Novel mutations in DNA2 associated with myopathy and mtDNA instability

The maintenance of mitochondrial DNA (mtDNA) relies on proteins encoded by nuclear genes. Mutations in their coding sequences result in heterogenous clinical presentations featuring mtDNA instability in affected tissues. DNA2 is a multi-catalytic protein involved in the removal of single strand DNA during mtDNA replication or Long Patch Base Excision Repair pathway. We have previously described DNA2 mutations in adult patients affected with familial and sporadic forms of mitochondrial myopathy. Here we describe four novel probands presenting with limb weakness associated with novel DNA2 molecular defects. Biochemical assays were established to investigate the functional effects of these variants

Novel mutations in DNA2 associated with myopathy and mtDNA instability

The maintenance of mitochondrial DNA (mtDNA) relies on proteins encoded by nuclear genes. Mutations in their coding sequences result in heterogenous clinical presentations featuring mtDNA instability in affected tissues. DNA2 is a multi-catalytic protein involved in the removal of single strand DNA during mtDNA replication or Long Patch Base Excision Repair pathway. We have previously described DNA2 mutations in adult patients affected with familial and sporadic forms of mitochondrial myopathy. Here we describe four novel probands presenting with limb weakness associated with novel DNA2 molecular defects. Biochemical assays were established to investigate the functional effects of these variants

An Approach to Identify Gene-Environment interactions and Reveal New Biological insight in Complex Traits

There is a long-standing debate about the magnitude of the contribution of gene-environment interactions to phenotypic variations of complex traits owing to the low statistical power and few reported interactions to date. to address this issue, the Gene-Lifestyle Interactions Working Group within the Cohorts for Heart and Aging Research in Genetic Epidemiology Consortium has been spearheading efforts to investigate G × E in large and diverse samples through meta-analysis. Here, we present a powerful new approach to screen for interactions across the genome, an approach that shares substantial similarity to the Mendelian randomization framework. We identify and confirm 5 loci (6 independent signals) interacted with either cigarette smoking or alcohol consumption for serum lipids, and empirically demonstrate that interaction and mediation are the major contributors to genetic effect size heterogeneity across populations. The estimated lower bound of the interaction and environmentally mediated heritability is significant (P \u3c 0.02) for low-density lipoprotein cholesterol and triglycerides in Cross-Population data. Our study improves the understanding of the genetic architecture and environmental contributions to complex traits

N-vector spin models on the sc and the bcc lattices: a study of the critical behavior of the susceptibility and of the correlation length by high temperature series extended to order beta^{21}

High temperature expansions for the free energy, the susceptibility and the second correlation moment of the classical N-vector model [also known as the O(N) symmetric classical spin Heisenberg model or as the lattice O(N) nonlinear sigma model] on the sc and the bcc lattices are extended to order beta^{21} for arbitrary N. The series for the second field derivative of the susceptibility is extended to order beta^{17}. An analysis of the newly computed series for the susceptibility and the (second moment) correlation length yields updated estimates of the critical parameters for various values of the spin dimensionality N, including N=0 [the self-avoiding walk model], N=1 [the Ising spin 1/2 model], N=2 [the XY model], N=3 [the Heisenberg model]. For all values of N, we confirm a good agreement with the present renormalization group estimates. A study of the series for the other observables will appear in a forthcoming paper.Comment: Revised version to appear in Phys. Rev. B Sept. 1997. Revisions include an improved series analysis biased with perturbative values of the scaling correction exponents computed by A. I. Sokolov. Added a reference to estimates of exponents for the Ising Model. Abridged text of 19 pages, latex, no figures, no tables of series coefficient

Renormalized couplings and scaling correction amplitudes in the N-vector spin models on the sc and the bcc lattices

For the classical N-vector model, with arbitrary N, we have computed through order \beta^{17} the high temperature expansions of the second field derivative of the susceptibility \chi_4(N,\beta) on the simple cubic and on the body centered cubic lattices. (The N-vector model is also known as the O(N) symmetric classical spin Heisenberg model or, in quantum field theory, as the lattice O(N) nonlinear sigma model.) By analyzing the expansion of \chi_4(N,\beta) on the two lattices, and by carefully allowing for the corrections to scaling, we obtain updated estimates of the critical parameters and more accurate tests of the hyperscaling relation d\nu(N) +\gamma(N) -2\Delta_4(N)=0 for a range of values of the spin dimensionality N, including N=0 [the self-avoiding walk model], N=1 [the Ising spin 1/2 model], N=2 [the XY model], N=3 [the classical Heisenberg model]. Using the recently extended series for the susceptibility and for the second correlation moment, we also compute the dimensionless renormalized four point coupling constants and some universal ratios of scaling correction amplitudes in fair agreement with recent renormalization group estimates.Comment: 23 pages, latex, no figure

Ataluren delays loss of ambulation and respiratory decline in nonsense mutation Duchenne muscular dystrophy patients

Aim: We investigated the effect of ataluren plus standard of care (SoC) on age at loss of ambulation (LoA) and respiratory decline in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) versus patients with DMD on SoC alone. / Patients & methods: Study 019 was a long-term Phase III study of ataluren safety in nmDMD patients with a history of ataluren exposure. Propensity score matching identified Study 019 and CINRG DNHS patients similar in disease progression predictors. / Results & conclusion: Ataluren plus SoC was associated with a 2.2-year delay in age at LoA (p = 0.0006), and a 3.0-year delay in decline of predicted forced vital capacity to <60% in nonambulatory patients (p = 0.0004), versus SoC. Ataluren plus SoC delays disease progression and benefits ambulatory and nonambulatory patients with nmDMD. / ClinicalTrials.gov: NCT01557400

Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions

Many human genes have adapted to the constant threat of exposure to infectious agents; according to the “hygiene hypothesis,” lack of exposure to parasites in modern settings results in immune imbalances, augmenting susceptibility to the development of autoimmune and allergic conditions. Here, by estimating the number of pathogen species/genera in a specific geographic location (pathogen richness) for 52 human populations and analyzing 91 interleukin (IL)/IL receptor genes (IL genes), we show that helminths have been a major selective force on a subset of these genes. A population genetics analysis revealed that five IL genes, including IL7R and IL18RAP, have been a target of balancing selection, a selection process that maintains genetic variability within a population. Previous identification of polymorphisms in some of these loci, and their association with autoimmune conditions, prompted us to investigate the relationship between adaptation and disease. By searching for variants in IL genes identified in genome-wide association studies, we verified that six risk alleles for inflammatory bowel (IBD) or celiac disease are significantly correlated with micropathogen richness. These data support the hygiene hypothesis for IBD and provide a large set of putative targets for susceptibility to helminth infections