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Results for “Receptor, Notch3”

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PubMed2005

PKC theta mediates pre-TCR signaling and contributes to Notch3-induced T-cell leukemia.

Protein kinase (PK)C theta is a critical regulator of mature T-cell activation and proliferation, being implicated in TCR-triggered nuclear factor (NF)-kappa B activation and providing important survival signals to leukemic T cells. We previously showed that overexpression of pT alpha/pre-TCR and constitutive activation of NF-kappa B characterize the T-cell leukemia/lymphoma developing in Notch3-IC transgenic mice. We report here that PKC theta is a downstream target of Notch3 signaling and that its activation and membrane translocation require a functional pre-TCR in order to trigger NF-kappa B activation in thymocytes and lymphoma cells of transgenic mice. Furthermore, deletion of PKC theta in Notch3-IC transgenic mice reduces the incidence of leukemia, correlating with decreased NF-kappa B activation. This paper therefore suggests that PKC theta mediates the activation of NF-kappa B by pre-TCR in immature thymocytes and contributes to the development of Notch3-dependent T-cell lymphoma.

Animals↗

PubMed2005

The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is caused by mutations of the Notch3 gene on 19p13. Varying phenotypic expression leads to under recognition and misdiagnosis. Prevalence therefore remains uncertain. We sought to estimate the prevalence of CADASIL in the west of Scotland. METHODS: A register for CADASIL was established at a regional neurosciences centre in 2002. All patients with genetically (exons 3, 4, 5, and 6) or histologically confirmed CADASIL residing in two defined administrative health areas were identified. Pedigree members at varying risk of carrying the mutation were also identified and the number of probable Notch3 mutation carriers in the defined population was predicted. Prevalence was calculated for definite CADASIL cases, with and without probable carrier numbers, based upon adult population figures from the 2002 national census. RESULTS: Twenty two individuals from seven pedigrees with confirmed CADASIL and resident in the defined geographical area were identified, yielding a prevalence of 1.98 (95% confidence interval 1.24-3.00) per 100 000 adults. An additional 37 individuals were predicted to be carriers of the Notch3 mutation, yielding a probable mutation prevalence of 4.14 (3.04-5.53) per 100,000 adults. CONCLUSIONS: The prevalence of genetically proven CADASIL was 1.98 per 100,000 adults in the defined population. This figure underestimates disease burden.

Adolescent↗

PubMed2003

Genetic, clinical and pathological studies of CADASIL in Japan: a partial contribution of Notch3 mutations and implications of smooth muscle cell degeneration for the pathogenesis.

We have examined Notch3 mutations in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) whose samples were submitted to us in Japan. The subjects were composed of 21 Japanese, 1 Iranian, 1 Korean and 1 Canadian families. Mutations in the Notch3 gene were found in 7 of 24 families examined. These were R133C in two unrelated Japanese families, and R213K, C174F and R169C in each Japanese family. In addition, we have found R90C in an Iranian family and C174R in a Korean family. Thus, contribution of Notch3 gene mutations is less than one fourth of Japanese CADASIL families, suggesting the existence of other causative genes in CADASIL. It is also of interest to know that Notch3 mutant CADASIL exists in other Asian countries. We next examined the localization of Notch3 protein in the tissue by immunohistochemistry. It was restricted to the wall of arterioles in the brain and other organs. In the brain, there was no difference in the staining pattern among arterioles in the cortex, white matter and meninges. The staining was negative in the venule and capillaries as well as in neurons and glial cells. From the staining pattern, it was recognized to be expressed in the vascular smooth muscle cells in the adult tissue. In an autopsy case with R213K mutation, we could see numerous cerebral infarcts and arteriole wall degeneration with deposits of granular osmiophilic material (GOM). However, it is interesting to note that occlusion of arterioles was rarely observed and the GOM was negative for Notch3 staining. These findings suggest that hemodynamic abnormalities due to smooth muscle cell degeneration may be important in the pathogenesis of CADASIL.

Age of Onset↗

PubMed2002

Investigation of Notch3 as a candidate gene for bipolar disorder using brain hyperintensities as an endophenotype.

