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PubMed2006

Insulin-like peptide 6: characterization of secretory status and posttranslational modifications.

Insulin-like peptide 6 (Insl6) is a member of the insulin/relaxin superfamily with unknown biological function(s). In the current report, we establish that meiotic and postmeiotic germ cells of the testis are the principal sites of expression of Insl6. Analysis of stably or transiently transfected cells revealed that Insl6 is a secreted protein localized to the endoplasmic reticulum and Golgi. Secretion could be detected in both CHO and GC2 germ cells and was sensitive to brefeldin A treatment. In cell lysates, the predominant Insl6 band was approximately 28 kDa in size. In contrast, the predominant Insl6 species in the supernatant was 8 kDa in size, suggesting posttranslational processing of the precursor protein. Ectopically expressed Insl6 is processed and secreted in furin-deficient LoVo cells and in CHO cells treated with a furin inhibitor, although the size profile of the secreted protein is altered suggesting that Insl6 is a substrate for furin action. Furthermore, mutation of a putative furin cleavage site in the Insl6 peptide resulted in aberrant processing of the Insl6 peptide. Additional investigations of the structure of Insl6 protein provided evidence for posttranslational modifications of Insl6, including the presence of disulfide bonds, glycosylation, and ubiquitination. On the basis of the demonstrated secretory status of Insl6, we speculate that the physical proximity of the germ cell to the Sertoli cell renders the Sertoli cell a likely candidate for Insl6 action.

Amino Acid Sequence↗
PubMed1976

Mutations in Neurospora crassa which affect multiple amino acid transport systems.

Characterization of a double mutant, his-6: hgu-4, which is unable to utilize L-histidyl-glycine as a source of histidine has revealed a new locus on linkage group V. The hgu-4 genotype results in a generalized reduced transport activity for amino acids, with a concomitant increased resistance to amino acid analogs. Transport rates and analog resistance for amino acids by this mutant are compared to the previously reported transport deficient mutants fpr-1, nap and un-3. Transport of L-aspartate as a function of temperature is examined in a variety of transport deficient strains in an attempt to explain the mode of action of mutation which pleiotropically affect several genetically and biochemically distinct amino acid transport systems.

Amino Acids↗
PubMed1992

[Frequency of non-disjunction and loss of sex chromosomes in oogenesis in the Drosophila melanogaster mutant I(1) ts 403 with a defect in the heat-shock protein system in anoxia and at high temperature].

A unique property of Drosophila melanogaster l(1)ts403 strain with the defect in heat shock protein system (HSP) is high frequency of losses and non-disjunction of sex chromosomes induced by heat shock (HS) (37 degrees C, 1 h). This effect was shown in only 6-14-th stages of oocytes. Anoxia was not effective in induction of these mutations. Successive action of anoxia and HS decreased loss frequency and non-disjunction in comparison with the only action of HS. These findings agree with the data in literature indicating that HSP synthesis was increased in the l(1)ts403 mutant when first anoxia and then HS were administered, in contrast to the action of HS only. The role of HSP in the recovery of HS-induced disruptions (chromosomal proteins and meiotic division apparatus) which can lead to chromosome non-disjunction and losses is discussed.

Animals↗
PubMed1996

Oncogenic role of heterotrimeric G proteins.

Mutations that constitutively activate the alpha chains of Gs and Gi2 by inhibiting their intrinsic GTPase activity are present in human endocrine tumours. The gsp oncogene is mainly found in pituitary GH secreting tumours and thyroid hyperfunctioning adenomas, where it induces a constitutive activation of the adenylyl cyclase-cAMP pathway. In pituitary and thyroid cells, this signal leads to abnormal proliferation and a persistent activation of differentiated functions. The gip2 oncogene has been identified in tumours of the ovary and adrenal cortex. Although the mechanisms of the oncogenic action of mutationally activated alpha i2 are less clear than those of alpha s, the protein can induce transformation of certain cell types. At least five other alpha chains, which share with alpha s and alpha i2 common structural and functional mechanisms of GTP hydrolysis, activate mitogenic pathways leading to transformation. In addition, the G protein beta gamma subunits clearly control signals involved in cell growth. So far, there is no evidence for mutations of these molecules in human tumours. Further studies will tell us whether at present we know of only two members of a much larger family of G protein oncogenes.

Adenylyl Cyclases↗
PubMed2005

A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis.

CONTEXT: Tumoral calcinosis is a disease characterized by ectopic calcification and hyperphosphatemia due to enhanced renal tubular phosphate reabsorption. Fibroblast growth factor (FGF)23 was identified as a responsible factor in hypophosphatemic diseases caused by renal phosphate leak. OBJECTIVE: The objective of the study was to analyze the involvement of FGF23 in the development of tumoral calcinosis. DESIGN: Serum FGF23 level was evaluated in a patient with tumoral calcinosis by two kinds of ELISA: full-length assay that detects only full-length FGF23 with phosphate-lowering activity and C-terminal assay that measures full-length as well as C-terminal fragment of FGF23. FGF23 gene was analyzed by direct sequencing of PCR products, and mutant FGF23 was analyzed by Western blotting after expression in mammalian cells. PATIENTS: A family of tumoral calcinosis patients were studied. RESULTS: Serum FGF23 was extremely high when measured by C-terminal assay. In contrast, it was low normal by full-length assay. Analysis of FGF23 gene detected a serine to phenylalanine mutation in codon 129. No wild-type allele of this codon was found in the patient. The brother of the proband showed the same base change. When this mutant FGF23 was expressed in vitro, full-length and N-terminal fragments were barely detectable by Western blotting, whereas C-terminal fragment with the same molecular weight as that from wild-type FGF23 could be detected. CONCLUSION: The production and serum level of C-terminal fragment of FGF23 are increased in this patient with tumoral calcinosis. Together with the recent similar report of FGF23 mutation, impaired action of full-length FGF23 seems to result in tumoral calcinosis.

Adult↗
PubMed2006

Does the mitochondrial genome play a role in the etiology of Alzheimer's disease?

We report here the analyses of complete mtDNA coding region sequences from more than 270 Alzheimer's disease (AD) patients and normal controls to determine if inherited mtDNA mutations contribute to the etiology of AD. The AD patients and normal individuals were carefully screened and drawn from two populations of European descent in an effort to avoid spurious effects due to local population anomalies. Overall, there were no significant haplogroup associations in the combined AD and normal control sequence sets. Reduced median network analysis revealed that the AD mtDNA sequences contained a higher number of substitutions in tRNA genes, and that there was an elevated frequency of replacement substitutions in the complex I genes of the control sequences. Analysis of the replacement substitutions indicated that those arising in the AD mtDNAs were no more deleterious, on average, than those in the control mtDNAs. The only evidence for the synergistic action of mutations was the presence of both a rare non-conservative replacement substitution and a tRNA mutation in 2 AD mtDNAs, from a total of 145, whereas such a combination of mutations was not observed in the control sequences. Overall, the results reported here indicate that pathogenic inherited mtDNA mutations do not constitute a major etiological factor in sporadic AD. At most, a small proportion of AD patients carry a pathogenic mtDNA mutation and a small proportion of cognitively normal aged individuals carry a mtDNA mutation that reduces the risk of AD.

Aged, 80 and over↗
PubMedDate not supplied

The phenotypic diversity of monogenic disease: lessons from the thalassemias.

