A short-sighted approach to high myopia-not just an eye problem.

We present the first case of rapid onset high myopia in early childhood as the presenting feature of Loeys-Dietz syndrome. The patient progressed from a normal degree of hyperopia (+2 diopter sphere [DS]) at 18 months of age to high myopia (-10 DS) 9 months later. Subsequent genetic testing revealed both her brothers and her father to carry the same TGFB3 pathogenic variant. This case aims to highlight the importance of considering systemic conditions in children with high myopia.

Analysis of the MTHFD1 promoter and risk of neural tube defects.

Genetic variants in MTHFD1 (5,10-methylenetetrahydrofolate dehydrogenase/5,10-methenyltetrahydrofolate cyclohydrolase/ 10-formyltetrahydrofolate synthetase), an important folate metabolic enzyme, are associated with a number of common diseases, including neural tube defects (NTDs). This study investigates the promoter of the human MTHFD1 gene in a bid to understand how this gene is controlled and regulated. Following a combination of in silico and molecular approaches, we report that MTHFD1 expression is controlled by a TATA-less, Initiator-less promoter and transcription is initiated at multiple start sites over a 126 bp region. We confirmed the presence of three database polymorphisms (dbSNP) by direct sequencing of the upstream region (rs1076991 C > T, rs8010584 G > A, rs4243628 G > T), with a fourth (dbSNP rs746488 A > T) not found to be polymorphic in our population and no novel polymorphisms identified. We demonstrate that a common SNP rs1076991 C > T within the window of transcriptional initiation exerts a significant effect on promoter activity in vitro. We investigated this SNP as a potential risk factor for NTDs in a large homogenous Irish population and determined that it is not an independent risk factor, but, it does increase both case (chi (2) = 11.06, P = 0.001) and maternal (chi (2) = 6.68, P = 0.01) risk when allele frequencies were analysed in combination with the previously identified disease-associated p.R653Q (c.1958 G > A; dbSNP rs2236225) polymorphism. These results provide the first insight into how MTHFD1 is regulated and further emphasise its importance during embryonic development.

Publisher Correction: BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Publisher Correction: BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome.

In the version of this article initially published, Wendy Bickmore and Madapura Pradeepa were incorrectly not indicated as corresponding authors. The error has been corrected in the HTML and PDF versions of the paper.

BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome.

We found that the clinical phenotype associated with BRD4 haploinsufficiency overlapped with that of Cornelia de Lange syndrome (CdLS), which is most often caused by mutation of NIPBL. More typical CdLS was observed with a de novo BRD4 missense variant, which retained the ability to coimmunoprecipitate with NIPBL, but bound poorly to acetylated histones. BRD4 and NIPBL displayed correlated binding at super-enhancers and appeared to co-regulate developmental gene expression.

Investigation of the molecular response to folate metabolism inhibition.

We investigated the molecular response to folate metabolism inhibition by exposing human lymphoblast cell lines to the methionine adenosyltransferase inhibitor cycloleucine. We carried out microarray analysis on replicate control and exposed cells by examining 47,000 transcripts on the Affymetrix HG U133 plus 2.0 arrays. We identified 13 genes that we considered reliable responders to cycloleucine treatment: chemokine receptor 3 (CXCR3), prostaglandin-endoperoxide synthase 2, growth arrest-specific 7, reduced folate carrier, klotho beta, early growth response 1, diaphanous homolog 3, prostaglandin D2 synthase (PGDS), butyrophilin-like 9, low-density lipoprotein receptor-related protein 11, chromosome 21 orf15, G-protein-coupled receptor 98 (GPR98) and cystathionine-beta-synthase (CBS). We further demonstrated that four of these genes, CXCR3, PGDS, GPR98 and CBS, consistently responded to cycloleucine treatment in additional experiments over a range of concentrations. We carried out gene-specific DNA methylation analysis on five genes, including CBS, and found no evidence that DNA methylation changes were mediating the gene expression changes observed. Pathway analysis of the microarray data identified four pathways of relevance for response to cycloleucine; the immune response NF-AT signaling pathway was the most statistically significant. Comparison with other gene expression studies focusing on folate deficiency revealed that gene products related to immune cells or the immune response is a common theme. This indicates that apart from their role in the immune response, it is likely that these gene products may also have a role to play in the cellular response to folate status.

The extent of left ventricular scar quantified by late gadolinium enhancement MRI is associated with spontaneous ventricular arrhythmias in patients with coronary artery disease and implantable cardioverter-defibrillators.

BACKGROUND: Characterization of sudden cardiac death (SCD) risk remains a challenge in the application of implantable cardioverter-defibrillator (ICD) therapy. Late gadolinium enhancement cardiac MRI (LGE-CMR) can accurately identify myocardial scar. We performed a retrospective, single-center observational study to evaluate the association between the extent and distribution of left ventricular scar, quantified using LGE-CMR, and the burden of ventricular arrhythmias in patients with coronary artery disease and ICDs. METHODS AND RESULTS: All patients included (2006 to 2009) had undergone LGE-CMR before ICD implantation. Scar (defined as myocardium with a signal intensity ≥50% of the maximum in scar tissue) was characterized in terms of percent scar, scar surface area, and number of transmural left ventricular scar segments. The end point was appropriate ICD therapy. Sixty-four patients (mean age, 66±11 years; male sex, 51) were included. During 19±10 months follow-up, appropriate ICD therapy occurred in 19 (30%) patients. In Cox regression analyses, both percent scar (hazard ratio per 10%, 1.75; 95% CI, 1.09 to 2.81; P=0.02) and number of transmural scar segments (hazard ratio per segment, 1.40; 95% CI, 1.15 to 1.70; P=0.001) were significantly associated with the occurrence of appropriate ICD therapy. CONCLUSIONS: In this pilot study, the extent of myocardial scar characterized by LGE-CMR was significantly associated with the occurrence of spontaneous ventricular arrhythmias. We hypothesize that scar quantification by LGE-CMR may prove a valuable risk stratification tool for the occurrence of ventricular arrhythmias, which may have implications for patient selection for ICD therapy.

The MTHFR 1298CC and 677TT genotypes have opposite associations with red cell folate levels.

Individuals homozygous for the thermolabile variant (677TT) of methylenetetrahydrofolate reductase exhibit reduced folate status as evidenced by a drop in the biomarker red cell folate (RCF) compared to those who carry at least one 677C allele. We now report that a different polymorphism in the same enzyme, namely 1298A>C, is associated with increased RCF levels. Thus, these two common polymorphisms change a metabolic phenotype in opposite directions suggesting that their cancer protective associations are by different mechanisms.