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Macular Telangiectasia type 2 (MacTel) is a relatively rare macular disease of adult onset presenting with distortions in the visual field and leading to progressive loss of visual acuity. For the purpose of a gene mapping study, several pedigrees were ascertained with multiple affected family members. Seventeen families with a total of 71 individuals (including 45 affected or possibly affected) were recruited at clinical centers in 7 countries under the auspices of the MacTel Project. The disease inheritance was consistent with autosomal dominant segregation with reduced penetrance. Genome-wide linkage analysis was performed, followed by analysis of recombination breakpoints. Linkage analysis identified a single peak with multi-point LOD score of 3.45 on chromosome 1 at 1q41-42 under a dominant model. Recombination mapping defined a minimal candidate region of 15.6 Mb, from 214.32 (rs1579634; 219.96 cM) to 229.92 Mb (rs7542797; 235.07 cM), encompassing the 1q41-42 linkage peak. Sanger sequencing of the top 14 positional candidates genes under the linkage peak revealed no causal variants in these pedigrees. [ABSTRACT FROM AUTHOR]

Circadian rhythms describe the behavioral and physiological changes that occur in living organisms in order to attune to a 24 hour cycle of day and night. The most striking aspect of circadian function is the sleep-wake cycle, however many other physiological processes are regulated in 24 hour oscillations, including blood pressure, body temperature, appetite, urine production, and the transcription and translation of thousands of circadian dependent genes. Circadian disruption and sleep disorders are strongly connected to neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, and Huntington's disease as well as others. Metal exposures have been implicated in neurodegenerative diseases, in some cases involving metals that are essential micronutrients but are toxic at high levels of exposure (such as manganese, copper, and zinc), and in other cases involving metals that have no biological role but are toxic to living systems (such as lead, mercury, and aluminum). In this review, we examine the evidence for circadian and sleep disorders with exposures to these metals and review the literature for possible mechanisms. We suggest that giving the aging population, the prevalence of environmental exposures to metals, and the increasing prevalence of neurodegenerative disease in the aged, more research into the mechanisms of circadian disruption subsequent to metal exposures is warranted.

Manganese is a metal that is required for optimal biological functioning of organisms. Absorption, cellular import and export, and excretion of manganese are all tightly regulated. While some genes involved in regulation, such as DMT-1 and ferroportin, are known, it is presumed that many more are involved and as yet unknown. Excessive exposure to manganese, usually in industrial settings such as mining or welding, can lead to neurotoxicity and a condition known as manganism that closely resembles Parkinson's disease. Elucidating transcriptional changes following manganese exposure could lead to the development of biomarkers for exposure. This unit presents a protocol for RNA sequencing in the worm Caenorhabditis elegans to assay for transcriptional changes following exposure to manganese. This protocol is adaptable to any environmental exposure in C. elegans. The protocol results in counts of gene transcripts in control versus exposed conditions and a ranked list of differentially expressed genes for further study., (Copyright © 2015 John Wiley & Sons, Inc.)

Purpose: To find the gene(s) responsible for macular telangiectasia type 2 (MacTel) by a candidate-gene screening approach., Methods: Candidate genes were selected based on the following criteria: those known to cause or be associated with diseases with phenotypes similar to MacTel, genes with known function in the retinal vasculature or macular pigment transport, genes that emerged from expression microarray data from mouse models designed to mimic MacTel phenotype characteristics, and genes expressed in the retina that are also related to diabetes or hypertension, which have increased prevalence in MacTel patients. Probands from eight families with at least two affected individuals were screened by direct sequencing of 27 candidate genes. Identified nonsynonymous variants were analyzed to determine whether they co-segregate with the disease in families. Allele frequencies were determined by TaqMan analysis of the large MacTel and control cohorts., Results: We identified 23 nonsynonymous variants in 27 candidate genes in at least one proband. Of these, eight were known single nucleotide polymorphisms (SNPs) with allele frequencies of >0.05; these variants were excluded from further analyses. Three previously unidentified missense variants, three missense variants with reported disease association, and five rare variants were analyzed for segregation and/or allele frequencies. No variant fulfilled the criteria of being causal for MacTel. A missense mutation, p.Pro33Ser in frizzled homolog (Drosophila) 4 (FZD4), previously suggested as a disease-causing variant in familial exudative vitreoretinopathy, was determined to be a rare benign polymorphism., Conclusions: We have ruled out the exons and flanking intronic regions in 27 candidate genes as harboring causal mutations for MacTel.

Although progress has been made in understanding the role of growth factors and their receptors in angiogenesis, little is known about how the Wnt family of growth factors function in the vasculature. Wnts are multifunctional factors that act through the frizzled receptors to regulate proliferation, apoptosis, branching morphogenesis, inductive processes, and cell polarity. All of these processes must occur as developing vascular structures are formed and maintained. Recent evidence has linked the Wnt/Frizzled signaling pathway to proper vascular growth in murine and human retina. Here we review the literature describing the angiogenic functions for Wnt signaling and focus on a newly discovered angiogenic factor, Norrin, which acts through the Wnt receptor, Frizzled4.