Abstract
A feature in patients with constitutional DNA-mismatch repair deficiency is agenesis of the corpus callosum, the cause of which has not been established. Here we report a previously unrecognized consequence of deficiency in MSH2, a protein known primarily for its function in correcting nucleotide mismatches or insertions and deletions in duplex DNA caused by errors in DNA replication or recombination. We documented that Msh2 deficiency causes dysmyelination of the axonal projections in the corpus callosum. Evoked action potentials in the myelinated corpus callosum projections of Msh2-null mice were smaller than wild-type mice, whereas unmyelinated axons showed no difference. Msh2-null mice were also impaired in locomotive activity and had an abnormal response to heat. These findings reveal a novel pathogenic consequence of MSH2 deficiency, providing a new mechanistic hint to previously recognized neurological disorders in patients with inherited DNA-mismatch repair deficiency.
Highlights
By showing that Msh[2] deficiency is associated with myelin defects, we have revealed previously unrecognized consequences of MSH2 deficiency, a protein that has been extensively characterized for its role in DNA mismatch repair and the increased risk of several types of human cancers in patients who inherit or acquire loss of function variants in MSH2
Msh[2] deficiency was associated with low Qki expression, which is consistent with dysmyeliniation[38]
Lower corpus callosum volume has been shown to be associated with the severity of disease characterized by dysmyelination[39,40], which is in accordance with our findings
Summary
CNS myelination are still incompletely understood. the identification of new transcriptional regulators of myelin gene expression and the discovery of signaling pathways that orchestrate the development of myelin have provided important new mechanistic insights[11]. We show that disruption of the MMR gene Msh[2] leads to low Qki expression and dysmyelination in the corpus callosum of mice. We show that the dysmyelinated axons in Msh2-deficient corpus callosum generate abnormal action potentials.
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