Assessment of SIPA1L2 as a candidate modifier of CMT1A identified in human GWAS


What’s New in ALS and CMT - molecular pathways, mutations, phenotype-genotype correlations

Poster Number: 212


George Murray, Timothy Hines, PhD, Robert Burgess, PhD


1. The Jackson Laboratory, 2. The Jackson Laboratory, 3. The Jackson Laboratory

A case-only genome-wide analysis of CMT1A patients found four intronic SNPs in signal-induced proliferation-associated 1 like 2 (SIPA1L2) to be statistically associated with foot dorsiflexion strength. Furthermore, reduction of Sipa1l2 by siRNA reduced peripheral myelin protein 22 (Pmp22) expression along with other myelination-related genes in the SOX10 co-expression network in the S16 Schwann cell cell-line (Tao et al., 2019). Given that duplication of PMP22 causes CTM1A in humans, reduction of SIPA1L2 may therefore be a promising therapeutic approach. To better understand the normal function of SIPA1L2, to independently validate the genetic association between SIPA1L2 and PMP22, and to assess reduction in SIPA1L2 as a therapeutic strategy for CMT1A, we created a Sipa1l2 CRISPR knockout mouse. We are performing detailed neuromuscular phenotyping in the Sipa1l2 knockout mice, including gene expression analysis in peripheral nerves, to better understand its normal function and to test its place in the Sox10 co-expression network. In addition, the Sipa1l2 knockout mice have been bred with the C3-PMP22 mice, a transgenic model of CMT1A overexpressing human PMP22, which recapitulate decrements in nerve conduction velocity and eventual demyelination observed in patients (Verhamme et al., 2011). We will analyze the progeny from these crosses at four- and six-months-of-age by behavioral, neurophysiological, and histological methods to determine if reducing Sipa1l2 levels alters the C3-PMP22 phenotype. The outcomes of these studies will improve our understanding of the normal function of SIPA1L2 and will serve as an in vivo test of this rare disease GWAS hit and its potential as a therapeutic target for CMT1A.