Alternative Splicing in the Human PMP22 Gene: Implications in CMT1A Neuropathy

ABSTRACT CMT1A patients commonly share PMP22 genetic overloading but they show phenotypic heterogeneity and variability in PMP22 mRNA and protein expression. Moreover, PMP22 mRNA levels do not correlate with clinical outcome measures in these patients, suggesting their uselessness as a disease biomarker. Thus, in‐depth analysis of PMP22 transcription and translation might help to define its pathogenic role in CMT1A. We focused on the alternative splicing of PMP22 gene to verify whether mRNA processing is altered in CMT1A. We identified three new PMP22 transcripts enriched in human sural nerve biopsies. One of them was an untranslated variant, whereas the other two originated from a PMP22 undescribed exon and encoded for a new putative protein localized in the endoplasmic reticulum. As splicing events in the PMP22 gene are differently regulated in tissues and during development, we analyzed the levels of PMP22 transcripts and their splicing pattern in human and experimental CMT1A. We found an altered PMP22 splicing ratio in the CMT1A rat. In addition, we showed a remarkable derangement in rat QKI expression, which is a critical regulator of splicing during myelination. Overall, our data suggest that an alteration of mRNA processing could be a pathogenic mechanism in CMT1A. Genotype‐phenotype correlations are not so obvious in PMP22‐related CMT. We found three previously undescribed PMP22 human splicing variants specifically expressed in the PNS. Two of them encoded a new putative PMP22 protein isoform mainly expressed in the ER. Moreover, PMP22 alternative splicing is dysregulated in CMT1A and likely under the control of QKI. Overall our data suggest that an alteration of mRNA processing could be a pathogenic mechanism in CMT1A.