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PubMed1994

Burkitt-like mutations in the c-myc gene locus in prolymphocytic leukemia.

The c-myc oncogene recently shown to act as a transcription factor, is involved in cellular proliferation. Deregulation of this gene can be one step in malignant transformation. In Burkitt's lymphoma (BL) the c-myc gene is consistently involved in chromosomal translocations and the first exon of the gene has been found to be a frequent target of somatic mutations. These mutations are believed to interfere with normal transcriptional regulation of the gene. We demonstrate a case of the rare prolymphocytic leukemia (PLL), a variant of chronic lymphocytic leukemia (CLL), that shows multiple Burkitt-like mutations in the first exon of c-myc and one nonconservative point mutation in the coding exon 2. Cytogenetic analysis revealed involvement of both chromosomes 8 in chromosomal translocations. Both chromosomes 8 are broken at (q23), the c-myc gene locus. Since the patient's leukemia cells exhibited high expression levels of the mutated allele of the c-myc mRNA, the point mutations alone may have accounted for transcriptional deregulation.

Amino Acid Sequence↗

PubMed2025

Gene and pathway analysis of genome-wide genetic associations of bladder cancer.

BACKGROUND: Although genetic variants associated with bladder cancer (BCa) risk have been identified through hypothesis-driven and genome-wide association studies, a systematic understanding of BCa genetic susceptibility at the gene and pathway levels remains to be achieved. MATERIALS AND METHODS: In this 2-stage functional genomics study, we used 5 independent tools for genome-wide gene mapping and ranking based on BCa genome-wide association studies summary statistics, followed by a meta-analysis of gene-level significance p values, to obtain a consensus gene ranking in terms of association with BCa. Subsequently, we performed preranked gene-set enrichment analysis to identify the functional pathways involved in BCa genetic susceptibility. Joint analysis with gene-set enrichment analysis, based on somatic alteration frequency, was performed to explore the pathway-level relationships between genetic susceptibility and somatic alterations in BCa. RESULTS: Other than the well-known BCa genes (such as FGFR3, MYC, TERT, CCNE1, and TP63), we additionally prioritized a set of novel genes likely to be genetically implicated in BCa development, including SETD2, a possible tumor suppressor gene involved in chromatin remodeling. We further demonstrated convergence between genetic associations and somatic alterations at both the gene (eg, FGFR3 and TERT) and pathway levels (eg, cell cycle and chromatin modification), as well as functional ontologies specifically implicated in germline predisposition to BCa (eg, CD8/TCR signaling, immune checkpoints, and cytokine signaling). CONCLUSIONS: We identified several novel genes associated with BCa and demonstrated that genetic variants contribute to the development of BCa by affecting antitumor immunity, response to toxic exposure, and RNA and protein homeostasis and synergizing with somatic alterations in various cancer-related pathways.

Bladder cancer↗

PubMed1993

Specificity variants in monoclonal antibodies reactive with peptide epitopes of the ring-infected erythrocyte surface antigen (RESA) of Plasmodium falciparum.

It has been suggested that repeat sequence antigens of Plasmodium falciparum may serve the parasite in immune evasion by modifying the host antibody response and impairing the development of protective immunity. According to this proposal networks of cross-reactive, repeat sequence malarial antigens have the ability to stimulate a high proportion of all somatically mutated B cells with altered antibody specificity, and thus to hinder the normal process of antibody affinity maturation. To determine the rate at which immunoglobulin mutations produce new reactivities with repeat sequence antigens, hybridoma cell lines specific for the ring-infected erythrocyte surface antigen (RESA) were examined for the incidence of specificity variants that arose naturally or as a result of treatment with the chemical mutagen ethylmethane sulphonate (EMS). From one of the cell lines variants were readily isolated having reactivity towards a very closely related repeat sequence epitope within the same RESA antigen. However, the other hybridoma/antigen combinations revealed no variants. In general, mutations giving rise to antibodies with altered specificity for related repetitive antigens were not readily induced and only limited support of the hypothesis was obtained.

Amino Acid Sequence↗

PubMed2006

Mutational analysis of the APC gene in cribriform-morula variant of papillary thyroid carcinoma.

