Norrie Disease

• Inherited eye disorder in male infants that causes abnormal development of the retina
• Immature retinal cells accumulates at the back of the eye

Norrie Disease

Cell Signaling Pathways

Quick Overview

Signal Transduction Pathway: series of steps, signaled by the reception on the cell surface, converted into a cellular response.

3 Processes

1. Reception

2. Transduction

3. Response

3 Main Types of Receptors

We're going to focus on these two because they are related to Norrie Disease

G Protein-Coupled Receptors

Receptor Tyrosine Kinase

Ion Channel Receptors

G Protein-Coupled Receptor

Tyrosine Kinase Receptor

Sources

Normal Chromosome

http://www.ncbi.nlm.nih.gov/gene/8945

http://www.sciencedirect.com/science/article/pii/S1350946212000134

http://www.ncbi.nlm.nih.gov/pubmed/10209158

http://ghr.nlm.nih.gov/gene/NDP

http://www.nature.com/subjects/g-protein-coupled-receptors

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861485/

http://www.brighthub.com/science/genetics/articles/95757.aspx

Mutated Chromosome

Vocabulary

NDP Gene: the gene that is responsible for the creation of the protein norrin.

Norrin: a protein that promotes vessel regrowth and establishes blood supply to the retina and inner ear. Also keeps infection and pathogens away from the blood.

GSK-3B (Glycogen Synthase Kinase-3 Beta): usually phosphorylates and destroys the Beta-catenin in the cell.

Beta-Catenin: a transcriptional co-activator controls key developmental gene expressions.

Tcf/Lef: transcription factors that help develop normal thymocyte (precursor of a T cell).

The genes that norrin helps activate makes sure that the blood vessels, like capillaries, are formed correctly.

It is important to the growth of the eye because the eye is dependent on the oxygen supplied by the blood.

1. Norrin Attaches to frizzled-4 and LRP 5/6 receptors.

Triggers Wnt Cascade.

• In X-Linked inheritance, fathers cannot pass on X-linked traits to the son.
• Females with 1 altered copy of the gene is a carrier.

2. Activates the dishevelled protein.

5. Beta-Catenin binds to Tcf and Lef in the nucleus.

Promotes target genes.

Wnt-Beta-Catenin ON

What is Norrie Disease?

ND is caused by mutations to a gene on the X chromosome.

How is it inherited?

• X-linked recessive disease
• Males (XY): one altered copy of the gene in each cell = ND
• Females (XX): a mutation in both copies of the gene = ND

4. More Beta-Catenin is can enter the nucleus.

3. Dishevelled protein inhibits the GSK-3B/Axin/APC complex and phosphorylation occurs.

Cannot destroy the Beta-Catenin.

Layer of sensory cells that detects light and color.

Results

Irises or the entire eyeball may shrink and deteriorate and/or develop cataract.

It can also cause mental retardation and psychosis.

Since the genes are not activated, the development of capillaries become ineffective and creates leaky blood vessels. This leads to Norrie Disease.

1. A flaw in the NDP gene leads to a defective norrin.

5. Since there is insufficient amount of Beta-Catenin and cannot reach the nucleus, Tcf and Lef transcription factors cannot promote target genes.

2. The defective norrin cannot bind to Frzd-4 and LRP 5/6 receptors.

The pathway is not activated.

Wnt-Beta-Catenin

OFF

3. The disheveled protein is not activated and cannot inhibit the GSK-3B/Axin/APC complex.

4. Beta-TrCP complex attaches to the GSK-3B/Axin/APC complex to activate proteasomal degradation or the degradation of the Beta-Catenin.