The mismatch repair system protects against intergenerational GAA repeat instability in a Friedreich ataxia mouse model

Copyright @ 2012 Elsevier. The article can be accessed from the link below.This article has been made available through the Brunel Open Access Publishing Fund.Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a dynamic GAA repeat expansion mutation within intron 1 of the FXN gene. Studies of mouse models for other trinucleotide repeat (TNR) disorders have revealed an important role of mismatch repair (MMR) proteins in TNR instability. To explore the potential role of MMR proteins on intergenerational GAA repeat instability in FRDA, we have analyzed the transmission of unstable GAA repeat expansions from FXN transgenic mice which have been crossed with mice that are deficient for Msh2, Msh3, Msh6 or Pms2. We find in all cases that absence of parental MMR protein not only maintains transmission of GAA expansions and contractions, but also increases GAA repeat mutability (expansions and/or contractions) in the offspring. This indicates that Msh2, Msh3, Msh6 and Pms2 proteins are not the cause of intergenerational GAA expansions or contractions, but act in their canonical MMR capacity to protect against GAA repeat instability. We further identified differential modes of action for the four MMR proteins. Thus, Msh2 and Msh3 protect against GAA repeat contractions, while Msh6 protects against both GAA repeat expansions and contractions, and Pms2 protects against GAA repeat expansions and also promotes contractions. Furthermore, we detected enhanced occupancy of Msh2 and Msh3 proteins downstream of the FXN expanded GAA repeat, suggesting a model in which Msh2/3 dimers are recruited to this region to repair mismatches that would otherwise produce intergenerational GAA contractions. These findings reveal substantial differences in the intergenerational dynamics of expanded GAA repeat sequences compared with expanded CAG/CTG repeats, where Msh2 and Msh3 are thought to actively promote repeat expansions.This study is funded under European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement number 242193/EFACTS. This article is made available through the Brunel Open Access Publishing Fund

Pms2 suppresses large expansions of the (GAA·TTC)n sequence in neuronal tissues

Copyright @ 2012 Bourn et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Expanded trinucleotide repeat sequences are the cause of several inherited neurodegenerative diseases. Disease pathogenesis is correlated with several features of somatic instability of these sequences, including further large expansions in postmitotic tissues. The presence of somatic expansions in postmitotic tissues is consistent with DNA repair being a major determinant of somatic instability. Indeed, proteins in the mismatch repair (MMR) pathway are required for instability of the expanded (CAG·CTG)(n) sequence, likely via recognition of intrastrand hairpins by MutSβ. It is not clear if or how MMR would affect instability of disease-causing expanded trinucleotide repeat sequences that adopt secondary structures other than hairpins, such as the triplex/R-loop forming (GAA·TTC)(n) sequence that causes Friedreich ataxia. We analyzed somatic instability in transgenic mice that carry an expanded (GAA·TTC)(n) sequence in the context of the human FXN locus and lack the individual MMR proteins Msh2, Msh6 or Pms2. The absence of Msh2 or Msh6 resulted in a dramatic reduction in somatic mutations, indicating that mammalian MMR promotes instability of the (GAA·TTC)(n) sequence via MutSα. The absence of Pms2 resulted in increased accumulation of large expansions in the nervous system (cerebellum, cerebrum, and dorsal root ganglia) but not in non-neuronal tissues (heart and kidney), without affecting the prevalence of contractions. Pms2 suppressed large expansions specifically in tissues showing MutSα-dependent somatic instability, suggesting that they may act on the same lesion or structure associated with the expanded (GAA·TTC)(n) sequence. We conclude that Pms2 specifically suppresses large expansions of a pathogenic trinucleotide repeat sequence in neuronal tissues, possibly acting independently of the canonical MMR pathway.IDB was supported by a postdoctoral fellowship from the National Ataxia Foundation. RMP was supported by Ataxia UK. SA was supported by The Wellcome Trust. This research was made possible by grants from the National Institutes of Health (NIH/NINDS) and the Muscular Dystrophy Association to S.I.B