INTRODUCTION: Familial adenomatous polyposis (FAP) is an inherited autosomal dominant syndrome caused by germline mutations in the adenomatous polyposis coli (APC) gene. Papillary thyroid cancer is one of the extracolonic manifestations of FAP. A characteristic histologic feature of this type of thyroid tumor is the cribriform-morula variant of papillary thyroid carcinoma (CMVPTC). METHODS: To investigate roles of the APC and beta-catenin genes in the development of CMVPTC, we examined germline and somatic mutations of these genes in a female patient with CMVPTC and FAP. The patient had undergone total colectomy at the age of 19 years and total thyroidectomy at age 25 years. RESULTS: Numerous tumors were disseminated in both lobes of the thyroid gland, and histopathologic examination revealed typical CMVPTC. DNA was extracted from peripheral blood leukocytes and 12 CMVPTC tumors, and exons 1-15 of the APC gene and exon 3 of the beta-catenin gene were examined. A germline mutation was detected in exon 13 of the APC gene, and this mutation generated a premature stop codon. Six somatic mutations (922delC, 1602delA, 1821delT, 1920delG, 2706del20, 2804insA) were found in the CMVPTC specimens. All mutations were truncating mutations in the N-terminus of the APC protein. Loss of heterozygosity was not observed in the remaining tumor tissues without somatic APC mutations. There were no mutations of the beta-catenin gene in peripheral blood leukocytes or 12 CMVPTC specimens. CONCLUSIONS: These results suggest that APC mutations play an important role in the development of CMVPTC and occur predominantly in the 5' side of the APC gene between codons 308 and 935.

Adenocarcinoma, Papillary↗

PubMed2026

A brief history of gene therapy for ornithine transcarbamylase deficiency.

Gene therapy encompasses the use of nucleic acids, including DNA and RNA, as therapeutic agents. This broad category includes approaches that permanently modify the genome to correct pathogenic variants, as well as strategies that restore gene expression without altering genomic DNA. In ornithine transcarbamylase (OTC) deficiency, the most common urea cycle disorder, the goal of somatic gene therapy is to restore hepatic expression of functional OTC enzyme and thereby reestablish urea cycle activity. Both viral and non-viral delivery platforms have been investigated in preclinical models and clinical studies to achieve therapeutic OTC expression. Despite contemporary medical therapy, individuals with OTC deficiency (OTCD) remain at risk for recurrent hyperammonemia which may result in neurocognitive impairment and reduced quality of life. Novel therapy that restores liver OTC expression and lessens chronic disease burden is highly desired. In this manuscript, we summarize the history of gene therapy development for OTC deficiency, spanning early preclinical investigations to contemporary clinical trials. Although a definitive cure through gene therapy has not yet been achieved, substantial progress has been made toward the development of safe and effective liver-directed nucleic acid therapeutics for this disorder.

Adeno-associated virus vector↗

PubMed2024

The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations.

Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as point mutations or mosaic chromosomal alterations (mCAs) in genes associated with hematologic malignancy, are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we used 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantified CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we developed a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We performed a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. After fine-mapping and variant-to-gene analyses, we identified seven genes associated with CH-LPMneg (TCL1A, TERT, SMC4, NRIP1, PRDM16, MSRA, SCARB1), and one locus associated with a sex-associated mutation pathway (SRGAP2C). We performed a secondary analysis excluding individuals with mCAs, finding that the genetic architecture was largely unaffected by their inclusion. Functional analyses of SMC4 and NRIP1 implicated altered HSC self-renewal and proliferation as the primary mediator of mutation burden in blood. We then performed comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we performed phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count and increased risk for incident peripheral artery disease, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS without a paired-tissue sample and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.

Journal Article↗

PubMed1985

Relapsing ophthalmoparesis-sensory neuropathy syndrome.

We studied two patients with recurrent sensory neuropathy and weakness of extraocular muscles. There was electrophysiologic evidence of multifocal demyelination of sensory nerves, with relative sparing of somatic motor nerves. Sural nerve biopsy in one patient showed segmental demyelination. We believe that these patients had an unusual form of inflammatory polyneuropathy--possibly a relapsing variant of the Miller-Fisher syndrome of acute idiopathic polyneuritis.

Female↗

PubMed1987

[Clinico-psychopathological characteristics of the mental disorders at a neurotic level detected in patients at a general polyclinic].

