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PubMedDate not supplied

Molecular analysis of GB virus C/hepatitis G virus in HIV-1-positive intravenous drug users in Belgium.

OBJECTIVE: A high prevalence of GB virus C (GBV-C)/hepatitis G virus (HGV) RNA and E2 antibodies is observable in human immunodeficiency virus type 1 (HIV-1)-infected individuals in Belgium, including intravenous drug users (IDUs), in whom the highest prevalence is observed. A molecular analysis of GBV-C/HGV could give indications on the origin of this infection in IDUs. METHODS: We directly sequenced 7 GBV-C/HGV isolates from this IDU population and performed a phylogenetic analysis comparing the results to known GBV-C/HGV sequences. RESULTS: All 7 isolates were GBV-C/HGV genome type 2. Three were found to be subtype 2a, and 4 belonged to the 2b subtype. No specific clustering was observed for strains obtained from IDUs in Belgium, and they were interspersed between other sequences with long branch lengths. CONCLUSION: Based on our results, it is unlikely that the IDUs were infected recently by GBV-C/HGV from a common ancestral virus.

Adult↗

PubMed2025

Complex Genetics and Regulatory Drivers of Hypermobile Ehlers-Danlos Syndrome: Insights from Genome-Wide Association Study Meta-analysis.

BACKGROUND: Hypermobile Ehlers-Danlos syndrome (hEDS) is the most common subtype of EDS, a group of heritable connective tissue disorders. Clinically, hEDS is defined by generalized joint hypermobility and chronic musculoskeletal pain, but its impact extends beyond the musculoskeletal system. Affected individuals frequently experience autonomic, gastrointestinal, immune, and neuropsychiatric involvement, highlighting both the multisystemic nature of the condition and challenges of diagnosis. In contrast to other EDS subtypes with defined genetic causes, the molecular basis of hEDS has remained elusive. METHODS: We conducted a genome-wide association study (GWAS) of hEDS across three case controls studies, including 1,815 cases and 5,008 ancestry-matched controls. Fixed-effects meta-analysis of 6.2 million variants was complemented with LDAK gene-based association testing, transcriptome-wide association studies, and integrative annotation across multiple tissues and cell types including eQTLs, enhancer marks and open chromatin accessibility profiles, supported by luciferase assays on one candidate variant. LD-score genetic correlations were assessed between hEDS and 19 frequently reported comorbid conditions. RESULTS: Two loci reached genome-wide significance, including a regulatory region near the atypical chemokine receptor 3 gene (ACKR3) on chromosome 2. Functional annotation supports ACKR3 risk alleles colocalize with eQTLs in tibial nerve, alter enhancer activity, and generate a de novo AHR transcription factor regulatory site, implicating neuroimmune and pain signaling pathways. Gene-based and transcriptome-wide analyses identified common variants in a locus containing multiple candidates, including SLC39A13, a zinc transporter critical for connective tissue development previously implicated in a rare form of EDS, and PSMC3, a gene involved in central nervous system development. LD-score regression revealed significant genetic correlations between hEDS and joint hypermobility, myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, depression, anxiety, autism spectrum disorder, migraine, and gastrointestinal diseases. CONCLUSIONS: These results establish the first evidence of common variant contributions to hEDS, supporting a complex, multisystem model involving neuroimmune-stromal dysregulation. Our findings add novel indications to hEDS pathogenesis and provide solid foundations for future molecular definition and therapeutic discovery.

Genome-wide association study↗

PubMed1993

Predominant and stable T cell responses to regions of myelin basic protein can be detected in individual patients with multiple sclerosis.

