Diouf Barthelemy, Devaraju Prakash, Janke Laura J, Fan Yiping, Frase Sharon, Eddins Donnie, Peters Jennifer L, Kim Jieun, Pei Deqing, Cheng Cheng, Zakharenko Stanislav S, Evans William E
Hematological Malignancies Program and Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, 38105, USA.
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, 38105, USA.
Sci Rep. 2016 Aug 1;6:30757. doi: 10.1038/srep30757.
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.
患有先天性DNA错配修复缺陷的患者的一个特征是胼胝体发育不全，其病因尚未明确。在此，我们报告了MSH2缺陷的一个此前未被认识到的后果，MSH2是一种主要因其在纠正由DNA复制或重组错误导致的双链DNA中的核苷酸错配、插入和缺失方面的功能而为人所知的蛋白质。我们记录到，Msh2缺陷会导致胼胝体轴突投射的髓鞘形成异常。Msh2基因敲除小鼠有髓鞘的胼胝体投射中的诱发动作电位比野生型小鼠小，而无髓鞘轴突则无差异。Msh2基因敲除小鼠的运动活动也受损，对热的反应异常。这些发现揭示了MSH2缺陷的一种新的致病后果，为先前认识到的遗传性DNA错配修复缺陷患者的神经疾病提供了新的机制线索。