Examination of patients observed at a general somatic outpatient centre showed that 31.2% of the patients had mental disorders of the borderline level. Most commonly occurring among the psychopathological syndromes were atypical affective conditions with definite somatization of mental disturbances, which was expressed in massive somatic sensations (senestopathies), vegetative irregularities, and somatic pathology of the functional character. Such conditions made up 62.7%. The given syndromologic type is defined as senestopathic-hypochondriac depression which is subdivided into two variants depending on the nature of the symptomatology. The study has shown that the revealed psychopathological syndromes of the borderline level predominantly refer to the endogenic process of low intensity and less frequently to personality pathology at the stage of decompensation.

Ambulatory Care↗

PubMed1984

Serendipitous cloning of a mitochondrial cDNA and its polymorphism.

A cDNA clone p5x23 was isolated from a library prepared from membrane bound mRNA from a human lymphoblastoid cell line. This clone was shown to detect a restriction fragment length polymorphism with the enzyme MspI, with frequency for the minor variant of about 10% in a Caucasian population. The clone apparently only detected homozygotes, and did not hybridize to any of a panel of human-mouse somatic cell hybrids containing all human chromosomes in various combinations. Sequence analysis of the clone showed that it encoded a part of the 3' end of the human mitochondrial cytochrome b gene.

Amino Acid Sequence↗

PubMed1982

Mapping of aminoacylase-1 and beta-galactosidase-A to homologous regions of human chromosome 3 and mouse chromosome 9 suggests location of additional genes.

Conserved linkage groups have been found on the X and autosomal chromosomes in several mammalian species. The identification of conserved chromosomal regions has potential for predicting gene location in mammals, particularly in humans. The genes for human aminoacylase-1 (ACY1, N-acylamino acid aminohydrolase, E.C.3.5.1.14), an enzyme in amino acid metabolism, and beta-galactosidase-A (GLB1, E.C.3.2.1.23), deficient in GM1-gangliosidosis, have been assigned to human chromosome 3. Using human-mouse somatic cell hybrids segregating translocations of human chromosome 3, expression of both ACY1 and GLB1 correlated with the presence of the p21 leads to q21 region of chromosome 3. In a previous study, assignment of these genes to mouse chromosome 9 used mouse-Chinese hamster somatic cell hybrids, eliminating mouse chromosomes. To approximate the size of the conserved region in the mouse, experiments were performed with recombinant inbred mouse strains. An electrophoretic variant of ACY-1 in mouse strains was used to map the Acy-1 gene 10.7 map U from the beta-galactosidase locus. These data suggest that there is a region of homology within the p21 leads to q21 region of human chromosome 3 and a segment of mouse chromosome 9. Since the mouse transferrin gene (Trf) is closely linked to the aminoacylase and beta-galactosidase loci, we predict that the human transferrin (TF) gene is on chromosome 3.

Amidohydrolases↗

PubMed1993

[Disorders of critical thinking in schizophrenic patients].

Basing on the results of clinical and pathopsychological examinations of 87 schizophrenics, the author distinguishes 7 clinical variants of criticism disturbances. These may be presenting in the increasing by severity order as: complete nosognosia, acceptance of some symptoms, shifting the disease to the past, somatization or psychologization of the disease, formal-logical (induced) acceptance of the disease, autoanosognosia, heteroanosognosia. Critical disturbances were found to depend on personality disorders and clinical characteristics of the disease. A differential approach to critical disorders in schizophrenics is important for planning relevant diagnostic, treatment and aftercare measures.

Adolescent↗

PubMed1998

Genetic and immunological properties of phage-displayed human anti-Rh(D) antibodies: implications for Rh(D) epitope topology.

Understanding anti-Rh(D) antibodies on a molecular level would facilitate the genetic analysis of the human immune response to Rh(D), lead to the design of therapeutically useful reagents that modulate antibody binding, and provide relevant information regarding the structural organization of Rh(D) epitopes. Previously, we described a Fab/phage display-based method for producing a large array of anti-Rh(D) antibodies from the peripheral blood lymphocytes of a single alloimmunized donor. In the current study, we present a detailed analysis of 83 randomly selected clones. Sequence analysis showed the presence of 28 unique gamma1 heavy chain and 41 unique light chain gene segments. These paired to produce 53 unique Fabs that had specificity for at least half of the major Rh(D) epitopes. Surprisingly, despite this diversity, only 4 closely related heavy chain germline genes were used (VH3-30, VH3-30.3, VH3-33, and VH3-21). Similarly, nearly all Vkappa light chains (15/18) were derived from one germline gene (DPK9). lambda light chains showed a more diverse VL gene usage, but all (23/23) used the identical Jlambda2 gene. Several Fabs that differed in epitope specificity used identical heavy chains but different light chains. In particular, 2 such clones differed by only 3 residues, which resulted in a change from epD2 to epD3 specificity. These results suggest a model in which footprints of anti-Rh(D) antibodies are essentially identical to one another, and Rh(D) epitopes, as classically defined by panels of Rh(D) variant cells, are not discrete entities. Furthermore, these data imply that the epitope specificity of an anti-Rh(D) antibody can change during the course of somatic mutation. From a clinical perspective, this process, which we term epitope migration, has significance for the design of agents that modulate antibody production and for the creation of mimetics that block antibody binding in the settings of transfusion reactions and hemolytic disease of the newborn.