The purpose of the study was to consider MRI hyperintensities as a potential endophenotype for bipolar disorder (BPD) and to investigate Notch3 (CADASIL) as a candidate gene for BPD. MRI scans were performed on 21 members of a family with a high incidence of BPD. Two-point and multipoint linkage analyses were performed and two exons of Notch3 were investigated with SSCP. Fifteen of 21 family members had MRI hyperintensities, including all bipolar patients and six family members with no affective illness. Two-point linkage analysis yielded negative results for all models. Multipoint linkage analysis yielded negative results except for Model 1a, in which a maximal LOD score was -1.24. A mutation screen of Exons 3 and 4 was negative. Notch3 does not appear to be a candidate gene for BPD in this family.

Adolescent↗

PubMed2004

A novel Notch3 gene mutation not involving a cysteine residue in an Italian family with CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to accumulating neurologic deficits and dementia. CADASIL has been linked to nucleotide substitutions and deletions in the Notch3 gene. All the mutations described until now lead to unpaired cysteine residue in the epidermal growth factor-like repeats. The authors report a family with CADASIL carrying a deletion in the Notch3 gene that did not involve a cysteine residue.

Adult↗

PubMed2003

Myocardial infarction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an angiopathy caused by mutations in the NOTCH3 gene. Typical microvascular changes are found throughout the arterial tree, but the documented disease expression is confined to the central nervous system. In an ongoing CADASIL study, we noted a number of patients with early acute myocardial infarction (before the age of 50 years), as well as patients with electrocardiogram (ECG) abnormalities. We analyzed these data to determine whether myocardial ischemia is associated with NOTCH3 mutations. ECGs were recorded in mutated (n = 41) and nonmutated (n = 22) individuals from 15 genetically confirmed CADASIL families, and blindly classified according to the Minnesota code. Cardiologic history was assessed and cardiovascular disease risk factors were determined. Evidence for myocardial infarction was defined as a positive history for acute myocardial infarction and/or a Minnesota Code 1 (Q-waves) on ECG. We examined CADASIL myocardial tissue ultrastructurally and immunohistochemically for evidence of microangiopathy. We found that almost 25% (10/41) of mutation carriers had evidence of myocardial infarction, versus none of the 22 nonmutation carriers (p = 0.011). Five had a medical history of acute myocardial infarction, and 5 had current pathologic Q-waves on ECG. Acute myocardial infarction occurred at a mean age of 39.6 +/- 5.22 years, and predated major neurologic symptoms of CADASIL in all cases. Pathologic examination of myocardial tissue revealed typical CADASIL arteriopathic changes of the coronary microvasculature. To our knowledge, this is the first study showing that NOTCH3 mutation carriers may be at increased risk of early acute myocardial infarction, expanding CADASIL disease expression beyond the central nervous system to include the heart.

Acute Disease↗

PubMedDate not supplied

Mutations of the notch3 gene in non-caucasian patients with suspected CADASIL syndrome.

The Notch3 gene has been recently identified as a causative gene for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). To investigate the genetic contribution of Notch mutations in familial cases with vascular leukoencephalopathy, we screened 13 patients from 11 unrelated families, which were selected on the basis of magnetic resonance imaging findings and positive family history. We identified three different missense mutations in 5 patients from 4 families. Two (Arg90Cys and Arg133Cys) are the same as previously reported in Caucasian patients, the other (Cys174Phe) is a novel mutation causing a loss of a cysteine in epidermal-growth-factor-like repeats of Notch3. These data indicate that the CADASIL Notch3 mutations were found in approximately 35% of familial cases with leukoencephalopathy, suggesting genetic heterogeneity of the disease.

Adult↗

PubMed2001

Two Japanese CADASIL families with a R141C mutation in the Notch3 gene.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary disease characterized by recurrent transient ischemic attacks (TIA) and strokes, and vascular dementia with Notch3 gene mutations as the cause of the disease. To date, there are only a few Japanese families ever reported with a mutation in the gene. Here, we report two more Japanese CADASIL families carrying a missense mutation in the Notch3 gene (R141C) with a unique lesion in the corpus callosum. This is the first report of two unrelated Japanese CADASIL families with a R141C mutation in the Notch3 gene. Although the disease is very rare among the Japanese population, our result suggests a possible relationship of this particular mutation (R141C) with the lesions of the corpus callosum.

Agenesis of Corpus Callosum↗

PubMedDate not supplied

[Clinical and neuroimaging findings in a family with CADASIL associated to C475T mutation].

