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PubMed2004

Arg332Cys mutation of NOTCH3 gene in the first known Taiwanese family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

The phenotype and genotype of cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy (CADASIL) in Caucasians have been well characterized, but CADASIL is less recognized in Asian populations. Here we investigated the first known Taiwanese family affected by CADASIL and identified an uncommon NOTCH3 mutation. The family had clinical manifestations in affected members including recurrent strokes, early dementia, and depression, but not migraine. A skin biopsy in the proband patient showed characteristic pathological findings of CADASIL on electron microscopy. Afterward, genetic analysis found an Arg332Cys mutation at exon 6 of NOTCH3. Neuropsychological evaluation showed vascular dementia in two of four affected people. Head MRI showed multiple infarcts in bilateral basal ganglia, thalami, periventricular white matter, external capsules, and brainstem, but involvement of the anterior temporal pole was found only in two people with milder symptoms. To our knowledge, the Arg332Cys NOTCH3 mutation at exon 6, which was identified in the studied family, has not been reported in Asian populations. Our findings emphasize the importance of genetic analysis of NOTCH3 for Asians with a phenotype typical of CADASIL.

Amino Acid Substitution↗
PubMed2003

Cerebral hemodynamics and white matter hyperintensities in CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small-vessel disease caused by mutations in the NOTCH3 gene on chromosome 19. On magnetic resonance imaging (MRI), subcortical white matter hyperintensities and lacunar infarcts are visualized. It is unknown whether a decrease in cerebral blood flow or cerebrovascular reactivity is primarily responsible for the development of white matter hyperintensities and lacunar infarcts. The authors used phase-contrast MRI in 40 NOTCH3 mutation carriers (mean age 45 +/- 10 years) and 22 nonmutated family members (mean age 39 +/- 12 years), to assess baseline total cerebral blood flow (TCBF) and cerebrovascular reactivity after acetazolamide. Mean baseline TCBF was significantly decreased in NOTCH3 mutation carriers. In young subjects, baseline TCBF was significantly lower than in nonmutation carriers (mean difference 124 mL/min). Furthermore, baseline TCBF did not differ significantly between mutation carriers with minimal and mutation carriers with moderate or severe white matter hyperintensities. No significant difference in mean cerebrovascular reactivity was found between mutation carriers and nonmutation carriers. This study suggests that a decrease in baseline TCBF in NOTCH3 mutation carriers precedes the development of white matter hyperintensities.

Adult↗
PubMed2002

CADASIL: a monogenic condition causing stroke and subcortical vascular dementia.

Mutations in Notch3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an inherited small vessel disease leading to subcortical strokes and vascular dementia. The phenotypic presentation is variable but remarkable for a high frequency of migraine with aura. Magnetic resonance images show a microangiopathic pattern of lesions. Prominent involvement of the temporopolar white matter and involvement of the temporopolar arcuate fibers are conspicuous findings seen in many patients. The underlying angiopathy is characterized by a unique type of ultrastructural basal lamina deposits and by degeneration of vascular smooth muscle cells which are the major source of Notch3 expression. In line with these findings there is evidence for a functional impairment of vascular smooth muscle cells. CADASIL has opened a new perspective in studying basic mechanisms of vessel wall degeneration and ischemic tissue damage related to small vessel disease.

Dementia, Multi-Infarct↗
PubMed2006

Overexpression of activated murine Notch1 and Notch3 in transgenic mice blocks mammary gland development and induces mammary tumors.

