Peripheral myelin protein 22 (PMP22) is a 160-residue integral membrane protein with four putative transmembrane spans. PMP22 is a major protein of peripheral nervous system (PNS) myelin, where its importance is underscored by the fact that heritable mutations in this protein result in Charcot-Marie-Tooth Disease (CMTD), the most common disorder of the PNS. Disease mutations induce misassembly of PMP22, resulting both in loss of its function and toxic accumulation of misfolded PMP22 in the cell. Here we present a structural comparison of the wild type and the L16P disease-linked mutant form of human PMP22 to obtain insight into the molecular basis of CMTD. Human PMP22 was expressed in Escherichia coli, and purified in the detergent tetradecylphosphocholine. The purified protein provided moderately well dispersed 1H-15N TROSY spectra. NMR resonance assignments for the wild type protein revealed that the 72 observed backbone amide peaks out of 157 expected originate exclusively from the N-terminal STREP tag, transmembrane region 1 (TM1), extracellular loop 1 (ECL1), and the extreme C-terminus. Chemical shift index analysis suggested the residues from TM1 (Met1 to Ile29) form an α-helix, while no secondary structure was predicted for ECL1 (Val30 to Pro58). The L16P mutant was analyzed in a similar manner. A significant finding for the mutant was that the resonances from Ile8 to Val17 located at the middle of TM1 were not observed due to line broadening. Moreover, chemical shift perturbations were observed for residues from Leu18 to Ile24 which are located at the C-terminal end of TM1. These observations suggest that the L16P mutation induced a global conformational change in TM1 that results in its recognition as being folding-defective by components of membrane protein folding quality control system of the endoplasmic reticulum.