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At least 199 records · Page 11Linked to original sources
PubMed2006

Genetic and functional evidence supporting SUMO4 as a type 1 diabetes susceptibility gene.

Genomewide linkage analyses since the early 1990s suggested over 20 genomic intervals that may contain susceptibility genes for type 1 diabetes. However, the identification of the specific genes in these intervals presents a formidable challenge due to a number of difficulties associated with genetic mapping and cloning of genes implicated in complex diseases. One of the difficulties is due to the presence of many weak and different susceptibility genes in different patients and populations, a phenomenon known as genetic heterogeneity. In 2004, we reported the cloning of a novel small ubiquitin-like modifier (SUMO) gene, SUMO4, in the IDDM5 interval on chromosome 6q25, and presented strong genetic and functional evidence suggesting that SUMO4 is a susceptibility gene for type 1 diabetes mellitus (T1DM). In this article, we will summarize genetic association data suggesting that SUMO4 is consistently associated with T1DM in the Asian populations while the association is more heterogeneous in the Caucasian populations. We will also discuss the possible molecular pathways through which sumoylation may regulate T1DM and autoimmunity.

Autoimmune Diseases↗
PubMed1984

Autonomic nervous system function in genetic neuromuscular disorders. Hereditary motor-sensory neuropathy and myotonic dystrophy.

Three quantitative measures of autonomic nervous system (ANS) function were evaluated in 12 patients with two types of autosomal dominant neuromuscular disorder, type 1 hereditary motor-sensory neuropathy and myotonic dystrophy. The three measures were latency of the pupillary light reflex, dark-adapted pupil size during parasympathetic blockade, and ECG RR interval variation. The results showed deficits in sympathetic and/or parasympathetic nervous system function in several patients, with a variability of expression expected in autosomal dominant genetic diseases. The ANS function may commonly be deficient in both of these disorders. Further investigation is required to determine the potential clinical importance of these findings.

Adult↗
PubMed2000

Apolipoprotein E and Alzheimer disease: an update on genetic and functional analyses.

Exceptional advances have been made in understanding the genetics of how common polymorphisms of the apolipoprotein E gene influence the risk and age of onset of Alzheimer disease (AD). The major genetic susceptibility locus for the common forms of AD, there are 3 common alleles, designated epsilon2, epsilon3, and epsilon4. The inheritance of each dose of APOE4 increases the risk of disease and decreases the age of onset; conversely, the APOE2 allele appears to be protective, by lowering the risk of disease and increasing the age of onset. Testing for the APOE4 allele can be a clinically useful tool in the early diagnosis of cognitively impaired patients suspected of having AD. The APOE4 allele also negatively influences functional recovery following a variety of brain insults. What remains in the study of apolipoprotein E is an explanation of how minor changes in a protein can produce such striking differences in risk and age of onset. In vitro and animal model studies strongly suggest that brain apolipoprotein E is a multifunctional molecule, with potential roles in amyloid deposition and clearance, microtubule stability, intracellular signaling, immune modulation, glucose metabolism, oxidative stress, and other cellular processes. While the relevance of these proposed functions to the etiology of AD remains a mystery, these and other hypotheses will be tested as the field of apoE neurobiology grows, adding relevant new data to the functions of apoE in health and in the pathogenic mechanisms leading to AD.

Alleles↗
PubMed2004

Genetic and functional confirmation of the causality of the DGAT1 K232A quantitative trait nucleotide in affecting milk yield and composition.

We recently used a positional cloning approach to identify a nonconservative lysine to alanine substitution (K232A) in the bovine DGAT1 gene that was proposed to be the causative quantitative trait nucleotide underlying a quantitative trait locus (QTL) affecting milk fat composition, previously mapped to the centromeric end of bovine chromosome 14. We herein generate genetic and functional data that confirm the causality of the DGAT1 K232A mutation. We have constructed a high-density single-nucleotide polymorphism map of the 3.8-centimorgan BULGE30-BULGE9 interval containing the QTL and show that the association with milk fat percentage maximizes at the DGAT1 gene. We provide evidence that the K allele has undergone a selective sweep. By using a baculovirus expression system, we have expressed both DGAT1 alleles in Sf9 cells and show that the K allele, causing an increase in milk fat percentage in the live animal, is characterized by a higher Vmax in producing triglycerides than the A allele.