T lymphocytes from patients with multiple sclerosis (MS) recognize multiple myelin basic protein (MBP) epitopes. This situation complicates the design of specific immunotherapies. We investigated to which extent the T cell response to MBP is heterogeneous in single subjects in terms of preferentially recognized regions of the molecule, major histocompatibility complex (MHC) restriction, and stability over time. From each of nine patients with MS, a minimum of six MBP-specific T lymphocyte lines (TLL) were assayed for the proliferative response to a panel of overlapping peptides, encompassing the whole MBP. Predominant T cell recognitions of distinct MBP regions were present in three patients, all HLA-DR2+, independently of the clinical features of their disease. T cell reactivity was preferentially directed to residues 16-38 in one patient. In this case the response was also stable over time, during different phases of the disease. Predominant reactivity to residues 86-99 was detected in the two other DR2+ patients. In each of the patients with other HLA-DR haplotypes (DR2-), as well as in three DR2+ non-MS donors, the T cell response to MBP appeared to be considerably more heterogeneous. The HLA restriction element varied among TLL recognizing the same MBP region, even when raised from the same individual. The genomic HLA typing, performed on the DRB1 and DRB5 genes in the DR2+ subjects, showed no obvious correspondence between preferential responses to regions of MBP and HLA-DR2 subtypes. In this context, a simple, new method for the genomic typing of the HLA-DRB1 gene in individuals with the HLA-DR2 serological specificity is also described. We conclude that predominant and stable T cell responses to a single MBP region can be detected in some patients with MS. In these individuals, the MHC restriction of the T cell recognition of predominant regions appears to be variable. Polymorphisms of the HLA-DR2 gene products alone do not account for the selection of the dominant MBP T cell epitope.

Adolescent↗

PubMed2026

Integrated Genomic and Proteomic Analysis Reveals T-B Lymphocyte Signatures in the MYCN Driven "Immune Desert" of Specific Neuroblastoma Subtypes.

AIMS: This study aims to systematically dissect how MYCN amplification shapes the immunosuppressive tumor microenvironment (TME) in high-risk neuroblastoma, elucidating key mechanisms underlying immune evasion. METHODS: We performed an integrated multi-omics analysis of bulk RNA-seq (n = 721), single-cell RNA-seq (n = 9), proteomic data (n = 49) and spatial transcriptomics (Visium, with external validation in melanoma). Analyses included unsupervised clustering, cell-cell communication inference, transcriptional regulatory network reconstruction, and spatial proximity assessment to map the immune landscape. RESULTS: A distinct molecular subtype (Class C), defined by MYCN amplification and poor prognosis, exhibited a comprehensive "immune desert" phenotype characterized by low immune scores and minimal leukocyte infiltration. Single-cell analysis confirmed significant depletion of T and B lymphocytes within the Class C TME. Dysregulated transcriptional networks were identified, including upregulation of REL and EOMES in T cells-with EOMES potentially driving exhaustion via regulation of Transient Receptor Potential (TRP) genes, and REL inhibition enhancing cytotoxic function in vitro. A unique immunosuppressive B-cell subset (B7) engaged in enhanced crosstalk with exhausted T cells and harbored a MYC-centered network linked to cell cycle dysregulation and poor survival. Spatial transcriptomics revealed significant proximity between B7-active regions and Treg/exhaustion-enriched areas, externally validated in melanoma. Proteomic data validated elevated REL expression in MYCN-amplified tumors. CONCLUSION: This work delineates the immunosuppressive architecture of MYCN-driven neuroblastoma, revealing novel regulatory nodes within specific lymphocyte compartments. Integrating single-cell, spatial, and proteomic evidence, we propose REL inhibition as a therapeutic candidate, the EOMES/TRP axis as a bioinformatically supported hypothesis, and the B7/MYC hub as a hypothesis supported by transcriptomic and spatial evidence.

Humans↗

PubMed1999

Central melatonin receptors in the rainbow trout: comparative distribution of ligand binding and gene expression.

To better define the role of melatonin in fish, we have compared in detail the distribution of 2-[125I]iodomelatonin binding sites with gene expression for melatonin receptor subtypes in a widely studied seasonal species, the rainbow trout. Three distinct partial sequences of the melatonin receptor gene were cloned from trout genomic DNA. Two of the sequences corresponded to the Mella receptor subtype, and one corresponded to the Mellb receptor subtype. Analysis of numerous clones failed to find a sequence equivalent to the Mel1c receptor subtype. Comparison of receptor gene expression with 2-[125I]iodomelatonin binding distribution indicated dendritic transport of the receptor. Melatonin receptors were associated predominantly with visually related areas of the trout brain, such as the thalamic region, the pretectal area, and the optic tectum. The pituitary was devoid of 2-[125I]iodomelatonin binding, and melatonin receptor gene expression was not detectable. It would appear from the results of the present study that melatonin in this species is involved primarily in the processing of visual signals. How melatonin interacts with circannual rhythms of growth and reproduction is unclear, although a direct interaction between melatonin and the hypothalamo-pituitary axis is not clearly indicated.

