A new <i>de novo</i> Notch3 mutation causing CADASIL

Coto, Eliécer; Menéndez, M J; Navarro, Reyes; García-Castro, Mónica; Álvarez, Victoria

doi:10.1111/j.1468-1331.2006.01337.x

Cited by 46 publications

(27 citation statements)

References 17 publications

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“…To date, more than 500 families with the disease have been identified worldwide, with close to unique 200 mutations reported. The overall prevalence is unknown (1/50,000 but likely underdiagnosed), and in addition to the hereditary forms rare sporadic cases have been reported [70, 71], as have homozygous patients with phenotypes not different from heterozygotes [72, 73]. The clinical presentation of the syndrome varies, and includes subcortical ischemic events, cognitive impairment and dementia, migraine with aura, mood disturbances and apathy [74].…”

Section: A Short History Of Notch In Human Diseasementioning

confidence: 99%

Notch and disease: A growing field

Louvi

Artavanis‐Tsakonas

2012

Seminars in Cell & Developmental Biology

168

144

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Signals through the Notch receptors are used throughout development to control cellular fate choices. Our intention here is to provide an overview of the involvement of Notch signaling in human disease, which, keeping pace with the known biology of the pathway, manifests itself in a pleiotropic fashion. A pathway with such broad action in normal development, a profound involvement in the biology of adult stem cells and intricate and complex controls governing its activity, poses numerous challenges. We provide an overview of Notch related pathologies identified thus far and emphasize aspects that have been modeled in experimental systems in order to understand the underlying pathobiology and, hopefully, help the definition of rational therapeutic avenues.

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Section: A Short History Of Notch In Human Diseasementioning

confidence: 99%

Notch and disease: A growing field

Louvi

Artavanis‐Tsakonas

2012

Seminars in Cell & Developmental Biology

168

144

View full text Add to dashboard Cite

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“…CADASIL is an adult-onset hereditary disease (although de novo cases have been reported [116,117]) that is characterized clinically by recurrent transient ischemic attacks (TIA), strokes (lacunar infarcts which occur in the absence of vascular risk factors), subcortical dementia (associated with pseudobulbar palsy), migraine with aura, and psychiatric disturbances [118]. On brain magnetic resonance imaging (MRI), symptomatic and asymptomatic patients are observed to have hyperintensity in the cerebral white matter on T2-weighted images, and hypointense regions suggestive of small infarcts in the deep white matter and basal ganglia on T1-weighted images [119,120].…”

Section: Cadasil (Cerebral Autosomal Domi-nant Arteriopathy With Subcmentioning

confidence: 99%

Notch Signaling in Normal and Disease States: Possible Therapies Related to Glycosylation

Rampal¹,

Luther²,

Haltiwanger³

2007

CMM

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The Notch signaling pathway is involved in a wide variety of highly conserved developmental processes in mammals. Importantly, mutations of the Notch protein and components of its signaling pathway have been implicated in an array of human diseases (T-cell leukemia and other cancers, Multiple Sclerosis, CADASIL, Alagille Syndrome, Spondylocostal Dysostosis). In mammals, Notch becomes activated upon binding of its extracellular domain to ligands (Delta and Jagged/Serrate) that are present on the surface of apposed cells. The extracellular domain of Notch contains up to 36 tandem Epidermal Growth Factor-like (EGF) repeats. Many of these EGF repeats are modified at evolutionarily-conserved consensus sites by an unusual form of O-glycosylation called O-fucose. Work from several groups indicates that O-fucosylation plays an important role in ligand mediated Notch signaling. Recent evidence also suggests that the enzyme responsible for addition of O-fucose to Notch, protein O-fucosyltransferase-1 (POFUT1), may serve a quality control function in the endoplasmic reticulum. Additionally, some of the O-fucose moieties are further elongated by the action of members of the Fringe family of beta-1,3-N-acetylglucosaminyltransferases. The alteration in O-fucose saccharide structure caused by Fringe modulates the response of Notch to its ligands. Thus, glycosylation serves an important role in regulating Notch activity. This review focuses on the role of glycosylation in the normal functioning of the Notch pathway. As well, potential roles for glycosylation in Notch-related human diseases, and possible roles for therapeutic targeting of POFUT1 and Fringe in Notch-related human diseases, are discussed.

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“…The mean age at disease onset was 58 (±20) years, 40 % were male, and 30 % of the patients had a recognized family history of CADASIL. We obtained the DNA from all the patients, and exons 3 and 4 were amplified and Sanger sequenced as reported (Coto et al 2006). …”

Section: Patients and Data Collectionmentioning

confidence: 99%

A Next-Generation Sequencing of the NOTCH3 and HTRA1 Genes in CADASIL Patients

et al. 2015

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Our purpose was to develop a next-generation sequencing procedure to search for NOTCH3 and HTRA1 mutations in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) features. A total of 70 patients were sequenced with semiconductor chips in an Ion Torrent Personal Genome Machine. The putative mutations were confirmed through Sanger sequencing of the corresponding patient. Six patients had a typical cysteine-involving NOTCH3 mutation. A new non-reported NOTCH3 variant (p.Pro2178Ser) was found in two patients. One patient was heterozygous for a non-reported HTRA1 variant, likely non-pathogenic (p.Ser139Ala). We found a typical NOTCH3 mutation in 9 % of the patients. None of the patients had HTRA1 variants with likely pathogenic effect. The next-generation sequencing (NGS) procedure here described would facilitate the rapid and cost-effective screening of large cohorts of CADASIL patients.

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A new de novo Notch3 mutation causing CADASIL

Cited by 46 publications

References 17 publications

Notch and disease: A growing field

Notch and disease: A growing field

Notch Signaling in Normal and Disease States: Possible Therapies Related to Glycosylation

A Next-Generation Sequencing of the NOTCH3 and HTRA1 Genes in CADASIL Patients

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