John Svaren, PhD – Slide of the Week

John Svaren, PhD - Slide of the Week

Title: A novel structural variant affecting a gene associated with neuromuscular disease

Legend: The most common cause of genetic neuropathy, classified as Charcot-Marie-Tooth disease, is a 1.4 Mb duplication of the PMP22 gene. This structural variant causes increased levels of PMP22. In recent studies, a patient with similar symptoms had a very small deletion in the 3’ UTR of the PMP22 gene. Since a 3’ UTR deletion can affect transcript levels by altering miRNA targeting, we tested if this patient had elevated levels of PMP22. We used a novel skin biopsy assay of myelinated nerves employing Nanostring technology, which we have developed as a clinical trial measure of PMP22 reduction for upcoming clinical trials of ASO/RNAi therapy for this disorder. The results showed that the 3’ UTR deletion causes highly elevated levels of the PMP22 transcript, making this one of the first mutations of this kind identified in a neuromuscular disorder. Bottom Graphic – CMT1A: 3 copies of PMP22, Unaff: 2 copies of PMP22, HNPP: another neuropathy with 1 copy of PMP22

Citation: Pipis, M., Won, S., Poh, R., Efthymiou, S., Polke, J. M., Skorupinska, M., Blake, J., Rossor, A. M., Moran, J. J., Munot, P., Muntoni, F., Laura, M., Svaren, J., & Reilly, M. M. (2023). Post-transcriptional microRNA repression of PMP22 dose in severe Charcot-Marie-Tooth disease type 1. Brain: A Journal of Neurology, 146(10), 4025–4032.

Abstract: Copy number variation (CNV) may lead to pathological traits, and Charcot-Marie-Tooth disease type 1A (CMT1A), the commonest inherited peripheral neuropathy, is due to a genomic duplication encompassing the dosage-sensitive PMP22 gene. MicroRNAs act as repressors on post-transcriptional regulation of gene expression and in rodent models of CMT1A, overexpression of one such microRNA (miR-29a) has been shown to reduce the PMP22 transcript and protein level. Here we present genomic and functional evidence, for the first time in a human CNV-associated phenotype, of the 3′ untranslated region (3′-UTR)-mediated role of microRNA repression on gene expression. The proband of the family presented with an early-onset, severe sensorimotor demyelinating neuropathy and harboured a novel de novo deletion in the PMP22 3′-UTR. The deletion is predicted to include the miR-29a seed binding site and transcript analysis of dermal myelinated nerve fibres using a novel platform, revealed a marked increase in PMP22 transcript levels. Functional evidence from Schwann cell lines harbouring the wild-type and mutant 3′-UTR showed significantly increased reporter assay activity in the latter, which was not ameliorated by overexpression of a miR-29a mimic. This shows the importance of miR-29a in regulating PMP22 expression and opens an avenue for therapeutic drug development.

John Svaren, PhD
John Svaren, PhD

Investigator: John Svaren, PhD

About the Lab: The Svaren laboratory is focused on the transcriptional and epigenetic regulation of myelination. Myelin is a vital constituent of the nervous system that increases the speed of action potentials and also provides trophic support for the long axons that project from neurons. Their studies are centered on the myelin-producing cells of the peripheral nervous system, called Schwann cells. The Svaren lab has focused on elucidating regulation of gene networks during Schwann cell development and response to injury. They have also recently found a novel role of the polycomb repressive complex 2, an epigenetic regulator, in controlling the regenerative responses of Schwann cells after peripheral nerve injury.

Slide of the Week Archives