Clearly, the thalassemias are associated with a remarkably diverse series of phenotypes. Much of this heterogeneity can be explained at the molecular level by variability of the primary mutation of the beta globin genes, and the effects of genetic variability at two other loci, that is the alpha and gamma gene loci. When all these factors are taken into consideration there still remains a considerable amount of phenotypic diversity that is not explainable in this way. It is becoming clear that there is potential for further diversity at unrelated loci that may modify the major complications of the disease. And there is yet another layer of potential genetic variability that reflects the way in which these diseases have come under intense selection by malaria over a relatively short period of time. Finally, there are many environmental and cultural factors that may modify a patient's reaction to the disease. It is apparent, therefore, that this group of monogenic diseases are highly diverse and that, although much of this heterogeneity can be ascribed to the action of one or two major modifying loci, phenotypic variability also reflects the action of even further genetic diversity stemming from the way this disease has spread and its evolutionary background. It is apparent, therefore, that when we start to dissect disease due to the action of multiple loci, together with a major environmental component, the situation will be infinitely more complex. Of course this should not stop us from attempting to isolate the major genes involved, but it is telling us that we should be very careful about making assumptions that we will be able accurately to predict phenotypes from genotypes; although we have made considerable progress toward this end for the thalassemias, even here we have to deal with a large number of genetic and environmental factors that may modify the primary action of mutations of the beta globin genes. It is issues of this kind that will set the limit on our current reductionist approach to the study of human disease and will make it all the more important that we develop a more holistic way of analyzing disease processes in the future.

Alleles↗
PubMed2006

[Use of homeotic mutation tasselseed2 for investigation of the action of maize meiotic genes during micro- and megasporogenesis].

The manifestation of the ms43 maize meiotic mutation in the megasporogenesis of ts2 ms43 double mutants has been studied. Combined genetical and cytological analysis of the progeny of diheterozygote selfing showed that the ms43 mei gene was not microsporogenesis-specific. The manifestation of ms43 in megasporogenesis of the double mutants proved to be affected by the ts2 mutation. It prevented formation of the phenotype characteristic of ms43 and distorted early developmental stages of the entire ovule. It is the first study of megasporogenesis in tasselseed2 mutant tassels. Cytological data on the afd1 mutation in single and double mutants are presented. Possible mechanisms of the interaction between the ms43 and ts2 mutations are discussed.

Gametogenesis↗
PubMed1980

Genetic analysis of the relationships between the cell surface and the nuclei in Paramecium tetraurella.

In Paramecium tetraurelia, a number of mutations have been shown to affect simultaneously cortical organization (attachment of trichocysts to the cortex) and nuclear divisions (Ruiz et al. 1976). In order to analyze the genetic and physiological basis of this correlation, and we have isolated new mutations affecting the properties of the trichocysts and studied their genetic relationships with other previously known mutations. Of 24 to 28 loci controlling the biogenesis and properties of the trichocysts, mutations only in the 16 to 20 loci tht control trichocysts attachment to the cortex result in nuclear defects. Cytological observations show that all these mutants display the same set of nucler abnormalities: in particular, rounded shape of the resting macronucleus mispositioning and defective elongation of the dividing macronucleus and unequal repartition of the marco- and micronuclei. This common syndrome is independent of both the mutagenic origin and the mutated locus. Furthermore, by microinjection, it is possible to localize the site of action of the mutations in either the trichocyst compartment or the nontrichocyst compartment. It was found by this technique that the nuclear syndrome is also independent of the site of action of the mutation. All the genetic and physiological data support the conclusion that the nuclear defects are the consequence of the lack of trichocyst attachement to the cortex: in wild-type cells, trichocyst attachment would induce a membranar or perimembranar state necessary for correct nuclear positioning during cell division. In the absence of trichocyst attachment, the cortical control of nuclear division would be abolished. The possible involvement of cytoskeletal links between surface and nuclei is discussed.

Animals↗
PubMed1996

Genomic organization of the human SCN5A gene encoding the cardiac sodium channel.

The voltage-gated cardiac sodium channel, SCN5A, is responsible for the initial upstroke of the action potential. Mutations in the human SCN5A gene cause susceptibility to cardiac arrhythmias and sudden death in the long QT syndrome (LQT). In this report we characterize the genomic structure of SCN5A. SCN5A consists of 28 exons spanning approximately 80 kb on chromosome 3p21. We describe the sequences of all intron/exon boundaries and a dinucleotide repeat polymorphism in intron 16. Oligonucleotide primers based on exon-flanking sequences amplify all SCN5A exons by PCR. This work establishes the complete genomic organization of SCN5A and will enable high-resolution analyses of this locus for mutations associated with LQT and other phenotypes for which SCN5A may be a candidate gene.