Animals↗

PubMed1984

Sea urchin actin gene subtypes. Gene number, linkage and evolution.

The actin gene family of the sea urchin Strongylocentrotus purpuratus was analyzed by the genome blot method, using subcloned probes specific to the 3' terminal non-translated actin gene sequence, intervening sequence and coding region probes. We define an actin gene subtype as that gene or set of genes displaying homology with a given 3' terminal sequence probe, when hybridized at 55 degrees C, 0.75 M-Na+. By determining the often polymorphic restriction fragment band pattern displayed in genome blots by each probe, all, or almost all of the actin genes in this species could be classified. Our evidence shows that the S. purpuratus genome probably contains seven to eight actin genes, and these can be assigned to four subtypes. Studies of the expression of the genes (Shott et al., 1983) show that the actin genes of three of these subtypes code for cytoskeletal actins (Cy), while the fourth gives rise to a muscle-specific actin (M). We denote the array of S. purpuratus actin genes indicated by our data as follows. There is a single CyI actin gene, two or possibly three CyII genes (CyIIa, CyIIb, and possibly CyIIc), three CyIII actin genes (CyIIIa, CyIIIb, CyIIIc), and a single M actin gene. Comparative studies were carried out on the actin gene families of five other sea urchin species. At least the CyIIa and CyIIb genes are also linked in the Strongylocentrotus franciscanus genome, and this species also has a CyI gene, an M actin gene and at least two CyIII actin genes. It is not clear whether it also possesses a CyIIc actin gene, or a CyIIIc actin gene. The genome of a more closely related congener, Strongylocentrotus dröbachiensis, includes 3' terminal sequences suggesting the presence of a CyIIc gene. In S. franciscanus and S. dröbachiensis the first intron of the CyI gene has remained homologous with intron sequences of both the CyIIa and CyIIb genes, indicating a common origin of these three linked cytoskeletal actin genes. Of the four S. purpuratus 3' terminal subtype probe sequences only the CyI 3' terminal sequence has been conserved sufficiently during evolution to permit detection outside of the genus Strongylocentrotus. An unexpected observation was that a sequence found only in the 3' untranslated region of the CyII actin gene in the DNA of S. dröbachiensis and S. purpuratus is represented as a large family of interspersed repeat sequences in the genome of S. franciscanus.

Actins↗

PubMed2001

High proportion of unrelated HIV-1 intersubtype recombinants in the Mbeya region of southwest Tanzania.

BACKGROUND: In Mbeya, a rural region of southwest Tanzania, HIV-1 subtypes A, C and D have been co-circulating since the early 1990s. OBJECTIVE: To define to what extent the co-existence of subtypes has led to recombinant HIV-1 strains and whether there is evidence for epidemic spread of any circulating recombinant form. METHODS: Nine HIV-1-seropositive young adults from Mbeya Town with no evident high-risk behaviour contributed peripheral blood mononuclear cells for this study. Nine virtually full-length-genome-sequences were amplified from this DNA and phylogenetically analysed. RESULTS: Out of the nine samples, two were subtype A (22%), two were subtype C (22%) and five were recombinants (56%): four A/C recombinants and one C/D recombinant. None of the recombinants were related to each other; all of them had different mosaic structures. Most of the genome in the recombinants was subtype C. CONCLUSION: A high proportion of unrelated intersubtype recombinants, none of them apparently spreading in the population, may be present in southwest Tanzania.

Adolescent↗

PubMed2001

Molecular characterization of a highly divergent HIV type 1 isolate obtained early in the AIDS epidemic from the Democratic Republic of Congo.

