ALTERED DOSAGE OF PERIPHERAL MYELIN PROTEIN 22 (PMP22) AFFECTS MYELIN PERIODICITY

PMP22 is a 22‐kD glycoprotein expressed by myelinating Schwann cells. PMP22 seems to play a dual role in regulating cell growth and in peripheral myelin compaction. Myelin formation and maintenance are the result of interactions between PMP22 and the peripheral myelin protein zero (P0), which form complexes at the myelin membrane and mutually contribute to stabilize the intraperiod lines and to held together the major dense lines. Both PMP22 and P0 mutations result in specific inherited demyelinating neuropathies, which are neuropathologically characterized by uncompaction of myelin lamellae and splitting of the major dense lines in some myelinated fibers (MF). However, the most common hereditary neuropathies, Charcot‐Marie‐Tooth 1A (CMT1A) and Hereditary Neuropathy with liability to Pressure Palsies (HNPP), are due to a duplication and a deletion respectively, of the PMP22 gene, leading to over‐ and underexpression of the protein. It is unknown how the altered PMP22 dosage impairs peripheral myelination. Using our imaging system for nerve morphometry directly connected to the electron microscope, we evaluated myelin lamellae periodicity in 150 MF from sural nerves of: 3 CMT 1A patients, 3 HNPP patients, and 3 normal controls. Furthermore, we measured myelin period in 50 MF obtained from a CMT1A culture model and in 50 MF from normal DRG cultures. Myelin periodicity was significantly increased in CMT1A patients (9.77 ± 0.9 nm) and in the CMT1A culture model (10.1 ± 0.1 nm) compared respectively to the normal sural nerves (9.1 ± 0.7 nm) and to the control cultures (9.6 ± 0.1 nm). Conversely, myelin periodicity was slightly reduced in HNPP patients (8.9 ± 0.7 nm). In conclusion, PMP22 overexpression induces widening of myelin lamellae, which may be recorded with appropriate morphometric techniques. As this change has been also observed in DRG cultures from a CMT1A rat model, it may be the first stage of the demyelination process going on in this disease. The observation that altered dosage of PMP22 significantly affects myelin periodicity provides further clues in understanding the role of this protein in the process of myelin assembly and maintenance.