Delta and Notch in Disease

There are many diseases linked to mutations in the Delta/Notch signalling pathway including different forms of cancer as well as

Alzheimers Disease. Read more about Alzheimer's Disease.

Leukemia

• Common mutations are in Notch 1.
• A truncated version of Notch1 is produced due to translocation of Notch1 with TCR-Beta.
• The result of this is constitutively active Notch pathway. β-cells of the immune system fail to mature and therefore cannont contribute to the immune system.

(Self-Made Image: Depicts crossing over of Notch1 on Chromosome 7, with TCR-β on Chromosome 9 to give truncated Notch1.)

 Alagille Syndrome

• Autosomal dominant disease.
• Occurs due to mutations in ligands.
• Jagged1 ligand can undergo mis-sense or non-sense mutations leading to a variety of phenotypes including liver malfunction, abnormal skeletal development and retardation.
• Jagged1 gene is haploinsufficient, this means that one normal copy of the gene is not enough/can not bring about normal function.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

• Autosomal dominant disease.
• Onset around 45 years old.
• Phenotype - reccurent strokes leading to dementia due to protein aggregates in smooth muscle of blood cells.

This mutation lies in Notch3 protein, generally in the first 5 EGF repeats of the extracellular domain. Here, there are normally 6 cysteines. Mutations can lead to either one extra (most commonly) or one less cysteine molecule. This structural change leads to mis-folding of Notch protein. Mis-folding can expose hydrophobic molecules on the surface which lead to aggregation of proteins.  

(The picture depicts brain MRI scans of patients with CADASIL.  

Image courtesey of: Wikimedia)