Numerous complete human immunodeficiency virus type 1 (HIV-1) genomes have been characterized for contemporary viruses, but few isolates obtained early in the HIV-1 epidemic have been studied. In this article, we describe the molecular characterization of an HIV-1 isolate (83CD003) that was obtained from an AIDS patient in Kinshasa, Democratic Republic of Congo (DRC) in 1983. The complete 83CD003 genome was sequenced in its entirety and found to encode uninterrupted open reading frames for all viral genes. Phylogenetic analysis revealed 83CD003 was a member of the major (M) group of HIV -1, but did not group with any of the known subtypes. Rather, it formed an independent lineage in all regions of its genome that was roughly equidistant from representatives of all other subtypes. Similarly, 83CD003 also did not cluster with any of several unclassified group M sequences that have been reported more recently to circulate in the DRC, suggesting that it may represent an early group M lineage thai is either rare or has gone extinct. The molecular clone of 83CD003 yielded an infectious virus after transfection into mammalian cells and its biological properties can be further studied.

Cell Line↗

PubMed2005

Determination of gag and env subtypes of HIV-1 detected among injecting drug users (IDUs) in Manipur, India: evidence for intersubtype recombination.

The majority of HIV-1 transmission in Manipur, one of the northeastern states of India, is through the sharing of needles and syringes among the injecting drug users (IDUs). A total of 28 HIV seropositive samples were used to determine the HIV-1 subtypes with respect to both gag and envelope genes. The specific regions within gag and envelope genes were amplified from PBMC DNA by nested PCR using appropriate primers. These amplicons were used in heteroduplex mobility assay followed by DNA sequencing. Phylogenetic analysis of the nucleotide sequences of respective regions showed that 89% of samples (25/28) were infected with subtype C with respect to both gag and envelope genes; however, 11% of the samples (3/28) showed subtype discordance with respect to the envelope (C2-V3) and gag (p24-p7) genomic regions. Simplot analysis of the discordant samples showed the presence of intersubtype recombination between subtype C and Thai B; two samples were found to be subtype C in envelope but Thai B in gag, whereas, one sample was found to be subtype Thai B in envelope and 'C' in gag region.

Adult↗

PubMed2002

The impact of pharmacogenetics and pharmacogenomics on drug discovery.

It is widely perceived at present that pharmacogenetics and pharmacogenomics are about to revolutionize the face of medicine. In a more realistic assessment, the implementation of molecular genetics and biology will provide us with better ways to treat illnesses, and has already begun to do so in an incremental and evolutionary fashion. However, it is unlikely to change fundamentally the direction of medical progress. Advances are most likely to be made in the area of pharmacodynamics, as we learn to differentiate broader conventional clinical diagnoses into separate molecular subtypes.

Gene Expression↗

PubMed2005

Genome-environment interactions in the molecular pathogenesis of dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by impaired contractility and dilation of the ventricles. In a subset of DCM patients, classical inheritance patterns occur (familial DCM), which have led to the identification of specific genomic loci and gene defects causing monogenic DCM subtypes. In the majority of DCM patients, however, there is no evidence for a monogenic etiology of the disorder (sporadic DCM), and in the absence of other recognizable etiological factors, these cases were classified as "idiopathic". Recent research suggests that cardiotropic viruses are important environmental factors in the pathogenesis of "idiopathic" cases and that DCM commonly results from interactions between genetic and environmental factors, whereas "pure" genetic forms are rather rare. Regarding genetics, the clinical cardiomyopathic phenotype associated with single gene defects may be highly variable for unknown reasons. Furthermore, a novel class of genetic defects was identified recently which provide a molecular basis for abnormal reactions of cardiomyocytes to environmental stress. These defects are paradigms of specific molecular links between genome and environment during the pathogenesis of DCM. Regarding environmental factors, a recent molecular virological study based on myocardial biopsies in a large series of sporadic DCM patients has detected cardiac viral infections in the majority of patients, with a broad spectrum of virus species being involved. Apparently, DCM does not only occur as a late sequela of acute viral myocarditis, but also in patients without clinical history of cardiac viral disease. Cardiotropic viruses thus emerge as prevalent environmental factors which may cause or influence the course of DCM in a large fraction of cases. Synopsis of current data suggests that a comprehensive picture of DCM pathogenesis can only be drawn if both genetic and environmental pathogenetic factors are considered. The course of cardiac viral infections depends strongly on genetic host factors and may range from rapid and complete virus elimination or silencing without clinical symptoms, to rapidly progressive or fatal disease. Viruses interact not only with genetically heterogenous host systems of virus uptake, migration, and antiviral immunity, but, due to their prevalence in DCM hearts, are also likely to encounter multiple structural proteins of cardiac cells known to be defective in familial DCM. The combined knowledge on DCM-associated gene defects and viruses therefore suggests in-depth studies on genome-environment interactions in DCM pathogenesis which may underlie the high clinical variability observed both in monogenic and virus-associated DCM and have implications for the clinical management of DCM patients.

