Submission Details

The PMP22 duplication was first reported in relation to autosomal dominant Charcot-Marie-Tooth disease type 1A in 1992 (Patel et al., PMID: 1303228). Before the introduction of increased dosage effect of PMP22 gene and its duplication causal to CMT1A, there were reports of families with autosomal dominant pattern of inheritance among affected individuals with slowed conduction velocities unlinked to the "Duffy Locus" on chromosome 1 (PMIDs: 6651251, 6865476). Later on, several studies found positive linkage to markers on chromosome 17 in patients with CMT1A clinical and electrophysiological features (though highly variable in severity, age of onset and progression) and DNA duplication at 17pl 1.2-pl2 region (PMIDs: 1822787, 2707366, 2589322, 2239969, etc). Several independent studies demonstrated the localization of the PMP22 gene in this region and introduced it as a candidate gene responsible for demyelinating CMT1A (PMIDs: 1297450, 1303229). There have been numerous publications describing hundreds of patients with CMT1A and the duplication of PMP22 gene or the chromosomal region containing this gene - we detail 10 probands with over 40 family members (PMIDs: 1453432, 8644705). The mechanism of demyelination in CMT1A is gene-dosage effect with toxic gain of function caused by PMP22 overexpression, mainly because the components of myelin are stoichiometrically balanced and can be disturbed due to any faulty expression of myelin sheath components. The pathomechanism of PMP22 overexpression and its gene-disease association has been demonstrated through various in vitro assays as well as animal models (PMIDs: 9467003, 8630243). Much more evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. In summary, PMP22 duplication is DEFINITIVELY associated with autosomal dominant Charcot-Marie-Tooth disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.