CMT - Part 3 Flashcards
Describe the molecular pathogenesis of CMT1A.
- The PMP22 gene is primarily expressed by the myelinating Schwann cells of peripheral nerves, making up about 2-5% of total peripheral myelin.
- The myelin sheath facilitates nerve conduction in axons.
- PMP22 is thought to stabilise the MPZ protein within myelin and may also have a role in Schwann cell growth and differentiation.
- The mechanism of pathogenesis in CMT1A caused by the common 1.5Mb duplication is likely to involve some form of gain-of-function process.
- Although the duplication leads to increased expression of PMP22 mRNA this does not always lead to a proportion increase in the amount of PMP22 protein produced.
- PMP22 over-expression may disrupt the timing and regulation of myelin protein production including PMP22 ultimately resulting in demyelination of peripheral nerves.
- The demyelination leads to abnormal axon structure and function thus causing slowing of nerve conduction and axonal loss.
- Gain-of-function point mutations in PMP22 cause CMT1E/CMT1A-like phenotypes but that appears to be distinct from CMT1A caused by PMP22 duplication.
- Loss-of-function mutations in PMP22 both deletions and point mutations cause HNPP.
Where is the PMP gene primarily expressed?
The PMP22 gene is primarily expressed by the myelinating Schwann cells of peripheral nerves, making up about 2-5% of total peripheral myelin.
What is the function of PMP22 protein?
PMP22 is thought to stabilise the MPZ protein within myelin and may also have a role in Schwann cell growth and differentiation.
Describe the structure and function of the MPZ protein. How do mutations in MPZ lead to CMT?
- MPZ is a very important protein in the peripheral nervous system and is the major protein constituent of myelin.
- The MPZ protein contains an immunoglobulin-like extracellular domain, membrane domain, and a cytoplasmic domain.
- MPZ molecules form homotetramers that facilitate cell to cell adhesion and is necessary for normal myelin compaction.
- Mutations in MPZ can cause demyelinating types of CMT (CMT1B) or an axonal phenotype (CMT2I/2J) as well as intermediate forms.
- Mutations altering the myelination process and compaction of myelin lead to early-onset forms of CMT1. The severity of the phenotype may be affected by whether the mutant protein can be trafficked to the plasma membrane.
- The axonal pathology in MPZ-associated CMT2 may result from disruption of the crosstalk between neuron and Schwann cells.
What types of CMT can mutations in MPZ cause?
Mutations in MPZ can cause demyelinating types of CMT (CMT1B) or an axonal phenotype (CMT2I/2J) as well as intermediate forms.
How are mutations in GJB1 thought to lead to disease?
- GJB1 encodes the connexin-32 protein. The normal role of this protein is to form gap junctions. These are communication channels allowing transport of small molecules between cells.
- Conexxin-32 containing gap junctions are expressed in myelinating Schwann cells and forms a means of communication between the different layers of the myelin sheath.
- Loss-of-function mutations in GJB1 disrupt this communication process leading to demyelination and subsequent neuropathy.
What is the function of the conexxin-32 protein encoded by the GJB1 gene?
- GJB1 encodes the connexin-32 protein. The normal role of this protein is to form gap junctions. These are communication channels allowing transport of small molecules between cells.
- Conexxin-32 containing gap junctions are expressed in myelinating Schwann cells and forms a means of communication between the different layers of the myelin sheath.
What is the function of the mitofusin-2 (MFN2) protein? How are mutations in MFN2 thought to lead to pathology?
- Mitofusin-2 (MFN2) is a mitochondrial protein that, via interaction with mitofusin-1, plays a major role in mitochondrial fusion.
- MFN2 mutations also affect mitochondrial transport as well as mitochondrial fusion.
- CMT2A which is caused by MFN2 mutations has been reported to affect only the longest axons which is consistent with a possible disruption in mitochondrial transport along the axon.
- These abnormalities in mitochondrial dynamics affect mitochondrial energy production in neurons thus disrupting axon function and leading to a clinical phenotype of axonal neuropathy.