Amino Acid Sequence↗

PubMed1997

H3.3A variant histone mRNA containing an alpha-globin insertion: modulated expression during mouse gametogenesis correlates with meiotic onset.

Replacement-variant H3.3 histones have been isolated and sequenced in different eukaryotes, but no functional H3.3A gene has been characterized in the mouse so far. We have cloned an H3.3A cDNA from a mouse fetal ovary library, differentially screened with testis versus somatic cDNA probes. We showed this gene contains a region homologous to the reverse and complementary alpha-globin gene. We believe such a structure could have been generated by retroposition during the evolution of both globin and histone gene families. The sequence coding for H3.3A is 76.6% homologous to the mouse H3.3B gene at the nucleotide level and differs in only one amino acid at the protein level. The high degree of homology between these genes and the H3.3 variant histones from other eukaryotes reveals the conservation of these replication-independent class of histones throughout evolution. Analysis of gene expression reveals a developmental regulation concurrent with meiotic progression, with the highest level of transcript detection coincident with meiotic onset during both oogenesis and spermatogenesis.

Amino Acid Sequence↗

PubMed2001

Mitochondrial genome instability in human cancers.

Malfunction of mismatch repair (MMR) genes produces nuclear genome instability (NGI) and plays an important role in the origin of some hereditary and sporadic human cancers. The appearance of non-inherited microsatellite alleles in tumor cells (microsatellite instability, MSI) is one of the expressions of NGI. We present here data showing mitochondrial genome instability (mtGI) in most of the human cancers analyzed so far. The mtDNA markers used were point mutations, length-tract instability of mono- or dinucleotide repeats, mono- or dinucleotide insertions or deletions, and long deletions. Comparison of normal and tumoral tissues from the same individual reveals that mt-mutations may show as homoplasmic (all tumor cells have the same variant haplotype) or as heteroplasmic (tumor cells are a mosaic of inherited and acquired variant haplotypes). Breast, colorectal, gastric and kidney cancers exhibit mtGI with a pattern of mt-mutations specific for each tumor. No correlation between NGI and mtGI was found in breast, colorectal or kidney cancers, while a positive correlation was found in gastric cancer. Conversely, germ cell testicular cancers lack mtGI. Damage by reactive oxygen species (ROS), slipped-strand mispairing (SSM) and deficient repair are the causes explaining the appearance of mtGI. The replication and repair of mtDNA are controlled by nuclear genes. So far, there is no clear evidence linking MMR gene malfunction with mtGI. Polymerase gamma (POLgamma) carries out the mtDNA synthesis. Since this process is error-prone due to a deficiency in the proofreading activity of POLgamma, this enzyme has been assumed to be involved in the origin of mt-mutations. Somatic cells have hundreds to thousands of mtDNA molecules with a very high rate of spontaneous mutations. Accordingly, most somatic cells probably have a low frequency of randomly mutated mtDNA molecules. Most cancers are of monoclonal origin. Hence, to explain the appearance of mtGI in tumors we have to explain why a given variant mt-haplotype expands and replaces part of (heteroplasmy) or all (homoplasmy) wild mt-haplotypes in cancer cells. Selective and/or replicative advantage of some mutations combined with a severe bottleneck during the mitochondrial segregation accompanying mitosis are the mechanisms probably involved in the origin of mtGI.

Base Pair Mismatch↗

PubMed2003

Tamoxifen-inducible glia-specific Cre mice for somatic mutagenesis in oligodendrocytes and Schwann cells.

