Modifiers of Charcot-Marie-Tooth Disease Type 1A Neuropathy in the Sox10/Egr2 Networ


Leeza Kopaeva

Document Type


Publication Date

Summer 2021

JAX Location

In: Student Reports, Summer 2021, The Jackson Laboratory


Charcot-Marie-Tooth Disease (CMT) is a heterogenous group of inherited neurological disorders affecting 1 in 2,500 people that causes muscle wasting and loss of sensation in the hands and feet. CMT1A is the most common subtype of this rare disease and is the result of a duplication affecting a region of Chromosome 17 that causes an increase in peripheral myelin protein 22 (PMP22) gene dosage. A human GWAS study of CMT1A patients conducted by the inherited neuropathy consortium demonstrated an association between SNPs in SIPA1L2 and CMT1A severity, suggesting that SIPA1L2 may modify the effects of PMP22 overexpression. SIPA1L2 and PMP22 are both part of the Sox10/Egr2 (the transcription factors for PMP22) network, and knockout of Sox10 and Sipa1l2 in rat Schwann cell cultures also decreases Pmp22 expression. This suggests that SIPA1L2 modifies PMP22 through Sox10/Egr2 and that decreasing Sipa1l2 may therefore effectively treat CMT1A. Transgenic mouse models of CMT1A with overexpression of Pmp22 have been created which recapitulate disease symptoms such as reduced nerve conduction velocity (NCV) and decreased myelination in the peripheral nervous system (PNS). Using neuromuscular phenotyping and comparative bioinformatics, we assessed Sipa1l2 as a therapeutic target for CMT1A, and sought to identify additional therapeutic targets in the Sox10-Egr2 co-expression network. Deletion of Sipa1l2 was not found to decrease phenotypic severity in our CMT1A mouse model (the C3 mouse). Evaluation of differential expression analysis conducted using publicly available RNA sequencing datasets from the related C22 mouse models of CMT1A and Schwann Cells derived from CMT1A patient induced Pluripotent Stem Cells (iPSCs) showed similar gene expression signatures in the Sox10/Egr2 gene network shared between human cells and mouse models. Not only did this confirm the validity of the mouse model at the level of the transcriptome, but it also revealed potential gene network interactions between valproic acid and multiple genes in the Sox10/Egr2 network, suggesting that a target of valproic acid may lie in the Sox10/Egr2 network.Further research in mice and patient cell lines using valproic acid may further elucidate the therapeutic potential of targeting the Sox10/Egr2 network to control Pmp22 overexpression and may identify other potential genetic targets and strategies for CMT1A treatment.

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