Cell Biology

                                               Charcot-Marie-Tooth disease

                Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders, affecting approximately 1 in 2,500 people in the United States.

The hypothesis is that CMTX mutations lead to a loss of normal cellular communication, which in turn may lead to Schwann cell dysfunction and peripheral neuropathy.

             Mutations in Cx32 may give rise to CMTX through one of several proposed mechanisms. Some mutations will lead to loss of function with no possibility of expression of functional channels. One non-sense mutation (ARG22STOP) is at a very upstream site and would likely lead to the expression of no functional protein. Other mutations in Cx32 lead to the abnormal accumulation of Cx32 proteins in the cytoplasm, particularly in the Golgi apparatus, and in many of those cases Cx32 is not identified in the plasma membrane.

              Cx32 forms a gap junction channels that allows the passage of molecules smaller than ~7 Å in radius.  Second messengers like cAMP and Ca2+ permeate wild-type Cx32 junctions.  As with all connexins, the complete cell-cell channel is composed of two opposing hemichannels, called connexons, each anchored in the plasma membrane of the opposing cells. 

                  Another very common result from the mutation that is shown in every CMT disease is the demyelination around neuron's axon.  The axon forms the connection between the Central Nervous System (the brain), and the Peripheral Nervous System (extremities), which send information back and forth.  The myelin sheath surrounds the axon and acts to produce an insulation, allowing the message known as action potential flow through faster.  People with CMTX lack the myelin sheath, resulting in slower messages from the brain to the extremities and muscles.