Whole blood transcriptome analysis reveals footprints of cattle adaptation to sub‐arctic conditions

201

Characterization of bovine embryos cultured under conditions appropriate for sustaining human naïve pluripotency.

In mammalian preimplantation development, pluripotent cells are set aside from cells that contribute to extra-embryonic tissues. Although the pluripotent cell population of mouse and human embryos can be cultured as embryonic stem cells, little is known about the pathways involved in formation of a bovine pluripotent cell population, nor how to maintain these cells in vitro. The objective of this study was to determine the transcriptomic profile related to bovine pluripotency. Therefore, in vitro derived embryos were cultured in various culture media that recently have been reported capable of maintaining the naïve pluripotent state of human embryonic cells. Gene expression profiles of embryos cultured in these media were compared using microarray analysis and quantitative RT-PCR. Compared to standard culture conditions, embryo culture in 'naïve' media reduced mRNA expression levels of the key pluripotency markers NANOG and POU5F1. A relatively high percentage of genes with differential expression levels were located on the X-chromosome. In addition, reduced XIST expression was detected in embryos cultured in naïve media and female embryos contained fewer cells with H3K27me3 foci, indicating a delay in X-chromosome inactivation. Whole embryos cultured in one of the media, 5iLA, could be maintained until 23 days post fertilization. Together these data indicate that 'naïve' conditions do not lead to altered expression of known genes involved in pluripotency. Interestingly, X-chromosome inactivation and development of bovine embryos were dependent on the culture conditions

Reduced Cancer Incidence in Huntington's Disease: Analysis in the Registry Study

Background: People with Huntington’s disease (HD) have been observed to have lower rates of cancers. Objective: To investigate the relationship between age of onset of HD, CAG repeat length, and cancer diagnosis. Methods: Data were obtained from the European Huntington’s disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects. Results: 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22–0.30). Individual cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p < 0.001). Conclusions: Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis

Association of Transcription Factor 4 (TCF4) variants with schizophrenia and intellectual disability

Genome wide association studies (GWAS) have revolutionized the study of complex diseases and have uncovered common genetic variants associated with an increased risk for major psychiatric disorders. A recently published schizophrenia GWAS replicated earlier findings implicating common variants in Transcription factor 4 (TCF4) as susceptibility loci for schizophrenia. By contrast, loss of function TCF4 mutations, although rare, cause Pitt-Hopkins syndrome (PTHS); a disorder characterized by intellectual disability (ID), developmental delay and behavioral abnormalities. TCF4 mutations have also been described in individuals with ID and non-syndromic neurodevelopmental disorders. TCF4 is a member of the basic helix-loop-helix (bHLH) family of transcription factors that regulate gene expression at E-box-containing promoters and enhancers. Accordingly, TCF4 has an important role during brain development and can interact with a wide array of transcriptional regulators including some proneural factors. TCF4 may, therefore, participate in the transcriptional networks that regulate the maintenance and differentiation of distinct cell types during brain development. Here, we review the role of TCF4 variants in the context of several distinct brain disorders associated with impaired cognition

Pitt-Hopkins Syndrome

Pitt-Hopkins syndrome (PTHS, MIM #610954) is characterized by severe intellectual disability, typical facial features and tendency to epilepsy, panting-and-holding breathing anomaly, stereotypic movements, constipation, and high myopia. Growth is normal or only mildly retarded, but half of the patients have postnatal microcephaly. Remarkably, congenital malformations are practically nonexistent. The cause of PTHS is de novo haploinsufficiency of the TCF4 gene (MIM *602272) at 18q21.2. Altogether 78 PTHS patients with abnormalities of the TCF4 gene have been published since 2007 when the etiology of PTHS was revealed. In addition, 27 patients with 18q deletion encompassing the TCF4 gene but without given PTHS diagnosis have been published, and thus, the number of reported patients with a TCF4 abnormality exceeds 100. The mutational spectrum includes large chromosomal deletions encompassing the whole TCF4 gene, partial gene deletions, frameshift (including premature stop codon), nonsense, splice site, and missense mutations. So far, almost all patients have a private mutation and only 2 recurrent mutations are known. There is no evident genotype-phenotype correlation. No familial cases have been reported. Diagnosis of PTHS is based on the molecular confirmation of the characteristic clinical features. Recently, a Pitt-Hopkins-like phenotype has been assigned to autosomal recessive mutations of the CNTNAP2 gene at 7q33q36 and the NRXN1 gene at 2p16.3