Acyltransferases↗
PubMed1993

Functional and genetic plasticities of the poliovirus genome: quasi-infectious RNAs modified in the 5'-untranslated region yield a variety of pseudorevertants.

Poliovirus RNA species with nucleotides 564 to 571 deleted or with a secondary structure domain (positions 564 to 629) replaced by a shorter irregular oligonucleotide have been engineered previously; these RNAs have been considered quasi-infectious (yielding a single late revertant plaque) and dead, respectively (E. Pilipenko, A. Gmyl, Y. Svitkin, S. Maslova, A. Sinyakov, and V. Agol, Cell 68:119-131, 1992). By using large amounts of these RNAs for transfections, revertant clones with a great variety of genetic changes (point mutations, insertions of foreign sequences, short or extended deletions) were isolated. The pattern of these changes supported the notion that an appropriately spaced oligopyrimidine-AUG tandem is important for efficient poliovirus RNA translation. Structural features within and around this tandem modulated the initiation efficiency. The functional and genetic plasticities of the poliovirus genome are briefly discussed.

Animals↗
PubMedDate not supplied

Tobacco mosaic virus RNA as genetic determinant: genesis of a discovery.

It is generally held that the American geneticists Alfred Hershey and Martha Chase were the first to elucidate, in 1952, the genetic functions of phage DNA. The discovery of the genetic functions of RNA in a plant virus (Tobacco mosaic virus, TMV) is commonly attributed to the American plant virologist Heinz Fraenkel-Conrat, and to the Germans Alfred Gierer and Gerhard Schramm, who came to the same conclusion independently in 1956. In reality, the first understandings dated back to about 1940, when several scientists discovered that TMV infectivity was closely related to the presence of undamaged RNA in the virus particles. A very important but underestimated contribution came from the English group of Roy Markham, Kenneth Smith and Richard Matthews in 1948. This group purified and characterized an isometric plant virus, Turnip yellow mosaic virus, and first showed that virus infectivity depended on the presence of the RNA, concluding that nucleic acid was essential for virus multiplication. This finding was confirmed by the same group one year later but it laid neglected. After a five year period, in which several groups attempted to solve the question of the function of TMV RNA, the American electron microscopist Roger Hart offered, in 1955, further direct evidence which correlated RNA to TMV infectivity. One year later, three research groups (Fraenkel-Conrat; Gierer and Schramm; Max Lauffer, David Trkule and Anne Buzzell) obtained evidence that put an end to the question, which was (and is) fundamental to molecular Genetics because it demonstrated that RNA can function independently of DNA.

RNA, Viral↗
PubMed1999

Functional and genetic integrity of the CD8 T-cell repertoire in advanced HIV infection.

BACKGROUND: HIV-specific cytotoxic T lymphocytes (CTL) can restrict HIV replication in acute and chronic infection, but disease progression occurs in parallel with declining CTL activity. An understanding of why CTL fail to control HIV replication might reveal important mechanisms of disease progression and enhance prospects for developing effective CTL-based immunotherapies. OBJECTIVES: To investigate the functional integrity, T-cell repertoire diversity, and HIV reactivity of CD8 T lymphocytes in individuals with advanced HIV infection. METHODS: Individuals were considered to have progressed to advanced HIV infection if their total T-cell count was < 500 x 10(6) cells/(l) on at least two successive clinic visits. CD8 T cells from these individuals were analyzed for CTL function, HIV reactivity and T-cell receptor (TCR) diversity by chromium release assays and reverse transcriptase polymerase chain reaction. RESULTS: CD8 T cells from all individuals with advanced HIV infection proliferated and differentiated into functional CTL in vitro. Despite extremely low T-cell counts and previous AIDS-defining illnesses, six individuals had inducible anti-HIV CTL responses. In two additional cases, HIV-specific CTL activity became detectable following significant treatment-associated remission of T-cell lymphopenia. Assessment of TCRbetaV gene family representation and betaV gene intrafamily diversity indicated CD8 T-cell repertoire diversity is maintained through advanced HIV infection. CONCLUSIONS: These data suggest that HIV-specific CTL activity can be selectively compromised while the functional and genetic integrity of the CD8 population as a whole remains intact. A substantial fraction of individuals retain inducible anti-HIV CTL activity through advanced HIV infection and, in at least some cases, effective treatment can restore HIV-specific CTL responses even at this late stage of disease.