INTRODUCTION: The term CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) refers to an autosomal dominant hereditary arteriopathy of the brain that is characterised by headache, recurring strokes and progressive cognitive deterioration. We report the case of another family with CADASIL and emphasise the importance of a genetic study in its diagnosis. CASE REPORT: A 62-year-old female patient with repeating lacunar strokes, subcortical dementia and a family history of dementia and strokes. Neuroimaging studies conducted on the patient and her siblings showed signs of leukoencephalopathy and lacunar infarctions. The ultrastructural study of the biopsy performed on a sample of the patient's skin, which included five dermal vessels, did not show any electron-dense deposits. The genetic study revealed the presence of mutation C475T in exon 4 of NOTCH3. CONCLUSIONS: The possible presence of CADASIL must be suspected in patients with symptoms of cerebrovascular disease or dementia who present characteristic alterations in the magnetic resonance brain scan, especially when there is a compatible family history. The first choice diagnostic procedure must be a genetic study.

Dementia, Multi-Infarct↗

PubMed2004

[NOTCH3 gene mutations in four Chinese families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy].

OBJECTIVES: To search for mutations in NOTCH3 gene in four Chinese families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). METHODS: Four probands from four unrelated families with typical manifestations of CADASIL were studied. The 1 approximately 12 coding exons and their flanking intron sequences of NOTCH3 gene were amplified by PCR and sequenced. Some family members in the pedigree 2 and 4 were also examined for the NOTCH3 gene mutations. RESULTS: Four heterozygous missense mutations were identified in the four families: the proband 1 carrying a 268C-->T mutation in exon 3, the proband 2 a 322 C-->T mutation in exon 3, the proband 3 a 328 C-->T mutation inexon 3, and the proband 4 a 1819 C-->T mutation in exon 11, which resulted in the amino acid substitutions of R90C, C108R, R110C, and R607C respectively. Among them the C108R is a novel mutation not reported previously. Additionally, some members in the pedigree 2 and 4 also harbored the same mutations with the probands. CONCLUSION: Four heterozygous missense mutations in NOTCH3 gene have been found in four Chinese families with CADASIL. Different point mutations in NOTCH3 lead to similar phenotype of the disease. To search for mutations in NOTCH3 in related patients will help further understand and accurately diagnose the disease and perform prenatal diagnosis in CADASIL families.

Adult↗

PubMed2005

Notch signaling coordinates the patterning of striatal compartments.

Numerous lines of evidence suggest that Notch signaling plays a pivotal role in controlling the production of neurons from progenitor cells. However, most experiments have relied on gain-of-function approaches because perturbation of Notch signaling results in death prior to the onset of neurogenesis. Here, we examine the requirement for Notch signaling in the development of the striatum through the analysis of different single and compound Notch1 conditional and Notch3 null mutants. We find that normal development of the striatum depends on the presence of appropriate Notch signals in progenitors during a critical window of embryonic development. Early removal of Notch1 prior to neurogenesis alters early-born patch neurons but not late-born matrix neurons in the striatum. We further show that the late-born striatal neurons in these mutants are spared as a result of functional compensation by Notch3. Notably, however, the removal of Notch signaling subsequent to cells leaving the germinal zone has no obvious effect on striatal organization and patterning. These results indicate that Notch signaling is required in neural progenitor cells to control cell fate in the striatum, but is dispensable during subsequent phases of neuronal migration and differentiation.

Animals↗

PubMed2005

The spectrum of Notch3 mutations in 28 Italian CADASIL families.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a cause of hereditary cerebrovascular disease. It results from mutations in the Notch3 gene, a large gene with 33 exons. A cluster of mutations around exons 3 and 4 was originally reported and limited scanning of these exons was suggested for the diagnosis in most cases. OBJECTIVE: To report Notch3 mutation analysis in 28 unrelated Italian CADASIL families from central and south Italy. RESULTS: The highest rate of mutations was found in exon 11 (21%) and only 18% of mutations were in exon 4. This may be related to the peculiar distribution of Notch3 mutations in the regions of origin of the families. CONCLUSIONS: The results suggest that limited scanning of exons 3 and 4 is inadvisable in CADASIL cases of Italian origin.

CADASIL↗

PubMed2004

Notch3 is required for arterial identity and maturation of vascular smooth muscle cells.

