User:DaamoonGhahari/sandbox

Practice Edits:

The architecture of the interrupted gene allows for the process of alternative splicing, where various mRNA products can be produced from a single gene

Advanced Genetics Assignment

Article: Peripheral myelin protein 22

Proposed Bibliography:

1. Watila, M. M., and S. A. Balarabe. Molecular and Clinical Features of Inherited Neuropathies due to PMP22 Duplication. Journal of the neurological sciences 355.1-2 (2015): 18-24. Web. 14 Oct. 2015

2. Van Itallie C. M., and J. M. Anderson. Claudins and epithelial paracellular transport. Annu Rev Physiol 2006;68:403–29.

3. Brennan, K. M., Bai, Y., and M. E. Shy. Demyelinating CMT–what’s known, what’s new and what’s in store? Neuroscience Letters, Volume 596, 2 June 2015, Pages 14-26, ISSN 0304-3940, http://dx.doi.org/10.1016/j.neulet.2015.01.059.

I intend to expand the current stub article by explaining the structure and function of PMP22 in the PNS, and how its gene alterations can lead to changes in gene dose or specifically how different neuropathies (such as Charcot–Marie–Tooth type 1A) are related to PMP22 gene alterations. I also want to expand and clarify how the PMP22 protein interacts with other proteins. I am planning on keeping the existing subheadings, but some possible additions include: PMP22 gene duplication and Gene Structure.

Sample Writing:

In the peripheral nervous system Schwann cells highly express PMP22, a transmembrane glycoprotein, which constitutes 2 to 5% of all proteins in compact myelin. PMP22 is 22kDa, made up of 160 amino acids, and is glycosylated in the endoplasmic reticulum, where it is also co-localised with the BiP chaperone.

Current Article Summary:

• unclear function, a little about protein structure
• clinical significance, related to neuropathies such as Charcot–Marie–Tooth disease type IA, and Dejerine–Sottas disease
• interaction with myelin protein zero

PERIPHERAL MYELIN PROTEIN 22

Peripheral Myelin Protein 22 (PMP22) is a human gene that encodes a 22 kDa transmembrane glycoprotein made up of 160 amino acids, and is mainly expressed in the Schwann cells of the peripheral nervous system. Schwann cells show high expression of PMP22, where it can constitute 2-5% of total protein content in compact myelin. Compact myelin is the bulk of the peripheral neuron's myelin sheath, a protective fatty layer that provides electrical insulation for the neuronal axon. The level of PMP22 expression is relatively low in the central nervous system of adults.

Like other membrane proteins, newly translated PMP22 protein is temporarily sequestered to the endoplasmic reticulum (ER) and Golgi apparatus for post-translational modifications. PMP22 protein is glycosylated with an N terminus-linked sugar and co-localized with the BiP chaperone protein in the ER. After the protein is transported to the Golgi apparatus it can then become incorporated in the plasma membrane of the cell.

Structure and Function

In humans, the PMP22 gene is located on chromosome 17p11.2 and spans approximately 40kb. The gene contains six exons conserved in both humans and rodents, two of which are 5’ untranslated exons (1a and 1b) and result in two different RNA transcripts with identical coding sequences. The two transcripts differ in their 5' untranslated regions and have their own promoter regulating expression. The remaining exons (2 to 5) include the coding region of the PMP22 gene, and are joined together after post-transcriptional modification (i.e. alternative splicing). The PMP22 protein is characterized by four transmembrane domains, two extracellular loops (ECL1 and ECL2), and one intracellular loop . ECL1 has been suggested to mediate a homophilic interaction between two PMP22 proteins, whereas ECL2 has been shown to mediate a heterophilic interaction between PMP22 protein and Myelin protein zero (MPZ).

Although the PMP22 mechanism of action in myelinating Schwann cells is not fully known, it plays an essential role in the formation and maintenance of compact myelin . When Schwann cells come into contact with a neuronal axon, expression of PMP22 is significantly up-regulated, whereas PMP22 is down-regulated during axonal degeneration or transection.PMP22 has shown association with zonula-occludens 1 and occludin, proteins that are involved in adhesion with other cells and the extracellular matrix, and also support functioning of myelin . Along with cell adhesion function, PMP22 is also up-regulated during Schwann cell proliferation, suggesting a role in cell-cycle regulation. PMP22 is detectable in non-neural tissues, where its expression has been shown to serve as growth-arrest-specific (gas-3) function.

Gene-Dosage

Improper gene dosage of the PMP22 gene can cause aberrant protein synthesis and function of myelin sheath. Since the components of myelin are stoichiometrically set, any irregular expression of a component can destabilization of myelin and neuropathic disorders. Alterations of PMP22 gene expression are associated with a variety of neuropathies, such as Charcot–Marie–Tooth type 1A (CMT1A), Dejerine–Sottas disease, and Hereditary Neuropathy with Liability to Pressure Palsy (HNPP). Too much PMP22 (e.g. caused by gene duplication) results in CMT1A, and too little PMP22 (e.g. caused by gene deletion) results in HNPP . Gene duplication of PMP22 is the most common genetic cause of CMT1A where the overproduction of PMP22 results in defects in multiple signalling pathways and dysfunction of transcriptional factors like KNOX20, SOX10 and EGR2.