Author(s): George C. Murray, The Jackson Laboratory & The University of Maine; Tim Hines, The Jackson Laboratory; Abby L.D. Tadenev, The Jackson Laboratory; Leeza Kopaeva, The Jackson Laboratory; Robert W. Burgess, The Jackson Laboratory //

ABSTRACT: The SOX10/EGR2 transcription factors regulate expression of multiple genes involved in Schwann cell development and myelination, including the CMT1A-causal gene peripheral myelin protein 22 (PMP22). Downregulation of genes in the SOX10/EGR2 network to mitigate the effect of elevated PMP22 gene dosage is a compelling therapeutic strategy for CMT1A (SRINIVASAN et al. 2012). One gene in this expression network, signal induced proliferation associated 1 like 2 (SIPA1L2), became a target for CMT1A treatments when a patient GWAS identified a significant association between intronic SNPs in SIPA1L2 and severity of CMT1A symptoms (TAO et al. 2019). We evaluated the efficacy of Sipa1l2 knockout for improvement of neuromuscular dysfunction in a mouse model of CMT1A. We found that Sipa1l2 knockout causes a modest, non-significant improvement in nerve conduction velocity at 6 months in vivo. To determine whether CMT1A mice model the transcriptomic shifts exhibited by patient Schwann cells, and therefore are good models for testing interventions targeting the SOX10/EGR2 network, we reinterrogated publicly accessible RNASeq datasets from CMT1A mice and patient Schwann cell lines (ZHAO et al. 2018; MUKHERJEE-CLAVIN et al. 2019). This analysis revealed relatively consistent differential expression of SOX10/EGR2 network genes between mouse sciatic nerves and patient cell lines, findings that support model validity. Analysis of shared gene sets involved in disease-relevant processes like neuron growth and myelination uncovered a predicted interaction between numerous SOX10/EGR2 network genes and valproic acid. Valproic acid is being evaluated as a treatment for axonal CMT2B caused by variants in Ras-associated protein RAB7 (RAB7). Rab7 and other genes involved in lysosome morphology exhibit high magnitude, significantly decreased expression in sciatic nerves of CMT1A mice suggesting that a degree of overlap in disease mechanisms may support the use of valproic acid for targeting the SOX10/EGR2 network for CMT1A. Future studies will evaluate valproic acid treatment for neuromuscular dysfunction in vivo and assess Sox10/Egr2 network involvement in additional CMT1A mouse models.

Source of Funding: NIH R37 NS054154 & R21 NS116936