The mouse mammary tumor virus (MMTV) provirus was found to target the Notch1 gene, producing insertional mutations in mammary tumors of MMTV/neu transgenic (Tg) mice. In these mammary tumors, the Notch1 gene is truncated upstream of the transmembrane domain, and the resulting Notch1 intracellular domain (Notch1(intra)), deleted of most extracellular sequences, is overexpressed. Although Notch1(intra) transforms mammary epithelial cells in vitro, its role in mammary gland tumor formation in vivo was not studied. Therefore, we generated MMTV/Notch1(intra) Tg mice that overexpress murine Notch1(intra) in the mammary glands. We observed that MMTV/Notch1(intra) Tg females were unable to feed their pups because of impaired ductal and lobulo-alveolar mammary gland development. This was associated with decreased proliferation of ductal and alveolar epithelial cells during rapid expansion at puberty and in early pregnancy, as well as decreased production of beta-casein. Notch1(intra) repressed expression of the beta-casein gene promoter, as assessed in vitro with a beta-casein/luciferase reporter construct. The MMTV/Notch1(intra) Tg females developed mammary gland tumors, confirming the oncogenic potential of Notch1(intra) in vivo. Furthermore, MMTV/Notch3(intra) Tg mice exhibited a very similar phenotype. Thus, these Tg mice represent novel models for studying the role of Notch1 or Notch3 in the development and transformation of the mammary gland.

Aging↗
PubMedDate not supplied

[Analysis of complex segregation in a large family with hereditary cerebrovascular disease in Antioquia, Colombia].

INTRODUCTION: Among different kinds of cerebrovascular diseases, few of them are caused by genetic disturbances, such as CADASIL (caused by Notch3 mutations), CARASIL, mitochondrial encephalopathy, MELAS and dementia typed Binswanger. However, to describe these type of cerebrovascular diseases related with genetic mutations could permit to determinate the causes of both hereditary and sporadic cerebrovascular diseases and then lead solutions. OBJECTIVE: To describe the genetic, environmental and cohort factors that determinate the presence of many affected people by a several cerebrovascular diseases in the pedigree of a large family from Antioquia (Colombia). PATIENTS AND METHODS: We performed one pedigree (268 individuals), through singular recruit and then complex segregation analysis with POINTER program. RESULTS: The model that more close to data is autosomal dominant mayor locus without influence of environmental factors. Frequency of allele of susceptibility to develop stroke or subcortical vascular dementia was 0.0006. Mayor gene is over epistatic effects or interactions with other gene. CONCLUSIONS: Described an autosomal dominant hereditary model through complex segregation analysis in a pedigree of patients with hereditary cerebral vascular diseases characterized by recurrent strokes, early onset subcortical dementia, hearing loss, antecedent of migraine and MRI signal abnormalities, subcortical infarcts and leukoencephalopathy. In this family the parameter calculated, autosomal dominant model, and clinical feature strongly support the diagnostic of CADASIL, linkage analysis and sequentiation will be performed to determinate if mutant gene is Notch3.

Adolescent↗
PubMed2001

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy): an Australian perspective.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy (CADASIL) is a recently described cause of stroke or stroke-like episodes. It is caused by mutations in the Notch3 gene on chromosome 19p. We sought to demonstrate mutations of the Notch3 gene in Australian patients suspected of having CADASIL. Patients from several families were referred to the study. A diagnosis was determined clinically and by neuroimaging. Those suspected of having CADASIL had sequencing of exons 3 and 4 of the Notch3 gene. Eight patients, two of whom were siblings, were suspected of having CADASIL. Five patients (including the siblings) had mutations. Because of strong clustering of Notch3 mutations in CADASIL, this has potential as a reliable test for the disease in Australian patients.

