Study of modifiers factors associated to mitochondrial mutations in individuals with hearing impairment

Hearing impairment is the most prevalent sensorial deficit in the general population. Congenital deafness occurs in about 1 in 1000 live births, of which approximately 50% has hereditary cause in development countries. Non-syndromic deafness can be caused by mutations in both nuclear and mitochondrial genes. Mutations in mtDNA have been associated with aminoglycoside-induced and non-syndromic deafness in many families worldwide. However, the nuclear background influences the phenotypic expression of these pathogenic mutations. Indeed, it has been proposed that nuclear modifier genes modulate the phenotypic manifestation of the mitochondrial A1555G mutation in the MTRNR1 gene. The both putative nuclear modifiers genes TRMU and MTO1 encoding a highly conserved mitochondrial related to tRNA modification. It has been hypothesizes that human TRMU and also MTO1 nuclear genes may modulate the phenotypic manifestation of deafness-associated mitochondrial mutations. The aim of this work was to elucidate the contribution of mitochondrial mutations, nuclear modifier genes mutations and aminoglycoside exposure in the deafness phenotype. Our findings suggest that the genetic background of individuals may play an important role in the pathogenesis of deafness-associated with mitochondrial mutation and aminoglycoside-induced.     

Synthesis of d-labeled and unlabeled benzoyloxysuccinimides and application to quantitative analysis of peptides and a protein by isotope differential mass spectrometry

Benzoyloxysuccinimide and its d₅-labeled version, which react with amino groups in the N-termini and lysine side chains in proteins, were synthesized and applied to quantitative analysis of peptides and a commercially available protein in combination with a MALDI mass spectrometer.     

Chromodomain蛋白在表观遗传调控中的功能

克罗莫结构域 (chromatin organization modifier domain, chromodomain)是与染色质结构相关的进化上保守的蛋白质模体。Chromodomain中芳香族氨基酸残基组成保守的疏水“box”结构与“组蛋白密码”中的二甲基或三甲基修饰的H3K9和H3K27结合, 同时chromodomain也可识别非组蛋白和特定的核酸结构。不同类型的chromodomain蛋白在基因转录调节、基因组重排修复和染色质重塑等过程中发挥重要调控作用, 从多个层次参与染色质表观遗传调节过程。本文综述chromodomain的分类和结构特征, 探讨进化中不同的chromodomain蛋白在细胞中的功能多样性, 为进一步研究chromodomain蛋白在细胞中的作用机制提供参考。     

Mitochondrial variants may influence the phenotypic manifestation of Leber's hereditary optic neuropathy-associated ND4 G11778A mutation

We report here the characterization of a five-generation Han Chinese family with Leber's hereditary optic neuropathy (LHON). Strik-ingly, this Chinese family displayed high penetrance and expressivity of visual loss. The average age-of-onset of vision loss was 18 years in this family. Nineteen (11 males/8 females) of 29 matrilineal relatives in this family developed visual loss with a wide range of severity,ranging from blindness to normal vision. Sequence analysis of mitochondrial genome in this pedigree revealed the presence of the ND4 G11778A mutation and 44 other variants belonging to Asian haplogroup M7b. The G11778A mutation is present at homoplasmy in matri-lineal relatives of this Chinese family. Of other variants, the CO1 G6480A, ND5 T12811C and Cytb A15395G located at highly conserved residues of corresponding polypeptides. In fact, these variants were implicated to be involved in other clinical abnormalities. Here, these variants may act in synergy with the primary LHON-associated Gl1778A mutation. Thus, the mitochondrial dysfunction caused by the primary ND4 G11778A mutation may be worsened by these mitochondrial variants. The results imply that the G6480A, T12811C and A15395G variants might have a potential modifier role in increasing the penetrance and expressivity of the primary LHON-associated G11778A mutation in this Chinese family.     

Expression and purification of human urodilatin by small ubiquitin-related modifier fusion in Escherichia coli

To prevent in vivo degradation, small peptides are usually expressed in fusion proteins from which target peptides can be released by proteolytic or chemical reagents. In this report, small ubiquitin-related modifier (SUMO) linked with a hexa-histidine tag was used as a fusion partner for the production of recombinant human urodilatin, a hormone for the treatment of acute decompensated heart failure. The fusion protein, which was overexpressed mainly as inclusion bodies in Escherichia coli, constituted about 25% of the total cell proteins. After purification by Ni-sepharose affinity chromatography and renaturation in refolding buffer, the fusion protein was cleaved with SUMO protease 1. Urodilatin was separated from the fusion partner by the subtractive chromatography using Ni-sepharose once again, and then further purified with reverse-phase high performance liquid chromatography. In vitro activity assay demonstrated that the recombinant urodilatin had a potent vasodilatory effect on rabbit aortic strips with an EC₅₀ of 1.77 ± 0.53 μg/ml, which was similar to that of the synthetic urodilatin standard. The expression strategy presented in this study allows convenient high yield and easy purification of small recombinant peptides with native sequences. Z. Sun and Z. Xia contribute equally to the work.     