Cardiomyopathy, Dilated↗

PubMed1996

Characterization of the regulatory regions of murine alpha 2C2 adrenoceptor subtype gene.

In order to delineate the regulatory mechanisms underlying the control of alpha 2 adrenoceptor expression, the sequence of 5' (1145 bp) and 3' (2682 bp) flanking regions of murine alpha 2C2 subtype gene were determined and characterized from a genomic phage clone MA2C2. The 5' flanking region has no TATA box yet with high GC content. The 3' flanking region is marked by the presence of a polyadenylation signal 2.3 kb down stream from the stop codon. The transcription start site was mapped by 5' rapid amplification of cDNA ends (RACE) and primer extension assays at nucleotide A, 415 bp upstream from the first initiation codon and resides in a motif resembling the consensus sequence of initiator found in many TATA-less promoters. An NcoI fragment (4.7 kb) immediately upstream from the translation initiation site was linked to a reporter gene lacZ. Using an in vitro transfection assay, cell lines of renal or neural origin were identified as permissive hosts for alpha 2C2 subtype expression. With its core promoter clearly defined and sequence of the regulatory regions at hand, this in vitro gene transfer system will facilitate the identification of putative cis-elements and transcription factors key to alpha 2C2 adrenoceptor expression.

Animals↗

PubMed1994

Cloning of a Xenopus laevis muscarinic receptor encoded by an intronless gene.

The Xenopus laevis oocyte has endogenous sites that bind muscarinic agonists, which have been pharmacologically characterized as M3 and/or M1 receptor subtypes. In order to define the molecular identify of the receptor protein we have analyzed a Xenopus oocyte cDNA library and cloned a 2.9 kb cDNA fragment encoding a muscarinic receptor (xMR). The deduced amino acid sequence reveals a protein of 484 residues with an apparent molecular weight of 54,188 Da. Amino acid comparison with previously cloned mammalian muscarinic receptors showed a 78% identity with the human m4 subtype, presenting at the same time clustered differences within the amino-terminal region and third intracellular loop Genomic Southern analysis displayed the presence of one main gene belonging to this subtype, and the PCR analysis revealed an intronless gene.

Amino Acid Sequence↗

PubMed2005

Array comparative genomic hybridization reveals genomic copy number changes associated with outcome in diffuse large B-cell lymphomas.

To identify, in high-resolution regions of DNA, the copy number changes associated with outcome in patients with diffuse large B-cell lymphoma (DLBCL), a disease with an approximately 50% mortality rate, we performed array comparative genomic hybridization (array-CGH) on specimens from 64 patients with newly diagnosed DLBCL treated with anthracycline-based chemotherapy. For the entire cohort, 55 commonly gained/lost regions, ranging in size from less than 1 Mbp to entire chromosomes, were identified using 1- to 2-Mbp and 2- to 4-Mbp resolution BAC arrays. Copy number changes of 9 minimal regions significantly correlated with overall survival, of which 6 were 10 Mbp or smaller. On multivariate analysis, loss of chromosomes 2 (2.4-4.1 Mbp) and 16 (33.8-35.6 Mbp) were found to be prognostic indicators of poor survival, independent of clinical features routinely used to predict outcome. Loss of chromosome 1 (78.2-79.1 Mbp) was predictive of good outcome. For a subset of 55 specimens classified according to cell-of-origin expression signature subtype, gain of chromosome 12 (45.4-53.8 Mbp) was found to be significantly associated with the germinal center B-cell-like DLBCL subtype. Overall, array-CGH identified relatively small genomic regions associated with outcome, which, along with follow-up expression studies, may reveal target genes important in DLBCL clinical behavior.