Animals↗
PubMed1999

Stabilization of the relaxosome and stimulation of conjugal transfer are genetically distinct functions of the R1162 protein MobB.

MobB is a small protein encoded by the broad-host-range plasmid R1162 and required for efficient mobilization of its DNA during conjugation. The protein was shown previously to stabilize the relaxosome, the complex of plasmid DNA and mobilization proteins at the origin of transfer (oriT). We have generated in-frame mobB deletions that specifically inactivate the stabilizing effect of MobB while still allowing a high rate of transfer. Thus, MobB has two genetically distinct functions in transfer. The effect of another deletion, extending into mobA, indicates that both functions require a specific region of MobA protein that is distinct from the nicking-ligating domain. The mobB mutations that specifically affected stability also resulted in poor growth of cells, due to increased transcription from the promoters adjacent to oriT. The effects of the mutations could be suppressed not only by full-length MobB provided in trans, as expected, but also by additional copies of oriT, cloned in pBR322. In addition, in the presence of MobA both the full-length and truncated forms of MobB stimulated recombination between oriT-containing plasmids. We propose a model in which MobB regulates expression of plasmid genes by altering the stability of the relaxosome, in a manner that involves the coupling of plasmid molecules.

Bacterial Proteins↗
PubMed1996

The Drosophila Broad-Complex early gene directly regulates late gene transcription during the ecdysone-induced puffing cascade.

The ensemble of tissue-specific changes that drives Drosophila metamorphosis is initiated by the steroid hormone ecdysone and proceeds through a transcriptional cascade comprised of primary response transcriptional regulators and secondary response structural genes. The Broad-Complex (BR-C) primary response early gene is composed of several distinct genetic functions and encodes a family of related transcription factor isoforms. Our objective in this study was to determine whether individual BR-C isoforms directly regulate secondary response target genes. A cluster of 10 salivary gland-specific secondary response L71 late genes are dependent on the BR-C rbp+ genetic function. Transgenic animals expressing individual BR-C isoforms were tested for their ability to provide the BR-C rbp+ genetic function by monitoring the transcriptional activation of the L71 genes. We found that the BR-C Z1 isoforms could complement the transcriptional defects seen in rbp mutants but the Z2, Z3, and Z4 isoforms could not. We conclude that the BR-C rbp+ function is provided by the BR-C Z1 isoform in prepupal salivary glands. L71 gene rescue was restricted to the prepupal salivary gland, suggesting the involvement of additional factors in L71 gene regulation. Interestingly, we found that the overexpression of Z3 or Z4 isoforms in BR-C+ salivary glands repressed L71 expression, indicating that BR-C proteins might also function as transcriptional repressors. Molecular mapping and characterization of the regulatory sequences that control L71-6 expression revealed several Z1 isoform binding sites. Mutagenesis of these Z1 binding sites resulted in the failure to activate late gene expression in vivo when measured by transgenic reporter genes. We conclude that the BR-C early gene directly activates late gene transcription by interacting with late gene cis-acting regulatory elements and that this interaction is responsible for the temporal linkage of early and late ecdysone-induced gene expression.

Animals↗
PubMedDate not supplied

[From molecular genetics to functional genomic and physiome].

After a brief overview on the advances in the molecular genetics knowledge the paper present new concepts of functional genomics and physiom. First, the results of a group of cell and molecular biology researchers in the filed of genic expression of biologic active endogenous substances, ion receptors and channels are discussed, underlining their influence on actual genomic trend of physiological sciences. Discussions continues on theoretical basis of gene therapy and in the end are presented the researches that made the transition from functional genom to the integrative concepts of physiom, cardiom and proteom, fulfilling the content of the classical notion of normal and pathologic physiology.

Gene Expression↗
PubMed1992

Genetic and functional analysis of the basic replicon of pPS10, a plasmid specific for Pseudomonas isolated from Pseudomonas syringae patovar savastanoi.

