL patient.

We report a 52-yr-old Korean woman with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) whose diagnosis was confirmed by skin biopsy and the presence of a novel mutation in the NOTCH3 gene. The patient's clinical features were rather unusual in that 1) clinical presentations were only two episodes of stroke and mild dementia unaccompanied by mood disturbances or migraine, and 2) there was no family history. Brain MRI showed T2 hyperintensities in both temporal pole areas in line with the recent suggestion by O'Sullivan et al. that the abnormality could be a radiologic marker of CADASIL. FDG-PET also showed a hypometabolism in the temporal pole areas with an abnormal finding on MRI in addition to the hypometabolism in cortical and subcortical regions. We could learn from this case that CADASIL may be included in the differential diagnoses in patients with vascular dementia associated with a small vessel disease, even in the absence of a family history, especially when there are no known stroke risk factors and when the MRI shows T2 hyperintensity in the temporal pole regions.

Amino Acid Substitution↗

PubMed2005

Impaired cerebral vasoreactivity in a transgenic mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy arteriopathy.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease causing stroke and dementia. The disease is caused by highly stereotyped mutations in NOTCH3, which is restrictively expressed in vascular smooth muscle cells (VSMCs). The mechanisms of compromised cerebral hemodynamics in CADASIL remain to be elucidated. We tested the hypothesis that mutant NOTCH3 impairs the vasomotor function of cerebral vessels. METHODS: Vasomotor function was examined in vivo in transgenic mice expressing a mutant NOTCH3 in VSMCs (TgNotch3R90C). Mice develop an age-dependent arteriopathy similar to that seen in CADASIL, without brain parenchyma lesions. Using laser-Doppler flowmetry, we assessed in awake TgNotch3R90C mice and wild-type littermates the cerebrovascular reactivity to 2 potent vasodilator stimuli (acetazolamide and hypercapnia) and cerebral blood flow (CBF) autoregulation during stepwise blood pressure elevations and reductions. Mice were studied at 18 months of age, when the CADASIL features are apparent, and at 10 months of age, before their appearance. RESULTS: Eighteen-month-old TgNotch3R90C mice showed reduced responses to hypercapnia and acetazolamide, higher cerebrovascular resistance during hypertension, and their lower limit of CBF autoregulation was shifted to higher blood pressures. Cerebrovascular responses were similarly impaired in 10-month-old TgNotch3R90C mice. CONCLUSIONS: Cerebrovascular reactivity is compromised early in TgNotch3R90C mice. The data show an impaired autoregulation and are suggestive of a decreased relaxation or increased resistance of cerebral vessels. Our findings indicate that vascular dysfunction is an early pathogenic event that may promote the subsequent development of brain ischemia in CADASIL.

Acetazolamide↗

PubMed2004

Retinal abnormalities in CADASIL: a retrospective study of 18 patients.

BACKGROUND: CADASIL is an inherited small vessel disease related to Notch3 gene mutations. AIM: To report retinal findings in symptomatic CADASIL patients. METHODS: Assessment of visual acuity (VA), testing of visual fields (VF), funduscopic examination (FE), and fluorescein angiography (FA) were carried out in 18 symptomatic patients. RESULTS: No visual symptoms were presented by our patients. VA was normal in all. Ophthalmologic abnormalities were found in 8 patients. VF were normal except for a right hemianopia in one subject due to ischemic stroke. FE and FA revealed significant abnormalities in seven other subjects (mean age: 55 years; range: 39-74): nerve fibre loss (n = 4), cotton wool spots (n = 3), sheathed arteries (n = 1), and tortuous arteries (n = 1). Only one patient with both tortuous arteries and nerve fibre loss had multiple vascular risk factors, and another patient with cotton wool spots was a current smoker. DISCUSSION: FE and FA revealed silent retinal abnormalities in CADASIL patients with nerve fibre loss in 22% and cotton wool spots in 17%. The presence of these abnormal retinal findings does not seem related to the severity of the disorder but may be considered as peripheral markers of this genetic disease.

Adult↗

PubMed2001

Mitochondrial dysfunction associated with a mutation in the Notch3 gene in a CADASIL family.

