Related Experiment Video
Updated: May 8, 2026
05:48
Cell Aggregation Assays to Evaluate the Binding of the Drosophila Notch with Trans-Ligands and its Inhibition by Cis-Ligands
Published on: January 2, 2018
Hypomorphic NOTCH3 alleles do not cause CADASIL in humans
Julie W Rutten1, Elles M J Boon, Michael K Liem
1Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Human Mutation
|September 4, 2013
Summary
Rare NOTCH3 mutations causing loss of function do not lead to Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). This suggests hypomorphic NOTCH3 alleles are not the cause of CADASIL.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a genetic condition linked to NOTCH3 gene mutations.
- The exact mechanism by which NOTCH3 mutations cause CADASIL, whether through neomorphic (new function) or hypomorphic (reduced function) effects, is debated.
Observation:
- This study identified two novel NOTCH3 mutations predicted to result in a loss of protein function.
- One mutation (c.307C>T, p.Arg103*) was found in individuals without CADASIL, despite presenting with neurological symptoms.
- Another mutation, a frameshift deletion, was identified in a CADASIL patient and inherited from a father who did not exhibit CADASIL-related skin abnormalities.
Findings:
- The identified mutations lead to premature stop codons, indicating a complete loss of NOTCH3 function.
- Individuals with these loss-of-function mutations did not develop the characteristic features of CADASIL.
- These findings challenge the hypothesis that hypomorphic NOTCH3 alleles are sufficient to cause CADASIL.
Implications:
- The results strongly suggest that CADASIL is not caused by hypomorphic NOTCH3 alleles.
- This research clarifies the pathogenetic mechanisms underlying CADASIL, focusing on specific types of NOTCH3 dysfunction.
- Understanding these genetic underpinnings is crucial for accurate diagnosis and potential therapeutic strategies for CADASIL and related cerebrovascular disorders.
Related Concept Videos
03:14Notch Signaling Pathway
The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
03:14Notch Signaling Pathway
The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
01:43Incomplete Dominance
Gregor Mendel's work (1822 - 1884) was primarily focused on pea plants. Through his initial experiments, he determined that every gene in a diploid cell has two variants called alleles inherited from each parent. He suggested that amongst these two alleles, one allele is dominant in character and the other recessive. The combination of alleles determines the phenotype of a gene in an organism.
02:41Lethal Alleles
Agouti: A Lethal Allele
Lucien Cuénot discovered lethal alleles in 1905 while studying the inheritance of coat color in mice. The agouti gene is responsible for the color of the coat in mice. This gene codes for an agouti-signaling protein, which is responsible for melanin distribution in mammals. The wild-type allele gives rise to gray-brown coat color in mice, while the mutant allele gives rise to yellow coat color. In addition to coat color, the agouti gene is associated with the yellow...
Lucien Cuénot discovered lethal alleles in 1905 while studying the inheritance of coat color in mice. The agouti gene is responsible for the color of the coat in mice. This gene codes for an agouti-signaling protein, which is responsible for melanin distribution in mammals. The wild-type allele gives rise to gray-brown coat color in mice, while the mutant allele gives rise to yellow coat color. In addition to coat color, the agouti gene is associated with the yellow...
01:19Cadherins in Tissue Organization
The cadherins are a superfamily of cell adhesion molecules comprising over 180 variants, with specific tissues expressing a particular combination of cadherin types. Cadherins generally exhibit homophilic binding; i.e., cadherins on one cell bind to cadherins of the same or closely related type on another cell. Thus, cells of the same type have a specific affinity to bind to each other and sort themselves into clusters to form tissues.
Cell Sorting During Development
Cell sorting plays an...
Cell Sorting During Development
Cell sorting plays an...