The sequence of a 1823 base-pair region containing the replication functions of pPS10, a narrow host-range plasmid isolated from a strain of Pseudomonas savastanoi, is reported. The origin of replication, oriV, or pPS10 is contained in a 535 base-pair fragment of this sequence that can replicate in the presence of trans-acting function(s) of the plasmid. oriV contains four iterons of 22 base-pairs that are preceded by G+C-rich and A+T-rich regions. A dnaA box located adjacent to the repeats of the origin is dispensable but required for efficient replication of pPS10; A and T are equivalent bases at the 5' end of the box. repA, the gene of a trans-acting replication protein of 26,700 Mr has been identified by genetic and functional analysis. repA is adjacent to the origin of replication and is preceded by the consensus sequences of a typical sigma 70 promoter of Escherichia coli. The RepA protein has been identified, using the minicell system of E. coli, as a polypeptide with an apparent molecular mass of 26,000. A minimal pPS10 replicon has been defined to a continuous 1267 base-pair region of pPS10 that includes the oriV and repA sequences.

Amino Acid Sequence↗
PubMed2004

Genetic and functional analysis of mitochondrial DNA-encoded complex I genes.

Mammalian mitochondrial NADH dehydrogenase (complex I) is a multimeric complex consisting of at least 45 subunits, 7 of which are encoded by mitochondrial DNA (mtDNA). The function of these subunits is largely unknown. We have established an efficient method to isolate and characterize cells carrying mutations in various mtDNA-encoded complex I genes. With this method, 15 mouse cell lines with deficiencies in complex I-dependent respiration were obtained, and two near-homoplasmic mutations in mouse ND5 and ND6 genes were isolated. Furthermore, by generating a series of cell lines with the same nuclear background but different content of an mtDNA nonsense mutation, we analyzed the genetic and functional thresholds in mouse mitochondria. We found that in wild-type cells, about 40% of ND5 mRNA is in excess of that required to support a normal rate of ND5 subunit synthesis. However, there is no indication of compensatory upsurge in either transcription or translation with the increase in the proportion of mutant ND5 genes. Interestingly, the highest ND5 protein synthesis rate was just sufficient to support the maximum complex I-dependent respiration rate, suggesting a tight regulation at the translational level. In another line of research, we showed that the mitochondrial NADH-quinone oxidoreductase of Saccharomyces cerevisiae (NDI1), although consisting of a single subunit, can completely restore respiratory NADH dehydrogenase activity in mutant human cells that lack the essential mtDNA-encoded subunit ND4. In particular, in these transfected cells, the yeast enzyme becomes integrated into the human respiratory chain and fully restores the capacity of the cells to grow in galactose medium.

Animals↗
PubMed1993

A partial cDNA clone of trypomastigote decay-accelerating factor (T-DAF), a developmentally regulated complement inhibitor of Trypanosoma cruzi, has genetic and functional similarities to the human complement inhibitor DAF.

Resistance to complement-mediated lysis in Trypanosoma cruzi is due to the expression of complement-regulatory factors by the virulent developmental forms of this protozoan parasite. An 87- to 93-kDa molecule, which we have termed T-DAF (trypomastigote decay-accelerating factor), is present on the surface of the parasite and inhibits complement activation in a manner functionally similar to the mammalian complement regulatory component, decay-accelerating factor. In this report, we characterized monospecific polyclonal and monoclonal antibodies which were obtained from mice and rabbits immunized with fast protein liquid chromatography-purified T-DAF. These polyclonal antibodies were shown to inhibit T-DAF activity and were capable of inducing lysis of the parasites. Both the polyclonal and monoclonal antibodies were used to screen a cDNA expression library prepared from T. cruzi trypomastigote mRNA. From this library, we obtained a partial lambda gt11 cDNA clone which showed genetic and functional similarity to the human C3 convertase inhibitor DAF (A. Nicholson-Weller, J. Burge, D. T. Fearon, P. F. Weller, and K. F. Austen, J. Immunol. 129:184-189, 1982).

Amino Acid Sequence↗
PubMed2003

Genetic and functional studies in multiple sclerosis patients from Martinique attest for a specific and direct role of the HLA-DR locus in the syndrome.

