title: 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.
authors.affiliation: Hematological Malignancies Program and Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, 38105, USA.
authors.forename: Barthelemy
authors.initials: B
authors.lastname: Diouf
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, 38105, USA.
authors.forename: Prakash
authors.initials: P
authors.lastname: Devaraju
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, 38105, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Janke
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, 38105, USA.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Cell and Tissue Imaging Resource, St. Jude Children's Research Hospital, Memphis, 38105, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Frase
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, 38105, USA.
authors.forename: Donnie
authors.initials: D
authors.lastname: Eddins
authors.affiliation: Cell and Tissue Imaging Resource, St. Jude Children's Research Hospital, Memphis, 38105, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Peters
authors.affiliation: Small Animal Imaging Center, St. Jude Children's Research Hospital, Memphis 38105, USA.
authors.forename: Jieun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis 38105, USA.
authors.forename: Deqing
authors.initials: D
authors.lastname: Pei
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis 38105, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, 38105, USA.
authors.forename: Stanislav S
authors.initials: SS
authors.lastname: Zakharenko
authors.affiliation: Hematological Malignancies Program and Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, 38105, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
mesh_terms: D000818:Animals; D003337:Corpus Callosum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D053843:DNA Mismatch Repair; D003711:Demyelinating Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005071:Evoked Potentials; D008124:Locomotion; D051379:Mice; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein / Q000172:deficiency* / Q000378:metabolism
chemical_list: C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein