Glucocerebrosidase (Gaucher disease)

Gaucher disease is the most common glycolipid storage disorder, characterized by storage of the glycolipid, glucocerebroside in the liver, spleen, and marrow. The most prevalent form of Gaucher disease is designated type I (MIM 230800). Patients with type I disease may have hepatomegaly, splenomegaly, bone lesions, and less commonly, lung disease, but are free of neurological involvement. Types II (MIM 230900) and III (MIM 2310000), the acute infantile and juvenile forms, respectively, of Gaucher disease, are characterized by the fact that the central nervous system is affected. © 1996 Wiley-Liss, Inc.     

Calreticulin chaperones regulate functional expression of vomeronasal type 2 pheromone receptors

A variety of social behaviors like intermale aggression, fear, and mating rituals are important for sustenance of a species. In mice, these behaviors have been implicated to be mediated by peptide pheromones that are sensed by a class of G protein-coupled receptors, vomeronasal receptor type 2 (V2Rs), expressed in the pheromone detecting vomeronasal organ. Matching V2Rs with their cognate ligands is required to learn what receptors the biologically relevant pheromones are acting on. However, this feat has been greatly limited by the unavailability of appropriate heterologous tools commonly used to study ligand receptor specificity, because this family of receptors fails to traffic to the surface of heterologous cells. Here we show that calreticulin, a housekeeping chaperone commonly expressed in most eukaryotic cells, is sparsely expressed in the vomeronasal sensory neurons (VSNs). Correspondingly, knockdown of calreticulin in commonly available cell lines enables V2Rs to efficiently target to the cell membrane. Using this knowledge, we have now been able to successfully surface express receptors and functionally identify cognate ligands. Additionally, calreticulin4, a homolog of calreticulin shows restricted and enriched expression in the VSNs. Interestingly, in heterologous cells, calreticulin4 does not inhibit surface expression of V2Rs and can in part carry out functions of calreticulin. On the basis of our data, we postulate that V2Rs may use a unique trafficking mechanism whereby an important and more commonly expressed chaperone is deleterious for membrane export and is replaced by a functionally equivalent homolog that does not inhibit export while carrying out its functions.     

Gene variants associated with schizophrenia in a Norwegian genome-wide study are replicated in a large European cohort

We have performed a genome-wide association study (GWAS) of schizophrenia in a Norwegian discovery sample of 201 cases and 305 controls (TOP study) with a focused replication analysis in a larger European sample of 2663 cases and 13,780 control subjects (SGENE-plus study). Firstly, the discovery sample was genotyped with Affymetrix Genome-Wide Human SNP Array 6.0 and 572,888 markers were tested for schizophrenia association. No SNPs in the discovery sample attained genome-wide significance (P < 8.7 × 10⁻⁸). Secondly, based on the GWAS data, we selected 1000 markers with the lowest P values in the discovery TOP sample, and tested these (or HapMap-based surrogates) for association in the replication sample. Sixteen loci were associated with schizophrenia (nominal P value < 0.05 and concurring OR) in the replication sample. As a next step, we performed a combined analysis of the findings from these two studies, and the strongest evidence for association with schizophrenia was provided for markers rs7045881 on 9p21, rs433598 on 16p12 and rs10761482 on 10q21. The markers are located in PLAA, ACSM1 and ANK3, respectively. PLAA has not previously been described as a susceptibility gene, but 9p21 is implied as a schizophrenia linkage region. ACSM1 has been identified as a susceptibility gene in a previous schizophrenia GWAS study. The association of ANK3 with schizophrenia is intriguing in light of recent associations of ANK3 with bipolar disorder, thereby supporting the hypothesis of an overlap in genetic susceptibility between these psychopathological entities.     

From the Cover: Patterns of genome evolution that have accompanied host adaptation in Salmonella

Many bacterial pathogens are specialized, infecting one or few hosts, and this is often associated with more acute disease presentation. Specific genomes show markers of this specialization, which often reflect a balance between gene acquisition and functional gene loss. Within Salmonella enterica subspecies enterica, a single lineage exists that includes human and animal pathogens adapted to cause infection in different hosts, including S. enterica serovar Enteritidis (multiple hosts), S. Gallinarum (birds), and S. Dublin (cattle). This provides an excellent evolutionary context in which differences between these pathogen genomes can be related to host range. Genome sequences were obtained from ∼60 isolates selected to represent the known diversity of this lineage. Examination and comparison of the clades within the phylogeny of this lineage revealed signs of host restriction as well as evolutionary events that mark a path to host generalism. We have identified the nature and order of events for both evolutionary trajectories. The impact of functional gene loss was predicted based upon position within metabolic pathways and confirmed with phenotyping assays. The structure of S. Enteritidis is more complex than previously known, as a second clade of S. Enteritidis was revealed that is distinct from those commonly seen to cause disease in humans or animals, and that is more closely related to S. Gallinarum. Isolates from this second clade were tested in a chick model of infection and exhibited a reduced colonization phenotype, which we postulate represents an intermediate stage in pathogen–host adaptation.The central importance of horizontal acquisition of mobile genetic elements in the development of virulence in bacteria has been well described. It has frequently been observed that, as pathogens acquire virulence determinants, they become increasingly adapted to a specific host (1, 2). Exquisitely host-restricted pathogens also often exhibit extensive genome decay, through insertion sequence element proliferation, genomic rearrangement, and/or pseudogene formation (1, 3, 4). Investigating mechanisms involved in host adaptation is key to an understanding of pathogen evolution and has directly translatable relevance to the epidemiology and potentially the control of human and zoonotic infectious disease.By concentrating upon individual pathogenic clades, insights have been obtained into specific adaptations relating to specific hosts; however, comparative analysis is relatively rare. By broadening this approach to examine multiple human and animal pathogens, derived from a single closely related lineage but with differing host specializations, there is an opportunity to understand the fundamental evolutionary processes involved in host adaptation. Lineage-specific changes that have become fixed can then be distinguished from those stochastic changes that differentiate individual isolates.A single lineage within Salmonella enterica presents such an opportunity. S. enterica is a leading cause of foodborne gastroenteritis, globally responsible for 80 million cases annually (5). Differentiation of S. enterica is largely based upon somatic (O) and flagellar (H) antigens, but it is increasingly being typed by genomic methods, such as multilocus sequence typing (MLST). Somatic serogrouping and MLST have identified a single lineage with closely related members that exhibit a range of different host specializations (6–9). These include two of the most important Salmonella pathogens: S. Enteritidis and S. Gallinarum. In addition to the contribution of S. Enteritidis to human disease, in many countries both of these pathogens are notifiable diseases in poultry farming and egg production. Despite their close phylogenetic relatedness, they exhibit strikingly different host ranges, with S. Enteritidis capable of infecting multiple host species, whereas S. Gallinarum is restricted to infection in galliforme birds. This lineage also includes S. Gallinarum biovar Pullorum (hereafter S. Pullorum), also restricted to galliformes, and S. Dublin, which is strongly associated with infection of cattle and more rarely that of humans (10). The Salmonella pathogens adapted to particular hosts are associated with a much more invasive disease than generalists like S. Enteritidis, which tend to cause enteritis.Fifty-nine isolates of this Salmonella lineage were selected to capture the diversity of sequence types, phage types, and geographical and temporal spread available at the time. Through genome sequencing, we generated a phylogeny to act as a framework with which to reconstruct the evolutionary history of the lineage, onto which observed gene loss and acquisition could be plotted.This dataset provides a compelling record of the degradation of common metabolic pathways during host specialization to date. We have documented the order of events during the evolution of an entire Salmonella lineage. To link this specifically to host adaptation, we have tested isolates occupying key positions in the phylogeny in their cognate host to assess the effects of gene degradation on the manner and severity of disease caused.     

假基因DUXAP8在肝癌中的表达及其临床意义

目的探讨DUXAP8在肝癌中的表达和临床意义,并探讨可能的作用机制。方法收集TCGA数据库中截至2019年6月的肝癌表达数据及临床资料,筛选出同时满足在癌组织与癌旁组织差异表达且影响患者预后的lncRNA。分析DUXAP8表达水平与肝癌患者临床病理特征以及预后的相关性。利用GO和KEGG通路富集方法分析与DUXAP8相关的基因生物功能及其可能参与的生物过程。利用STRING数据库和Cytoscape进行蛋白质相互作用分析并筛选关键基因,然后对关键基因的表达量及其预后情况进行分析并进行文献检索分析。肝癌组织和癌旁组织DUXAP8表达比较采用Wilcoxon秩和检验和Wilcoxon符号秩和检验。不同临床病理特征的患者DUXAP8表达水平比较采用Wilcoxon秩和检验。利用Kaplan-Meier法绘制生存曲线并采用log-rank检验进行组间比较;采用Cox回归分析预后影响因素。Pearson相关法分析DUXAP8的相关基因。结果非配对样品及配对样品肝癌组织和癌旁组织中DUXAP8的表达水平存在显著差异(P值均<0.001),肝癌组织中DUXAP8表达明显升高。在不同年龄、T分期的患者中DUXAP8表达差异显著(P值均<0.05),年龄≥60岁或T分期等级为T3或T4,DUXAP8表达量较高。单因素分析显示,临床分期、T分期、DUXAP8表达量与患者总生存期相关(P值均<0.001),多因素Cox回归分析结果显示,临床分期晚[风险比(HR)=1.648,95%可信区间(95%CI):1.330~2.709,P<0.001]、高DUXAP8表达仍是预后差的独立危险因素(HR=1.849,95%CI:1.262~2.713,P<0.01)。DUXAP8高表达的样本中,富集了与维持肿瘤细胞的增殖和细胞周期等相关的基因。TOP2A、KIF2C、TTK、PLK1、CDCA8、CDC20、NCAPG、BUB1B、BUB1和CCNA2为DUXAP8相关靶基因的Hub基因,主要参与细胞有丝分裂和细胞周期等过程,是肝癌患者预后不良的相关因素(P值均<0.05)。结论DUXAP8高表达是肝癌患者预后不良的危险因素,DUXAP8可能通过影响细胞增殖、周期等过程促进肝癌的发生发展。     

Microdeletion/duplication at the Xq28 IP locus causes a de novo IKBKG/NEMO/IKKgamma exon4_10 deletion in families with incontinentia pigmenti

The Incontinentia Pigmenti (IP) locus contains the IKBKG/NEMO/IKKgamma gene and its truncated pseudogene copy, IKBKGP/deltaNEMO. The major genetic defect in IP is a heterozygous exon4_10 IKBKG deletion (IKBKGdel) caused by a recombination between two consecutive MER67B repeats. We analyzed 91 IP females carrying the IKBKGdel, 59 of whom carrying de novo mutations (65%). In eight parents, we found two recurrent nonpathological variants of IP locus, which were also present as rare polymorphism in control population: the IKBKGPdel, corresponding to the exon4_10 deletion in the pseudogene, and the MER67Bdup, that replicates the exon4_10 region downstream of the normal IKBKG gene. Using quantitative DNA analysis and microsatellite mapping, we established that both variants might promote the generation of the pathological IKBKGdel. Indeed, in family IP‐516, the exon4_10 deletion was repositioned in the same allele from the pseudogene to the gene, whereas in family IP‐688, the MER67Bdup generated the pathological IKBKGdel by recombination between two direct nonadjacent MER67Bs. Moreover, we found an instance of somatic recombination in a MER67Bdup variant, creating the IKBKGdel in an IP male. Our data suggest that the IP locus undergoes recombination producing recurrent variants that might be “at risk” of generating de novo IKBKGdel by NAHR during either meiotic or mitotic division. Hum Mutat 30:1–8, 2009. © 2009 Wiley‐Liss, Inc.