DNMT1 Y495C mutation interferes with maintenance methylation of imprinting control regions.

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 and R1 mouse embryonic stem cells (mESCs) overexpressing WT and the mutant mouse proteins respectively, with the R1 (wild-type) cells. In case of R1, 15 out of the 20 imprinting control regions were hypomethylated with transcript level dysregulation of multiple imprinted genes in ESCs and neurons.

DNMT1 downregulation as well as its overexpression distinctly affect mostly overlapping genes implicated in schizophrenia, autism spectrum, epilepsy, and bipolar disorders.

Data on schizophrenia (SZ), epilepsy (EPD) and bipolar disorders (BPD) suggested an association of DNMT1 overexpression whereas certain variants of the gene were predicted to result in its increased expression in autism spectrum disorder (ASD). In addition, loss of DNMT1 in frontal cortex resulted in behavioral abnormalities in mice. Here we investigated the effects of increased as well as lack of DNMT1 expression using neurons as a model for abnormal neurogenesis and 10,861 genes showing transcript level dysregulation in datasets from the four disorders.

Correction: CalPen (Calculator of Penetrance), a web-based tool to estimate penetrance in complex genetic disorders.

[This corrects the article DOI: 10.1371/journal.pone.

CalPen (Calculator of Penetrance), a web-based tool to estimate penetrance in complex genetic disorders.

Mutations conferring susceptibility to complex disorders also occur in healthy individuals but at significantly lower frequencies than in patients, indicating that these mutations are not completely penetrant. Therefore, it is important to estimate the penetrance or the likelihood of developing a disease in presence of a mutation. Recently, a method to calculate penetrance and its credible intervals was developed on the basis of the Bayesian method and since been used in literature.