Anthracyclines↗

PubMed1990

Nuclear genotype affects mitochondrial genome organization of CMS-S maize.

A WF9 strain of maize with the RD subtype of the S male-sterile cytoplasm (CMS-S) was converted to the inbred M825 nuclear background by recurrent backcrossing. The organization of the mitochondrial genomes of the F1 and succeeding backcross progenies was analyzed and compared with the progenitor RD-WF9 using probes derived from the S1 and S2 mitochondrial episomes, and probes containing the genes for cytochrome c oxidase subunit I (coxI), cytochrome c oxidase subunit II (coxII) and apocytochrome b (cob). Changes in mitochondrial DNA (mtDNA) organization were observed for S1-, S2-, and coxI-homologous sequences that involve loss of homologous restriction enzyme fragments present in the RD-WF9 progenitor. With the coxI probe, the loss of certain fragments was accompanied by the appearance of a fragment not detectable in the progenitor. The changes observed indicate the effect of the nuclear genome on the differential replication of specific mitochondrial subgenomic entities.

Apolipoproteins B↗

PubMed1998

Epstein-Barr virus strain characterization.

The Epstein-Barr virus (EBV), a ubiquitous human herpesvirus originally described in cultured lymphoblasts from African Burkitt's lymphoma, is the causative agent of infectious mononucleosis, but appears to be involved in the pathogenesis of a variety of diseases. EBV has the ability to establish lifelong persistent infection, where only a restricted pattern of the viral proteins is expressed. Periodic reactivation of EBV occurs, where mature EBV particles are produced. Strain variation is potentially important in the biology and epidemiology of EBV, and in attempts to relate EBV to associated diseases. Analysis of the EBV genomes isolated from patients with EBV-associated diseases and from various parts of the world has so far failed to identify conclusive disease-specific viral subtypes. This review focuses on the different strategies which have been used for strain characterization or subtyping of EBV.

Adaptation, Physiological↗

PubMed2005

HIV type 1 strains common in Europe, Africa, and Asia cocirculate in Yemen.

To determine the HIV-1 genetic diversity in Yemen, 19 strains collected from men and women were sequenced in pol and six of those were full genome sequenced; all were phylogenetically analyzed. Using the pol sequence data, nine (47.3%) were subtype B, six (31.6%) subtype C, two (10.5%) subtype D, one strain (5.3%) subtype A, and another (5.3%) a unique recombinant form (URF). Concordant phylogenies were also obtained for the six strains full genome sequenced. Most of the strains were from the capitol, Sana'a (n=16). Five of the C strains clustered with African Cs, and one clustered with the Indian C strains. Of the two subtype D strains, one clustered with Ugandan strains and one with Cameroon. The subtype A strain was similar to a Cameroon variant of subtype A and the URF strain was a recombinant between CRF11, CRF13, and subtype B. The HIV epidemic in Yemen is extremely complex, with strains of HIV-1 that have originated in East and West Africa, Europe, and India.

Adult↗

PubMedDate not supplied

Genomic assessment of pediatric acute leukemia.

Advances in molecular genetics have revolutionized our understanding of acute myeloid and lymphoblastic leukemia. Structural and numerical chromosomal aberrations are common, and their detection is vital for leukemia diagnosis, risk stratification, and monitoring of response to therapy. Fusion proteins resulting from chromosomal translocations are necessary but not sufficient for leukemogenesis, and there is intense research activity to elucidate the cooperating molecular abnormalities that may be suitable targets for novel therapeutic approaches. Candidate gene approaches have identified mutations in kinases and transcription factors in a proportion of patients, but more comprehensive genomic approaches are required. Gene expression profiling accurately classifies known subtypes of acute leukemia and has highlighted potentially leukemogenic abnormalities in gene expression. Newer techniques, such as single-nucleotide polymorphism arrays to analyze changes in gene copy number and zygosity, cancer genome sequencing, and RNA interference, are promising tools to identify mutations, although at present, data from these approaches are limited. This review provides an overview of these techniques in clinical practice and as research tools to develop new therapeutic approaches in pediatric leukemia.

Acute Disease↗