Aged↗
PubMed2006

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: two novel mutations in the NOTCH3 gene in Chinese.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disorder caused by NOTCH3 mutations, usually localized to exons 3 and 4, and characterized by recurrent subcortical infarctions, dementia and leukoencephalopathy. So far, there has been only limited information about CADASIL in Chinese population. OBJECTIVES: To analyze the NOTCH3 mutations in ethnic Chinese in Taiwan with clinically suspected CADASIL and to characterize their clinical and molecular features. METHODS: Mutation analysis of NOTCH3 by direct nucleotide sequencing was performed in eight unrelated Chinese patients with clinically suspected CADASIL. Skin biopsy with ultrastructural studies by electronic microscopy was performed in four patients. RESULTS: Five NOTCH3 mutations, S118C, R141C, R332C, R544C and C977S, respectively, were identified from five patients, of which S118C and C977S are novel. None of these nucleotide sequence variations could be found among 50 healthy controls. Among the five mutations, two were in exon 4, and the other three were in exons 6, 11 and 18, respectively. Skin biopsy showed the presence of characteristic granular osmiophilic material only in the patient with the NOTCH3 mutation of R332C. CONCLUSION: Our study demonstrated the clinical and molecular features of CADASIL in Chinese patients and broadened the spectrum of NOTCH3 mutations. Lack of evidence of a strong clustering of mutations in a particular exon tentatively suggests that a comprehensive screening of NOTCH3 mutation is still necessary for molecular diagnosis of CADASIL in Chinese population.

Adult↗
PubMed2006

Varicose veins associated with CADASIL result from a novel mutation in the Notch3 gene.

No genetically diagnosed cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) pedigrees with venous insufficiency have been described. In a CADASIL pedigree with varicose veins, the authors have identified a novel heterozygous mutation in the 3' splice acceptor site of intron 15 of the Notch3 gene. This, based on mRNA analysis, resulted in skipping of exon 16 including eight cysteine residues of EGF-like repeats.

Adult↗
PubMedDate not supplied

[Vascular hereditary dementia CADASIL type in Colombia. III. Linkage analysis to notch3 gene].

OBJECTIVE: To perform linkage analysis between the Short Tandem Repeats (STR) microsatellite markers D19S923, D19S929, D19S22, which are in strong genetic linkage to Notch3 gene in order to contrast the hypothesis that the vascular hereditary dementia phenotype described in a multigenerational extended pedigree from Colombia correspond to CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). Even we know that using techniques as the Single Strand Conformational Polymorphisms (SSCP) could determine mutations in Notch3, the rationality of this approach is that intronic variations could not be defined and that we are interested in determine if some forms of the clinical presentation and its phenotypic variability make part of CADASIL. INTRODUCTION: The CADASIL phenotype is caused by mutations in the Notch3 gene. Clinical features of CADASIL are: 1. Recurrent cerebra-vascular episodes; 2. Migraine history; 3. History of transitory ischemic attack and, 4. Behavior changes and dementia. MATERIAL AND METHODS: By using SIMLINK we showed that the extended genealogy had the enough power to detect significant LOD (logarithm of oods) score values when Notch3 was considered the disorder cause. Linkage analysis was carried out by using parametric and non parametrical methods. The Elston-Stewart general method was used as the parametrical analysis and the sib pair method as the non-parametrical one. We perform simulations changing the affection status codification by including as affected or not including those individuals with migraine. Furthermore, in order to detect the stability of the results, we changed the penetrance values, the genetic frequencies on both, the marker loci and the affection locus. RESULTS: The maximum pair-wise LOD score was 2.04 which was detected at the marker D19S23 with q= 0.11cM. This distance correspond exactly with the Notch3 location. That is 100 times more probable that there is linkage that there is not. In other words this probability could be explained as if the phenotype correspond to CADASIL than to other vascular dementia. The non parametric results were compatibles with the parametric ones. When the migraine symptom was considered as a part of the affected status, the LOD score values showed not linkage. CONCLUSIONS: The results of the linkage analysis to these STR microsatellite markers suggest that the vascular hereditary dementia phenotype described in this family correspond to CADASIL caused by a polymorphism on the Notch3 gene. On the contrary, these same results suggest that the migraine phenotype is not a part of the progressive dementia.

CADASIL↗
PubMed2006

Genetic variants of the NOTCH3 gene in migraine--a mutation analysis and association study.

