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Msh2 deficiency leads to dysmyelination of the corpus callosum, impaired locomotion, and altered sensory function in mice.

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.

SUBMITTER: Diouf B

PROVIDER: S-EPMC4967871 | biostudies-other | 2016 Aug

REPOSITORIES: biostudies-other

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Msh2 deficiency leads to dysmyelination of the corpus callosum, impaired locomotion, and altered sensory function in mice.

Diouf Barthelemy B Devaraju Prakash P Janke Laura J LJ Fan Yiping Y Frase Sharon S Eddins Donnie D Peters Jennifer L JL Kim Jieun J Pei Deqing D Cheng Cheng C Zakharenko Stanislav S SS Evans William E WE

Scientific reports 20160801

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 corpu ...[more]

PMID: 27476972

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Project description:The Corpus Callosum (CC) is an important structure that includes the majority of fibers connecting the two brain hemispheres. Several neurodegenerative diseases may alter CC size and morphology leading to its atrophy and malfunction which may play a role in the pathological manifestations found in these diseases. The purpose of the current study is to determine any possible changes in CC size in patients suffering from Alzheimer's disease. The Study also investigated the effect of acetylcholinesterase inhibitors (AChEIs) on the size of CC and its association with improvement in the Alzheimer disease severity scores. Midsagittal size of CC were recorded prospectively from 439 routine T1-weighted MRI brain images in normal individuals. The internal skull surface was measured to calculate CC/ internal skull surface ratio. Two groups of patients were studied: 300 (150 male / 150 female) were healthy subjects and 130 (55 males / 75 females) had Alzheimer disease. Out of the 130 Alzheimer disease pateints, 70 patients were treated with Donepezil or Rivastigmine or both. The size of the CC was measured based on T1-weighted MRI images after the treatment to investigate any possible improvement in CC size. The mean surface area of CC in controls was 6.53±1.105 cm2. There was no significant difference between males and females (P < 0.627), and CC/ internal skull surface ratio was 4.41±0.77%. Patients with mild or severe Alzheimer disease showed a significant reduction in CC size compared to healthy controls. Treating mild Alzheimer patients with either Donepezil or Rivastigmine exerts a comparable therapeutic effect in improving the CC size. There was more improvement in the size of CC in patients with severe Alzheimer disease by using combined therapy of Donepezil and Rivastigmine than using single a medication. we measured the mean size of the various portions of the corpus callosum in normal individuals and Alzheimer patients before and after taking Donepezil and Rivastigmine. Alzheimer patients have pronounced reduction in CC which is corrected after taking Donepezil and Rivastigmine leading to remarkable improvement in Alzheimer disease severity scores.

Dataset Information

Msh2 deficiency leads to dysmyelination of the corpus callosum, impaired locomotion, and altered sensory function in mice.

Publications

Msh2 deficiency leads to dysmyelination of the corpus callosum, impaired locomotion, and altered sensory function in mice.

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