Formation of a fully functional artery proceeds through a multistep process. Here we show that Notch3 is required to generate functional arteries in mice by regulating arterial differentiation and maturation of vascular smooth muscle cells (vSMC). In adult Notch3-/- mice distal arteries exhibit structural defects and arterial myogenic responses are defective. The postnatal maturation stage of vSMC is deficient in Notch3-/- mice. We further show that Notch3 is required for arterial specification of vSMC but not of endothelial cells. Our data reveal Notch3 to be the first cell-autonomous regulator of arterial differentiation and maturation of vSMC.

Actins↗

PubMed2006

Loss of notch activity in the developing central nervous system leads to increased cell death.

Many cells in the mammalian brain undergo apoptosis as a normal and critical part of development but the signals that regulate the survival and death of neural progenitor cells and the neurons they produce are not well understood. The Notch signaling pathway is involved in multiple decision points during development and has been proposed to regulate the survival and apoptosis of neural progenitor cells in the developing brain; however, previous experiments have not resolved whether Notch activity is pro- or anti-apoptotic. To elucidate the function of Notch signaling in the survival and death of cells in the nervous system, we have produced single and compound Notch conditional mutants in which Notch1 and Notch3 are removed at different times during brain development and in different populations of cells. We show here that a large number of neural progenitor cells, as well as differentiating neurons, undergo apoptosis in the absence of Notch1 and Notch3, suggesting that Notch activity promotes the survival of both progenitors and newly differentiating cells in the developing nervous system. Finally, we show that postmitotic neurons do not require Notch activity indefinitely to regulate their survival since elevated levels of cell death are observed only during embryogenesis in the Notch mutants and are not detected in neonates.

Animals↗

PubMed2001

A CADASIL case with normal skin biopsy and without mutations in exons 3 and 4 of the Notch3 gene.

The diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is usually confirmed by genetic testing or skin biopsy. We here report the case of a 69-year-old woman with recurrent transient ischemic attacks (TIAs) and strokes, seizures, and dementia without any mutations in exons 3 and 4 of the Notch3 gene and with a normal skin biopsy, but who showed characteristic CADASIL abnormalities on brain pathological examination. Our findings suggest that negative results in these two tests do not exclude the disease and a leptomeningeal biopsy or a second skin biopsy should be considered in such cases.

Aged↗

PubMed2005

The prenatal diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) by mutation analysis.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an important cause of hereditary stroke. Mutations in the Notch3 gene are clearly causally linked to this progressive vascular disorder. Cerebral ischemic attacks, cognitive decline, strokes, and vascular dementia constitute the major manifestations of this disorder. This report details the prenatal detection of a Notch3 mutation in the fetus of a couple where the father had a known mutation in this gene. This is the first report of a prenatal diagnosis of CADASIL, and another example of a serious, highly penetrant, and relentlessly progressive degenerative genetic disorder presenting decades after birth and for which prenatal diagnosis is an option.

Abortion, Eugenic↗

PubMed1996

Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.

Stroke is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent subcortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis. We have previously mapped the mutant gene to chromosome 19. Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We have identified mutations in CADASIL patients that cause serious disruption of this gene, indicating that Notch3 could be the defective protein in CADASIL patients.

Adult↗

PubMed2001

An animal model for the molecular genetics of CADASIL. (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy).

BACKGROUND: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an inherited condition that causes repeated small-scale strokes in adults. CADASIL is caused only by mutations in the human NOTCH3 gene that increase or decrease the number of cysteines within the epidermal growth factor (EGF) repeats of the NOTCH3 protein. Drosophila: lethal-Abruptex is a similar condition because it is also caused only by mutations that increase or decrease the number of cysteines within the EGF repeat portion of the Notch protein. SUMMARY OF COMMENT: Drosophila: lethal-Abruptex and human CADASIL are precisely analogous at the molecular level, and both are genetically dominant. These precise similarities, together with the fact that the structure and function of Notch has been highly conserved throughout the animal kingdom, provide an animal model for the molecular and genetic aspects of human CADASIL. It also provides support for Spinner's proposal that CADASIL results from dominant inhibition of the Notch pathway. CONCLUSIONS: Because the phenotypes of Notch mutations are cell-autonomous, the symptoms of CADASIL indicate that adult vascular smooth muscle cells require the continuing function of the NOTCH3 pathway in the adult. For this reason, further analysis of the NOTCH3 pathway may provide more general insights into the biology of vascular smooth muscle cells. In the case of CADASIL, the powerful genetic tools available in Drosophila: should help to facilitate future research.

Animals↗