Mutations in the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Exons 3 and 4 are mutation hotspots. Migraine is a clinical hallmark of CADASIL. The objective of this study was to investigate whether genetic variants in exons 3 and 4 of the NOTCH3 gene are associated with migraine. Exons 3 and 4 of the NOTCH3 were analysed for mutations and polymorphisms by direct DNA sequencing in 97 migraineurs and the same number of control individuals. No mutations in exons 3 and 4 of the NOTCH3 gene were found in 97 patients with migraine. However, association analysis revealed significant association of the single nucleotide polymorphism (SNP) rs1043994 with migraine.

Adolescent↗
PubMed2001

Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is a small-artery disease of the brain caused by NOTCH3 mutations that lead to an abnormal accumulation of NOTCH3 within the vasculature. We aimed to establish whether immunostaining skin biopsy samples with a monoclonal antibody specific for NOTCH3 could form the basis of a reliable and easy diagnostic test. We compared the sensitivity and specificity of this method in two groups of patients suspected of having CADASIL with complete scanning of mutation-causing exons of NOTCH3 (in a retrospective series of 39 patients) and with limited scanning of four exons that are mutation hotspots (prospective series of 42 patients). In the retrospective series skin biopsy was positive in 21 (96%) of the 22 CADASIL patients examined and negative in all others; in the prospective series, seven of the 42 patients had a positive skin biopsy whereas only four had a mutation detected by limited NOTCH3 scanning. Our immunostaining technique is highly sensitive (96%) and specific (100%) for diagnosis of CADASIL.

Adult↗
PubMed2006

Notch3 gene amplification in ovarian cancer.

Gene amplification is one of the common mechanisms that activate oncogenes. In this study, we used single nucleotide polymorphism array to analyze genome-wide DNA copy number alterations in 31 high-grade ovarian serous carcinomas, the most lethal gynecologic neoplastic disease in women. We identified an amplicon at 19p13.12 in 6 of 31 (19.5%) ovarian high-grade serous carcinomas. This amplification was validated by digital karyotyping, quantitative real-time PCR, and dual-color fluorescence in situ hybridization (FISH) analysis. Comprehensive mRNA expression analysis of all 34 genes within the minimal amplicon identified Notch3 as the gene that showed most significant overexpression in amplified tumors compared with nonamplified tumors. Furthermore, Notch3 DNA copy number is positively correlated with Notch3 protein expression based on parallel immunohistochemistry and FISH studies in 111 high-grade tumors. Inactivation of Notch3 by both gamma-secretase inhibitor and Notch3-specific small interfering RNA suppressed cell proliferation and induced apoptosis in the cell lines that overexpressed Notch3 but not in those with minimal amount of Notch3 expression. These results indicate that Notch3 is required for proliferation and survival of Notch3-amplified tumors and inactivation of Notch3 can be a potential therapeutic approach for ovarian carcinomas.

Chromosomes, Human, Pair 19↗
PubMedDate not supplied

Notch3 intracellular domain accumulates in HepG2 cell line.

BACKGROUND: By mediating local cell-cell interactions, the Notch signaling pathway seems to control a variety of processes from cell fate decisions during development, to stem cell renewal and to differentiation in many adult tissues. Hence, perturbed Notch signaling may be involved both in the development and the spread of cancer. The expression and the functional role of some major components of the Notch signaling pathway in human hepatocellular carcinoma (HCC) are poorly characterized. MATERIALS AND METHODS: Notch3, HES1, Jagged1 and Delta1 were analyzed both at the RNA and protein levels in the HepG2 liver cell line derived from human HCC. RESULTS: The results of this study demonstrated, for the first time, that both Jagged1 and Delta1 ligands and the downstream effector gene HES1 are expressed in the HepG2 actively proliferating cell line. Moreover, a high expression of Notch3 intracellular domain, indicative of constitutively activated Notch signaling, was the only detectable Notch3 subunit in HepG2. CONCLUSION: These findings suggest that Notch3 may be involved in mechanisms controling the differentiation and the spread of HCC and that Notch3 activation may be dependent on both Jagged1 and Delta 1 ligands.