SELECTION FOR RECOMBINATION IN SMALL POPULATIONS

Abstract The reasons that sex and recombination are so widespread remain elusive. One popular hypothesis is that sex and recombination promote adaptation to a changing environment. The strongest evidence that increased recombination may evolve because recombination promotes adaptation comes from artificially selected populations. Recombination rates have been found to increase as a correlated response to selection on traits unrelated to recombination in several artificial selection experiments and in a comparison of domesticated and nondomesticated mammals. There are, however, several alternative explanations for the increase in recombination in such populations, including two different evolutionary explanations. The first is that the form of selection is epistatic, generating linkage disequilibria among selected loci, which can indirectly favor modifier alleles that increase recombination. The second is that random genetic drift in selected populations tends to generate disequilibria such that beneficial alleles are often found in different individuals; modifier alleles that increase recombination can bring together such favorable alleles and thus may be found in individuals with greater fitness. In this paper, we compare the evolutionary forces acting on recombination in finite populations subject to strong selection. To our surprise, we found that drift accounted for the majority of selection for increased recombination observed in simulations of small to moderately large populations, suggesting that, unless selected populations are large, epistasis plays a secondary role in the evolution of recombination.     

Natural products as modulators of the nuclear receptors and metabolic sensors LXR,FXR and RXR

Nuclear receptors (NRs) represent attractive targets for the treatment of metabolic syndrome-related diseases. In addition, natural products are an interesting pool of potential ligands since they have been refined under evolutionary pressure to interact with proteins or other biological targets.This review aims to briefly summarize current basic knowledge regarding the liver X (LXR) and farnesoid X receptors (FXR) that form permissive heterodimers with retinoid X receptors (RXR). Natural product-based ligands for these receptors are summarized and the potential of LXR, FXR and RXR as targets in precision medicine is discussed.     

Divergence and evolution of assortative mating in a polygenic trait model of speciation with gene flow

Assortative mating is an important driver of speciation in populations with gene flow and is predicted to evolve under certain conditions in few‐locus models. However, the evolution of assortment is less understood for mating based on quantitative traits, which are often characterized by high genetic variability and extensive linkage disequilibrium between trait loci. We explore this scenario for a two‐deme model with migration, by considering a single polygenic trait subject to divergent viability selection across demes, as well as assortative mating and sexual selection within demes, and investigate how trait divergence is shaped by various evolutionary forces. Our analysis reveals the existence of sharp thresholds of assortment strength, at which divergence increases dramatically. We also study the evolution of assortment via invasion of modifiers of mate discrimination and show that the ES assortment strength has an intermediate value under a range of migration‐selection parameters, even in diverged populations, due to subtle effects which depend sensitively on the extent of phenotypic variation within these populations. The evolutionary dynamics of the polygenic trait is studied using the hypergeometric and infinitesimal models. We further investigate the sensitivity of our results to the assumptions of the hypergeometric model, using individual‐based simulations.     

Small molecule SUMOylation activators are novel neuroprotective agents

Neuronal loss characterizes many of the most intractable nervous system diseases that deprive our ageing population of their quality of life. Neuroprotective pharmacological modalities are urgently needed to address this burgeoning population. Small ubiquitin-like modifier (SUMO) conjugation has been established as an endogenous neuroprotective response, and we have discovered several classes of small molecules that enhance SUMO conjugation. Herein we describe the hit to lead campaign that enabled the discovery of 3 diverse classes of drug-like SUMOylation activators. Optimized compounds were ultimately validated in cell-based models of neuronal loss and provide a foundation for establishing systemically active SUMO activators to treat degenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and stroke.     

Effects and mechanism of Chinese tarantula toxins on the Kv2.1 potassium channels

Three neurotoxins, Jingzhaotoxin-I, -III, and -V (JZTX-I, -III, and -V), isolated from the venom of the Chinese tarantula Chilobrachys Jingzhao, are 29-36-amino acid peptides. Electrophysiological recordings carried out in Xenopus laevis oocytes show that these toxins acted as gating modifier of voltage-dependent K+ channels. They slow the rate of Kv2.1 channel activation and increase the tail current deactivation, suggesting that toxin-bound channels can still open but are modified. JZTX-III selectively inhibits Kv2.1 channels, and JZTX-V exhibits a higher affinity to Kv4.2 channels than to Kv2.1 channels, whereas JZTX-I inhibits Kv2.1 and Kv4.1 channels with low affinity. Structure-function analysis indicates that electrostatic interactions can benefit for toxin affinity and the feature of electrostatic anisotropy may be correlated with the different affinity of the toxins for the Kv2.1 and Kv4.1 channels. Furthermore, phylogenetic analysis of these and other gating modifiers provides clues for the exploration of toxin-channel interaction.