How T118M peripheral myelin protein 22 predisposes humans to Charcot–Marie–Tooth disease

Reply to Record et al. “The role of PMP22 T118M in Charcot–Marie–Tooth disease remains unsolved”

“…PMP22 encodes peripheral myelin protein 22. We agree that T118M PMP22 is not the cause of a Mendelian disease under WT/T118M heterozygous conditions—this is a major conclusion of this article ( 1 ). However, our data are consistent with previous reports of linkage of T118M PMP22 to very rare cases of mild Charcot–Marie–Tooth (CMT) disease.…”

“…For L16P (severe disease), trafficking and total expression are uncoupled at all but the lowest levels of expression, like T118M. This led us to look at aggregation to uncover further differences between L16P and T118M, as described in this work ( 1 ).…”

“…We also suggest why. While the T118M PMP22 protein resembles 100%-penetrant PMP22 variants in that it is unstable ( 3 ), prone to mistraffic ( 1 , 3 , 4 ), and exhibits reduced partitioning into ordered-phase membrane domains ( 5 ), this work ( 1 ) shows that the T118M protein differs from other disease variants and even from WT in that it is resistant to formation of intracellular aggregates.…”

“…Data for WT and T118M PMP22 surface trafficking efficiencies as a function of total expression level are presented in Figure 3 of Ref. ( 1 ). Corresponding data for other CMT disease mutations (mild, moderate, and severe) as a function of cellular expression data were previously reported (Fig.…”