Basic Helix-Loop-Helix Proteins↗
PubMed2003

Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation.

The Notch signaling pathway is an evolutionarily conserved signaling mechanism and mutations in its components disrupt cell fate specification and embryonic development in many organisms. To analyze the in vivo role of the Notch3 gene in mice, we created a deletion allele by gene targeting. Embryos homozygous for this mutation developed normally and homozygous mutant adults were viable and fertile. We also examined whether we could detect genetic interactions during early embryogenesis between the Notch3 mutation and a targeted mutation of the Notch1 gene. Double homozygous mutant embryos exhibited defects normally observed in Notch1-deficient embryos, but we detected no obvious synergistic effects in the double mutants. These data demonstrate that the Notch3 gene is not essential for embryonic development or fertility in mice, and does not have a redundant function with the Notch1 gene during early embryogenesis.

Animals↗
PubMed2005

CADASIL with NOTCH3 S180C presenting anticipation of onset age and hallucinations.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease leading to strokes and vascular dementia. The average age of onset for stroke is 45 years with a range of about 30 to 70 years. We describe a Japanese CADASIL family showing S180C in the exon 4 of NOTCH3, presenting an anticipation of the onset age for stroke. MRI demonstrated a similar extent of white matter involvement in younger and older individuals, supporting the presence of anticipation. In addition, hallucinations in 71% of affected patients, and delusions in 57% were also described. Our findings in this family suggest that a specific NOTCH3 mutation was related to unique clinical features, although such correlations have seldom been encountered in CADASIL.

Adult↗
PubMed2000

De novo mutation in the Notch3 gene causing CADASIL.

CADASIL, an autosomal dominant arteriopathy responsible for stroke and dementia, is caused by strongly stereotyped mutations in the Notch3 gene. We report a patient with a condition strongly suggestive of CADASIL (migraine, stroke, and white matter abnormalities), except that this patient did not have any first-degree relatives with similar symptoms. This patient carried a heterozygous Arg182Cys mutation in the Notch3 gene; this mutation was absent in his two biological parents. These data demonstrate the occurrence of a de novo noninherited mutation in the Notch3 gene, which indicates that CADASIL should not be rejected in the absence of a family history. Therefore, our finding suggests that CADASIL may be more frequent than anticipated.

Brain↗
PubMed2004

Impaired vascular mechanotransduction in a transgenic mouse model of CADASIL arteriopathy.

BACKGROUND AND PURPOSE: CADASIL is an inherited small-vessel disease responsible for lacunar strokes and cognitive impairment. The disease is caused by highly stereotyped mutations in Notch3, the expression of which is highly restricted to vascular smooth muscle cells (VSMCs). The underlying vasculopathy is characterized by degeneration of VSMCs and the accumulation of granular osmiophilic material (GOM) and Notch3 protein within the cell surface of these cells. In this study, we assessed early functional changes related to the expression of mutant Notch3 in resistance arteries. METHODS: Vasomotor function was examined in vitro in arteries from transgenic mice that express a mutant Notch3 in VSMC. Tail artery segments from transgenic and normal wild-type male mice were mounted on small-vessel arteriographs, and reactivity to mechanical (flow and pressure) forces and pharmacological stimuli were determined. Mice were studied at 10 to 11 months of age when VSMC degeneration, GOM deposits, and Notch3 accumulation were not yet present. RESULTS: Passive arterial diameter, contraction to phenylephrine, and endothelium-dependent relaxation to acetylcholine were unaffected in transgenic mice. By contrast, flow-induced dilation was significantly decreased and pressure-induced myogenic tone significantly increased in arteries from transgenic mice compared with wild-type mice. CONCLUSIONS: This is the first study to our knowledge providing evidence that mutant Notch3 impairs selectively the response of resistance arteries to flow and pressure. The data suggest an early role of vascular dysfunction in the pathogenic process of the disease.

Animals↗