ArticleEMBO molecular medicine2015
Homozygous NOTCH3 null mutation and impaired NOTCH3 signaling in recessive early-onset arteriopathy and cavitating leukoencephalopathy.
Article in EMBO molecular medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers, 1 of them a synthesis that pooled it.
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Who cites it
38 citing papers in PubMed, 1 synthesis or guideline pooled it, 58 citations in OpenAlex.
- Sex differences and risk factors for bleeding in Alagille syndrome.EMBO molecular medicine · 2022Pooled it
- An in trans NOTCH3 loss-of-function variant modifies disease severity in CADASIL: A family-based study.Journal of the Chinese Medical Association : JCMA · 2026Article
- A novel homozygous loss-of-function NOTCH3 variant in a Moroccan patient: expanding the spectrum beyond CADASIL.Neurogenetics · 2025Article
- Small Vessel Disease Phenotype Associated With MonoallelicNeurology · 2025Observational
- Analyses of NOTCH3 variants in Chinese patients with clinically diagnosed Alzheimer's disease and frontotemporal dementia.Alzheimer's research & therapy · 2025Article
- The pathogenesis of cerebral small vessel disease and vascular cognitive impairment.Physiological reviews · 2025Review
- Notch3 is an asymmetric gene and a modifier of heart looping defects in Nodal mouse mutants.PLoS biology · 2025Article
- Gain of Function NOTCH3 Variants Cause Familial Partial Lipodystrophy Due to Activation of Senescence Pathways.Diabetes · 2025Article
- CADASIL orFrontiers in neurology · 2025Review
- CADASIL: A NOTCH3-associated cerebral small vessel disease.Journal of advanced research · 2024Review
- Clinical and neuroradiological spectrum of biallelic variants in NOTCH3.EBioMedicine · 2024Article
- Distinct neurological phenotypes associated with biallelic loss of NOTCH3 function: evidence for recessive inheritance.Molecular biology reports · 2024Article
- Pathophysiology of cerebral small vessel disease: a journey through recent discoveries.The Journal of clinical investigation · 2024Review
- Progress to Clarify HowBiomolecules · 2024Review
- Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice.The Journal of clinical investigation · 2024Article
- Ultra-Rare Variants Identify Biological Pathways and Candidate Genes in the Pathobiology of Non-Syndromic Cleft Palate Only.Biomolecules · 2023Article
- A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency.Science immunology · 2023Article
- Systematic gene-disease relationship (GDR) curation unveils 61 gene-disease associations and highlights the impact on genetic testing.Genetics in medicine open · 2023Article
- Update on the Epidemiology, Pathogenesis, and Biomarkers of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.Journal of clinical neurology (Seoul, Korea) · 2023Review
- Early-Onset Vascular Leukoencephalopathy Caused by Bi-Allelic NOTCH3 Variants.Neuropediatrics · 2022Article
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Authors and funding
20 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Notch signaling is essential for vascular physiology. Neomorphic heterozygous mutations in NOTCH3, one of the four human NOTCH receptors, cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Hypomorphic heterozygous alleles have been occasionally described in association with a spectrum of cerebrovascular phenotypes overlapping CADASIL, but their pathogenic potential is unclear. We describe a patient with childhood-onset arteriopathy, cavitating leukoencephalopathy with cerebral white matter abnormalities presented as diffuse cavitations, multiple lacunar infarctions and disseminated microbleeds. We identified a novel homozygous c.C2898A (p.C966*) null mutation in NOTCH3 abolishing NOTCH3 expression and causing NOTCH3 signaling impairment. NOTCH3 targets acting in the regulation of arterial tone (KCNA5) or expressed in the vasculature (CDH6) were downregulated. Patient's vessels were characterized by smooth muscle degeneration as in CADASIL, but without deposition of granular osmiophilic material (GOM), the CADASIL hallmark. The heterozygous parents displayed similar but less dramatic trends in decrease in the expression of NOTCH3 and its targets, as well as in vessel degeneration. This study suggests a functional link between NOTCH3 deficiency and pathogenesis of vascular leukoencephalopathies.
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