Inducible transgenesis provides a valuable technique for the analysis of gene function in vivo. We report the generation and characterization of mouse lines carrying glia lineage-specific transgenes expressing an improved variant of the tamoxifen-inducible Cre recombinase, CreERT2, where the recombinase is fused to a mutated ligand binding domain of the human estrogen receptor. Using a PLP-CreERT2 transgene, we have generated mice that show specific inducible Cre function, as analyzed by cross-breeding experiments into the Rosa26 Cre-LacZ reporter line, in developing and adult Schwann cells, in mature myelinating oligodendrocytes, and in undifferentiated NG2-positive oligodendrocyte precursors in the adult. Using a P0Cx-CreERT2 transgene, we have also established mouse lines with inducible Cre function specifically in the Schwann cell lineage. These tamoxifen-inducible CreERT2 lines will allow detailed spatiotemporally controlled analysis of gene functions in loxP-based conditional mutant mice in both developing and adult Schwann cells and in the oligodendrocyte lineage.

Animals↗

PubMed1988

[One of the variants of masked depression with hyperthermia in schizophrenia in children].

Clinical and psychopathological description of depression in 20 schizophrenic children is presented. The major signs of the disease were hyperthermia, cenesthopathic headaches and vertigo with depression. Hyperthermia suggested a somatic ailment which was not confirmed after the patients' investigation. The unique picture of the disease is accounted for by depression traits as well as the individual and age-related features of its pathogenesis.

Adolescent↗

PubMed2002

MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients.

Allelic variants of the MDR-1 gene have been shown recently to influence protein expression and P-glycoprotein (P-gp) function in healthy volunteers. Therefore, 405 acute myeloid leukemia patients were investigated for somatic genotypes of the three most frequent single nucleotide polymorphisms (SNPs) in exons 12, 21, and 26. In all three loci, homozygous wild-type alleles were classified as genotype A, heterozygous as B, and homozygous mutant (alternative) allele as C. Patients with the C genotype in exons 12 and 26 showed a lower median age (both P < 0.05). Additionally, the C genotype in exons 12 and 26 was associated with cytogenetic poor risk aberrations (both P < 0.05). A possible regulatory impact of the SNPs on MDR1 mRNA expression was investigated by a Real time-PCR assay. MDR1 expression was strongly correlated with a decreased complete remission rate (P = 0.01) but failed to predict decreased overall survival (OS). There was a significant association of the A genotype in exons 21 (P = 0.05) and 26 (P < 0.05) with lower MDR1 expression, whereas the B variants showed highest MDR1 values at all three investigated gene loci. The A genotype in exon 26 was associated with lower OS (P < 0,01). In these patients, worse OS is likely attributable to an increased risk of relapse (P < 0.001). We were able to detect a linkage disequilibrium of the investigated SNPs, indicating combined polymorphisms that could affect the regulation of MDR1 expression. The A genotype of all SNPs demonstrated both lowest MDR1 values and significantly decreased OS (P < 0.05) with a high probability of relapses (P < 0.01). These observations indicate that allelic variants of the MDR1 gene may influence therapy outcome by additional mechanisms, different from P-gp expression on acute myeloid leukemia blasts, possibly involving pharmacokinetic effects of P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Tumor formation in mice with somatic inactivation of the retinoblastoma gene in interphotoreceptor retinol binding protein-expressing cells.

The retinoblastoma suppressor gene product Rb has been assigned a critical role in cell cycle regulation, the induction of differentiation, and inhibition of oncogenic transformation. Inheritance of a mutant RB allele in humans is responsible for bilateral retinoblastoma, a malignant tumor of the retina. Trilateral retinoblastoma (TRB) is a rare variant of familial retinoblastoma in which, in addition to retinal tumors, tumors develop from the pineal gland, an organ ontologically related to the retina. Germline inactivation of Rb in mice leads to mid-gestational lethality with defects in erythropoeisis and neurogenesis. This embryonic lethality prohibits the analysis of Rb function in selected cell types at later stages of development or in the adult. Here, we describe the Cre-LoxP mediated somatic inactivation of Rb in a subset of neuroendocrine cells, including photoreceptor cells. We observed neuroendocrine tumors of the pineal and pituitary gland. These tumors invariably showed inactivation of Rb and Trp53. Remarkably, loss of Rb in photoreceptor cells does not lead to retinoblastoma or any phenotypic changes, not even when photoreceptor cells are made deficient in Rb, p107 and Trp53. Our results highlight the important differences that exist in tumor susceptibility between mice and man (e.g pineal gland) and question the photoreceptor cell origin of human retinoblastoma.

Alleles↗