Hereditary Sensory and Autonomic Neuropathy Type 1E (HSAN1E) is a rare autosomal dominant neurological disorder due to missense mutations in DNA methyltransferase 1 (DNMT1). To investigate the nature of the dominant effect, we compared methylomes of transgenic R1^wtDnmt1 and R1^Dnmt1Y495C mouse embryonic stem cells (mESCs) overexpressing WT and the mutant mouse proteins respectively, with the R1 (wild-type) cells. In case of R1^Dnmt1Y495C, 15 out of the 20 imprinting control regions were hypomethylated with transcript level dysregulation of multiple imprinted genes in ESCs and neurons. Non-imprinted regions, minor satellites, major satellites, LINE1 and IAP repeats were unaffected. These data mirror the specific imprinting defects associated with transient removal of DNMT1 in mESCs, deletion of the maternal-effect DNMT1o variant in preimplantation mouse embryos, and in part, reprogramming to naïve human iPSCs. This is the first DNMT1 mutation demonstrated to specifically affect Imprinting Control Regions (ICRs), and reinforces the differences in maintenance methylation of ICRs over non-imprinted regions. Consistent with nervous system abnormalities in the HSAN1E disorder and involvement of imprinted genes in normal development and neurogenesis, R1^Dnmt1Y495C cells showed dysregulated pluripotency and neuron marker genes, and yielded more slender, shorter, and extensively branched neurons. We speculate that R1^Dnmt1Y495C cells produce predominantly dimers containing mutant proteins, leading to a gradual and specific loss of ICR methylation during early human development.

1E 型遗传性感觉和自主神经病 (HSAN1E) 是一种罕见的常染色体显性神经系统疾病，由 DNA 甲基转移酶 1 ( DNMT1 ) 错义突变所致。为了研究显性效应的本质，我们将分别过表达 WT 和突变小鼠蛋白的转基因R1 ^wtDnmt1和R1 ^Dnmt1Y495C小鼠胚胎干细胞 (mESC) 的甲基化组与R1（野生型）细胞进行了比较。在R1 ^Dnmt1Y495C的情况下，20 个印记控制区域中有 15 个发生低甲基化，ESC 和神经元中多个印记基因的转录水平失调。非印记区域、次要卫星、主要卫星、LINE1 和 IAP 重复不受影响。这些数据反映了与 mESC 中 DNMT1 的瞬时去除、植入前小鼠胚胎中母体效应 DNMT1o 变体的删除以及部分重编程为初始人类 iPSC 相关的特定印记缺陷。这是第一个被证明专门影响印记控制区 (ICR) 的DNMT1突变，并强化了 ICR 与非印记区维持甲基化的差异。与 HSAN1E 疾病中的神经系统异常以及正常发育和神经发生中印记基因的参与一致，R1 ^Dnmt1Y495C细胞表现出多能性和神经元标记基因失调，并产生更细长、更短和广泛分支的神经元。我们推测R1 ^Dnmt1Y495C细胞主要产生含有突变蛋白的二聚体，导致人类早期发育过程中 ICR 甲基化逐渐且特定的丧失。