Transmission fiber chromatic dispersion dependence on temperature: implications on 40 Gb/s performance

In this letter we will evaluate the performance degradation of a 40 km high-speed (40 Gb/s) optical System, induced by optical fiber variations of the chromatic dispersion induced by temperature changes. The chromatic dispersion temperature sensitivity will be estimated based on the signal quality parameters

The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues

Friedreich ataxia (FRDA) is caused by a homozygous GAA repeat expansion mutation within intron 1 of the FXN gene, leading to reduced expression of frataxin protein. Evidence suggests that the mutation may induce epigenetic changes and heterochromatin formation, thereby impeding gene transcription. In particular, studies using FRDA patient blood and lymphoblastoid cell lines have detected increased DNA methylation of specific CpG sites upstream of the GAA repeat and histone modifications in regions flanking the GAA repeat. In this report we show that such epigenetic changes are also present in FRDA patient brain, cerebellum and heart tissues, the primary affected systems of the disorder. Bisulfite sequence analysis of the FXN flanking GAA regions reveals a shift in the FRDA DNA methylation profile, with upstream CpG sites becoming consistently hypermethylated and downstream CpG sites becoming consistently hypomethylated. We also identify differential DNA methylation at three specific CpG sites within the FXN promoter and one CpG site within exon 1. Furthermore, we show by chromatin immunoprecipitation (ChIP) analysis that there is overall decreased histone H3K9 acetylation together with increased H3K9 methylation of FRDA brain tissue. Further studies of brain, cerebellum and heart tissues from our GAA repeat expansion-containing FRDA YAC transgenic mice reveal comparable epigenetic changes to those detected in FRDA patient tissue. We have thus developed a mouse model that will be a valuable resource for future therapeutic studies targeting epigenetic modifications of the FXN gene to increase frataxin expression

Convergence of genes and cellular pathways dysregulated in autism spectrum disorders

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation

Food Allergy and Anaphylaxis in Infants and Preschool-Age Children

Food allergy (FA) prevalence data in infants and preschool-age children are sparse, and proposed risk factors lack confirmation. In this study, 19 children’s day care centers (DCC) from 2 main Portuguese cities were selected after stratification and cluster analysis. An ISAAC’s (International Study of Asthma and Allergies in Childhood) derived health questionnaire was applied to a sample of children attending DCCs. Outcomes were FA parental report and anaphylaxis. Logistic regression was used to explore potential risk factors for reported FA. From the 2228 distributed questionnaires, 1217 were included in the analysis (54.6%). Children’s median age was 3.5 years, and 10.8% were described as ever having had FA. Current FA was reported in 5.7%. Three (0.2%) reports compatible with anaphylaxis were identified. Reported parental history of FA, personal history of atopic dermatitis, and preterm birth increased the odds for reported current FA. A high prevalence of parental-perceived FA in preschool-age children was identified. Risk factor identification may enhance better prevention

Reported Drug Allergy among Children Attending Day Care Centers

Introdução: A prevalência de alergia a fármacos na população geral não se encontra devidamente caraterizada, existindo poucos estudos publicados que tenham abordado esta situação em crianças com idades inferior a seis anos de idade. Este estudo tem como objetivo principal estimar a prevalência de alergia a medicamentos reportada pelos pais de crianças de infantários de Lisboa e do Porto. Material e Métodos: No âmbito da Fase II do projeto “ENVIRH – Ambiente e Saúde em Creches e Infantários” foi aplicado um questionário sobre alergia a medicamentos aos pais das crianças, recrutadas por amostragem aleatória estratificada dos infantários. Resultados: Foram analisados 1 169 questionários, 52,5% de rapazes. A idade média foi de 3,5 ± 1,5 anos. A prevalência de alergia a medicamentos reportada foi de 4,1% (IC 95%: 3,0 - 5,2%). Os fármacos mais referidos foram os antibióticos (em 27 reações) e os AINEs (em seis reações). Na análise multivariável, a alergia a medicamentos reportada associou-se diretamente com a idade da criança (OR 1,19; IC 95% 1,01 - 1,41) e com a referência a alergia alimentar (OR 3,19; IC95% 1,41 - 7,19) e inversamente com o nível de escolaridade dos pais (OR 0,25; IC95% 0,10 - 0,59). Discussão: Apesar das limitações do estudo, os resultados encontram-se de acordo com o reportado por outros autores e sugerem que a prevalência reportada de alergia a medicamentos seja elevada no grupo etário estudado. Conclusão: Torna-se necessário que situações de alergia a medicamentos reportadas pelos pais sejam devidamente estudadas, no sentido de evitar evicções desnecessárias que possam condicionar opções terapêuticas em futuras situações de doença