BACKGROUND: Cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by recurrent subcortical ischemic strokes and dementia caused by mutations in the Notch3 gene. In Drosophila melanogaster, Notch signaling has a pleiotropic effect, affecting most tissues of the organism during development. OBJECTIVE: To characterize a potential mitochondrial dysfunction associated with mutations in the Notch3 gene. METHODS: Biochemical, histochemical, molecular, and genetic analyses were performed on muscle biopsy specimens and fibroblasts obtained from patients of a Spanish family with CADASIL. Additional biochemical and molecular analyses of the N(55e11) mutant of D. melanogaster were performed. RESULTS: In muscle biopsy specimens, a significant decrease was found in the activity of complex I (NADH [reduced form of nicotinamide adenine dinucleotide] dehydrogenase), and in one patient, histochemical analysis showed the presence of ragged-red fibers with abnormal cytochrome c oxidase staining. Reduced fibroblast activity of complex V (ATP synthase) was found. Supporting data on patients with CADASIL, it was found that the mutation N(55e11) in Drosophila decreases the activity of mitochondrial respiratory complexes I and V. CONCLUSIONS: Mitochondrial respiratory chain activity responds, directly or indirectly, to the Notch signaling pathway. Mitochondrial dysfunction in patients with CADASIL may be an epiphenomenon, but results of this study suggest that the pathophysiology of the disease could include a defect in oxidative phosphorylation.

Adult↗

PubMed2002

Lessons from CADASIL.

Vascular dementia (VaD) includes several different vascular mechanisms and changes in the brain. Among VaD, CADASIL is an inherited angiopathy caused by mutations in the Notch3 gene. The pathological hallmark of CADASIL is a granular osmiophilic material deposit (GOM) that is not only found in the brain, but also in the peripheral vascular tree. Consequently, a window into the brain was opened from a strictly neurological disease with tremendous consequences thanks to a skin biopsy. The latter was and continues to be used as a diagnostic tool for CADASIL, despite an immunohistochemical test that is now available. The skin biopsy first used as a diagnostic tool revealed the existence of numerous other VaDs presenting systemic vascular changes. Later, skin biopsy became a research tool, and a morphological skin vessel change classification was proposed on 300 patients. Interestingly, similar skin vessel lesions appear to be related to the same biological modifications. In addition, an early destruction of the medial muscle cells was noticed in 74% of cases. Because vascular smooth muscle cells secrete a powerful endothelial permeability factor (VEGF), their destruction could lead to a decrease in vascular permeability. Cocultures of endothelial cells with vascular muscle cells showed that their presence doubled vascular permeability. Thus, alteration or the loss of vascular muscle cells likely results in hypopermeability, in addition to vessel wall hypotonia and a watershed hypoperfusion. The wealth of information brought forth by knowledge of CADASIL provided new tools for research and clues for understanding the consequences of vascular impairments in dementia.

Dementia, Multi-Infarct↗

PubMed2006

Characteristics of CADASIL in Korea: a novel cysteine-sparing Notch3 mutation.

OBJECTIVE: To elucidate the phenotype, genotype, and MRI findings of Korean patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and mutation carriers. METHODS: The authors studied 40 members of nine unrelated Korean CADASIL families. After genetic analysis of Notch3, clinical and MRI findings were correlated in 27 mutation carriers. RESULT: Notch3 mutation sites were C174R (one family, n = 3), R133C (one family, n = 3), R587C (one family, n = 1), R544C (two families, n = 5), and R75P (four families, n = 15). The clinical features were typical of CADASIL, but the frequency of migraine in the Korean population appears low. MRI abnormalities were found in 54% of the mutant carriers, the most common being white matter hyperintensities. The prevalence of lacunes and microbleeds increased with patient age. Anterior temporal areas were less often involved in subjects with R75P mutations than in those where mutations occurred in other sites (p = 0.02). Gradient echo imaging identified microbleedings in 33% of mutation carriers (64% of those with abnormal MRI), whereas diffusion-weighted MRI showed abnormal findings in only one patient. Neurologic disability was related to the number of lacunar infarcts and the lesion volume of white matter hyperintensities (p < 0.001) whereas MMSE score was related to the number of lacunar infarcts (p < 0.005). CONCLUSIONS: Although Korean cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) mutation carriers show similar clinical and MRI findings, these abnormalities appear less frequently than in other populations. Relatively frequent microbleedings on gradient echo imaging suggest that treatment should be individualized according to MRI findings. The novel mutation of R75P, not involving a cysteine residue, is related to less frequent involvement of the anterior temporal area, thus broadening the spectrum of CADASIL.

Adult↗