Among candidate genes involved in multiple sclerosis (MS) genetic susceptibility, MHC genes and particularly HLA-DRB1*1501-DQB1*0602 haplotype play a major role. Based on the strong linkage disequilibrium observed in Caucasians between DRB1*1501 and DQB1*0602 alleles, it is still impossible to draw a firm conclusion about the DRB1 or DQB1 locus involvement. In order to address this issue a strategy associating a genetic and a functional approach was conducted in a population of-non-Caucasian MS patients. We observed that in Martinicans (55 MS and 100 controls), the DRB1*15 and DRB1*07 alleles were positively associated with the disease. However in Martinicans the most common DRB1*15 subtype was *1503 and not *1501. Moreover, in Martinicans, the frequency of DQB1*0602, found in association with other DRB1 alleles than DRB1*15 (42% of DQB1*0602 haplotypes), was not increased in DRB1*15-negative MS patients, suggesting a neutral role of DQB1*0602 in MS genetics. In a second step, we demonstrated the capability of the DRB1*1503 allele associated with MS in Martinicans to present the immunodominant autoantigen MBP 85-99 peptide to a DRB1*1501 restricted MBP specific T cell line. Interestingly, structural features of DRB1*1501 or DRB1*1503 molecules are in good fit with the hypothesis that *1501 and *1503 molecules may act similarly in MS development by presenting the same immunodominant MBP peptide. On the whole, our results show a prominent role of the DRB1 locus (DRB1*1501 and/or DRB1*1503 alleles) in the immunodominant MBP 85-99 peptide presentation to genetically different MS patients and suggest a neutral role of the DQB1 encoded molecule in MS susceptibility.

Alleles↗
PubMed2002

Maternal obesity alters adiposity and monoamine function in genetically predisposed offspring.

The impact of maternal obesity on brain monoamine function in adult offspring of dams selectively bred to express diet-induced obesity (DIO) or diet resistance (DR) was assessed by making dams obese or lean during gestation and lactation. After 12 wk on chow and 4 wk on a 31% fat diet, offspring hypothalamic nucleus size and [(3)H]nisoxetine binding to norepinephrine transporters (NET) and [(3)H]paroxetine binding to serotonin transporters (SET) were measured. Offspring of obese DIO dams became more obese than all other groups, but maternal obesity did not alter weight gain in DR offspring (25). Maternal obesity was associated with 10-17% enlargement of ventromedial nuclei (VMN) and dorsomedial nuclei in both DIO and DR offspring. Offspring of obese DIO dams had 25-88% lower NET binding in the paraventricular nuclei (PVN), arcuate nuclei, VMN, and the central amygdalar nuclei, while offspring of obese DR dams had 43-67% higher PVN and 90% lower VMN NET binding and a generalized increase in SET binding across all hypothalamic areas compared with other groups. Thus maternal obesity was associated with alterations in offspring brain monoamine metabolism, which varied as a function of genotype and the development of offspring obesity.

Adipose Tissue↗
PubMed1997

Genetic and functional changes in mitochondria associated with aging.

This review is devoted to the molecular genetics and bioenergetics of human mitochondria related to the mechanism of aging. Morphological and functional changes of mitochondria associated with age and age-related disease are overviewed with special reference to the changes in enzymes encoded by mitochondrial-inherent genome. The somatically acquired mutations and oxidative damage of the genome, which lead an individual to the fragmentation of mitochondrial DNA, cellular energy crisis, naturally occurring cell death (apoptosis), and tissue degeneration and atrophy, are reviewed with relation to the inherited point mutational genotypes and the deletion types of mitochondrial DNA. Theories of aging are discussed with disclosed evidence relevant to them. Some trials to prevent age-related damage in mitochondria are introduced for the development of what may be called mitochondrial medicine.

Aging↗
PubMed1997

Multiple identification of a particular type of hereditary C1q deficiency in the Turkish population: review of the cases and additional genetic and functional analysis.

Complete selective deficiencies of the complement component C1q are rare genetic disorders that are associated with recurrent infections and a high prevalence of lupus erythematosus-like symptoms. All C1q deficiencies studied at the genetic level revealed single-base mutations leading to termination codons, frameshifts or amino acid exchanges and these were thought to be responsible for the defects as no other aberrations were found. One particular mutation, leading to a stop codon in the C1qA gene, was first identified in members of a Gypsy family from the Slovak Republic. The same mutation has been found in all cases of C1q deficiency from Turkey that have been investigated. Here we present the results of genetic analysis of the C1q genes from three families and give information on further C1q-deficient members of two families that have not been reported elsewhere. Reviewing all cases of C1q deficiency from Turkey prompted us to hypothesize that one particular defective allele is present in the population of southeast Europe and Turkey. With a novel polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and allele-specific PCR we are able to detect even asymptomatic, heterozygous carriers of the mutation, which will enable genetic counseling of the affected individuals.

Amino Acid Sequence↗