Alqueva. Changing Ecologies of the Montado Landscape. Alentejo, Portugal

In the past decade Alqueva Dam brought a tremendous landscape change in all three sectors-environmental, social and economic. While the dam and reservoir was a project which was carefully executed, there are certain issues which need to be monitored/rectified as the reservoir goes into 5th straight year with full capacity. The Alentejo region is currently under threats from environmental stress (drought, climate change and habitat disturbances), social stress (with declining population in nearby villages) and is also struggling to attract people to this economically backward region in Portugal. This report presents analysis and recommendations proposed by Environmental Planning Students from UC Berkeley to create and revise holistic strategies that measure the effects of the dam and future proposals to improve human access and ecological values of Alentejo region.Portuguese Studies Program, UCBerkeley ; EDI

Retinal Neurodegeneration in Diabetic Patients Without Diabetic Retinopathy

PURPOSE: To compare the thickness of all retinal layers between a nondiabetic group and diabetic patients without diabetic retinopathy (DR). METHODS: Cross-sectional study, in which all subjects underwent an ophthalmic examination including optical coherence tomography. After automatic retinal segmentation, each retinal layer thickness (eight separate layers and overall thickness) was calculated in all nine Early Treatment Diabetic Retinopathy Study (ETDRS) areas. The choroidal thickness (CT) also was measured at five locations. Generalized additive regression models were used to analyze the data. RESULTS: A total of 175 patients were recruited, 50 nondiabetic subjects and 125 diabetic patients without DR, stratified into three groups according to diabetes duration: group I (10 years, n = 31). Overall, groups I and III of diabetic patients had a decrease in the photoreceptor layer (PR) thickness, when compared with the nondiabetic subjects in six ETDRS areas (P < 0.0007). Patients with more recent diagnosis (group I) had thinner PR than those with moderate duration (group II). Interestingly, patients with longer known disease (group III) had the thinnest PR values. There were no overall differences in the remaining retinal parameters. CONCLUSIONS: Retinal thickness profile is not linear throughout disease duration. Even in the absence of funduscopic disease, PR layer in diabetic patients seems to differ from nondiabetic subjects, thus suggesting that some form of neurodegeneration may take place before clinical signs of vascular problems arise.info:eu-repo/semantics/publishedVersio

Friedreich ataxia patient tissues exhibit increased 5-hydroxymethylcytosine modification and decreased CTCF binding at the FXN locus

© 2013 Al-Mahdawi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,distribution, and reproduction in any medium, provided the original author and source are credited.This article has been made available through the Brunel Open Access Publishing Fund.Friedreich ataxia (FRDA) is caused by a homozygous GAA repeat expansion mutation within intron 1 of the FXN gene, which induces epigenetic changes and FXN gene silencing. Bisulfite sequencing studies have identified 5-methylcytosine (5 mC) DNA methylation as one of the epigenetic changes that may be involved in this process. However, analysis of samples by bisulfite sequencing is a time-consuming procedure. In addition, it has recently been shown that 5-hydroxymethylcytosine (5 hmC) is also present in mammalian DNA, and bisulfite sequencing cannot distinguish between 5 hmC and 5 mC.The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement number 242193/EFACTS (CS), the Wellcome Trust [089757] (SA) and Ataxia UK (RMP) to MAP