Amino Acid Sequence↗
PubMed1993

Retroviruses, apoptosis and autogenes.

Autoimmunity and autoimmune disease are not the same. Autoimmunity is a normal consequence of aging, potentially reversible and possibly physiological. Autoimmune disease is dependent on genetic, viral, hormonal and psychoneuroimmunological factors. Aside from the apparently normal regulation of autoimmune responses by immune response genes, little is known about other genetic factors. Here, Norman Talal and John Mountz propose the term autogene to describe non-MHC genes which directly or indirectly interfere with important immunoregulatory actions. When mutated or otherwise genetically altered (e.g. by retrotransposon insertion), these genes predispose to immune dysregulation, lymphoproliferation and autoimmunity.

Animals↗
PubMed2004

Pharmacogenetics and psychopharmacology.

Genetic factors play a major role in the differential responses to treatment or the incidence of adverse drug effects in psychopharmacotherapy. The aim of pharmacogenetics is to elucidate this variability caused by hereditary differences. From hypotheses on the mechanisms of drug action, several mutations in genes coding for neurotransmitter receptors, neurotransmitter-degrading enzymes, transport proteins or enzymes of the drug metabolizing system have been identified and investigated. Although there exists some controversy among the results, many studies are supportive of the hypothesis that psychopharmacogenetics will be helpful in predicting an individual's drug response while minimizing the rate of side effects. The inclusion of functional genomics, which investigates the complex gene and/or protein expression in response to a given drug, could help lead to the development of novel and safer drugs.

Drug Therapy↗
PubMed2001

Impact of aging on stress-responsive neuroendocrine systems.

Throughout life organisms are challenged with various physiological and psychological stressors, and the ability to handle these stressors can have profound effects on the overall health of the organism. In mammals, the effects of stressors on the aging process and age-related diseases are complex, involving the nervous, endocrine and immune systems. Certain types of mild stress, such as caloric restriction, may extend lifespan and reduce the risk of diseases, whereas some types of psychosocial stress are clearly detrimental. We now have a basic understanding of the brain regions involved in stress responses, their neuroanatomical connections with neuroendocrine pathways, and the neuropeptides and hormones involved in controlling responses of different organ systems to stress. Not surprisingly, brain regions involved in learning and memory and emotion play prominent roles in stress responses, and monoaminergic and glutamatergic synapses play particularly important roles in transducing stressful sensory inputs into neuroendocrine responses. Among the neuropeptides involved in stress responses, corticotropin-releasing hormone appears to be a pivotal regulator of fear and anxiety responses. This neuropeptide is responsible for activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is critical for mobilizing energy reserves and immune responses, and improper regulation of the HPA axis mediates many of the adverse effects of chronic physical and psychosocial stress. In the brain, for instance, stress may contribute to disease processes by causing imbalances in cellular energy metabolism and ion homeostasis, and by inhibiting neuroprotective signaling pathways. There is considerable evidence that normal aging impacts upon neuroendocrine stress responses, and studies of the molecular and cellular mechanisms underlying the pathogenic actions of mutations that cause age-related neurological disorders, such as Alzheimer's disease, are revealing novel insight into the involvement of perturbed neuroendocrine stress responses in these disorders.

Aging↗
PubMed1993

Self-esteem and counterfactual thinking.

Two studies examined the relation between self-esteem and counterfactual thinking (consideration of "might-have-been" alternatives to reality). Ss imagined themselves in scenarios with another actor that resulted in either success or failure. Ss then "undid" the outcome by altering events that preceded the outcome. Following success, high self-esteem (HSE) Ss were more likely than low self-esteem (LSE) Ss to mutate their own actions. Following failure, LSE Ss were more likely than HSE Ss to mutate their own actions. Also, the structure of counterfactuals was influenced by outcome valence but not by self-esteem: Subtractive structures (in which antecedents are removed) were elicited by success, whereas additive structures (in which antecedents are added) were elicited by failure. The importance of the self and individual differences in self-esteem to counterfactual thinking is discussed.

Adult↗
PubMedDate not supplied

Cell-autonomous action of zebrafish spt-1 mutation in specific mesodermal precursors.

In zebrafish, as in Xenopus, the well-orchestrated cell movements of gastrulation can be dissected into several components, including epiboly, involution, convergence and extension. Embryos homozygous for the recessive lethal mutation spt-1(b104) or 'spadetail' have a complex set of defects in the trunk of the embryo that may arise secondarily after loss of one of these movements, convergence, from those precursors that would normally have given rise to trunk somitic mesoderm. We have now tested this hypothesis by transplanting cells between wild-type and mutant embryos, to identify the cells that spt-1 affects directly. Our results show that the mutation autonomously affects only those mesodermal precursors located along the lateral margin of the early gastrula blastoderm. Other mesodermal cells and all ectodermal precursors seem not to require function of the wild-type gene. Our findings reveal an unexpectedly delicate genetic control of vertebrate gastrulation.

Animals↗
PubMed2002

Haplotype and linkage disequilibrium analysis to characterise a region in the calcium channel gene CACNA1A associated with idiopathic generalised epilepsy.

Idiopathic generalised epilepsy (IGE) is a common form of epilepsy, including several defined and overlapping syndromes, and likely to be due to the combined actions of mutations in several genes. In a recent study we investigated the calcium channel gene CACNA1A for involvement in IGE, unselected for syndrome, by means of association studies using several polymorphisms within the gene. We reported a highly significant case/control association with a silent single nucleotide polymorphism (SNP) in exon 8 that we confirmed by within-family analyses. In this present study we screened the gene for novel SNPs within 25 kb of exon 8, which have enabled us to define the critical region of CACNA1A in predisposing to IGE. Several intronic SNPs were identified and three, within 1.5 kb of exon 8 and in strong linkage disequilibrium with each other and with the original SNP, were significantly associated with IGE (P=0.00029, P=0.0015 and P=0.010). The associations were not limited to an IGE syndrome or other subgroup. Another SNP, 25 kb away, in intron 6 was also significantly associated with IGE (P=0.0057) but is not in linkage disequilibrium with the SNPs around exon 8. Haplotype predictions revealed even more significant associations (3-marker haplotype: P<10(-6)). Logistic regression showed that all the data can be explained by two of the SNPs, which is consistent with two functionally significant variants being responsible for all five associations, although a single variant cannot be excluded. The functionally significant variant(s) are unlikely to be exonic and suggests an effect on expression or alternative splicing.

Adolescent↗
PubMed2000

Complementation of physiological and behavioral defects by a slowpoke Ca(2+) -activated K(+) channel transgene.

The Drosophila slowpoke gene encodes a large conductance calcium-activated potassium channel used in neurons, muscle, and some epithelial cells. Tissue-specific transcriptional promoters and alternative mRNA splicing generate a large array of transcripts. These distinct transcripts are thought to tailor the properties of the channel to the requirements of the cell. Presumably, a single splice variant cannot satisfy the specific needs of all cell types. To test this, we examined whether a single slowpoke splice variant was capable of complementing all slowpoke behavioral phenotypes. Null mutations in slowpoke cause animals to be semiflightless and to manifest an inducible "sticky-feet" phenotype. The well-characterized slowpoke transcriptional control region was used to direct the expression of a single slowpoke splice variant (cDNA H13) in transgenic flies. The endogenous gene in these flies had been inactivated by the slo(4) mutation. Action-potential recordings and voltage-clamp recordings demonstrated the production of functional channels from the transgene. The transgene completely complemented the flight defect, but not the sticky-feet phenotype. We conclude that distinct slowpoke channel isoforms, produced by alternative splicing, are not interchangeable and are required for proper function of different cell types.

Action Potentials↗