How T118M peripheral myelin protein 22 predisposes humans to Charcot–Marie–Tooth disease
Year: 2022
Type: article
Abstract: Data from gnomAD indicate that a missense mutation encoding the T118M variation in human peripheral myelin protein 22 (PMP22) is found in roughly one of every 75 genomes of western European lineage (1:120 in the overall human population). It is unusual among PMP22 variants that cause Charcot-Marie-Tooth (CMT) disease in that it is not 100% penetrant. Here, we conducted cellular and biophysical studies to determine why T118M PMP22 predisposes humans to CMT, but with only incomplete penetrance. We found that T118M PMP22 is prone to mistraffic but differs even from the WT protein in that increased expression levels do not result in a reduction in trafficking efficiency. Moreover, the T118M mutant exhibits a reduced tendency to form large intracellular aggregates relative to other disease mutants and even WT PMP22. NMR spectroscopy revealed that the structure and dynamics of T118M PMP22 resembled those of WT. These results show that the main consequence of T118M PMP22 in WT/T118M heterozygous individuals is a reduction in surface-trafficked PMP22, unaccompanied by formation of toxic intracellular aggregates. This explains the incomplete disease penetrance and the mild neuropathy observed for WT/T118M CMT cases. We also analyzed BioVU, a biobank linked to deidentified electronic medical records, and found a statistically robust association of the T118M mutation with the occurrence of long and/or repeated episodes of carpal tunnel syndrome. Collectively, our results illuminate the cellular effects of the T118M PMP22 variation leading to CMT disease and indicate a second disorder for which it is a risk factor.
Source: Journal of Biological Chemistry
Institutions: Vanderbilt University, Vanderbilt University Medical Center
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: National Science Foundation, National Sleep Foundation, Vanderbilt University Medical Center, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G123344359, Console upgrades for biological NMR spectrometers, G1967470738, G3485139178, Automated Storage and Retrieval of Biological Systems, G4293071939, G5673529183, G5877334990, MRI: Acquisition of a 900 MHz Ultra-High Field NMR Spectrometer, G6399140587, The Vanderbilt Institute for Clinical and Translational Research (VICTR), G9000043901, G9000054231, G9000122305, G949362299, G95160140
OpenAlex ID: W4313312980