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PubMed1991

Kinds and locations of mutations arising spontaneously in the coding region of the HPRT gene of finite-life-span diploid human fibroblasts.

Spontaneous thioguanine-resistant mutants were derived from populations of finite-life-span, diploid human fibroblasts by means of a fluctuation analysis. cDNA was prepared from mutant HPRT mRNA and amplified by the polymerase chain reaction, and the sequence of the product was analyzed. Exon deletions, which very likely arose from mutations in the intron splice site consensus sequences, were found in 10 of the 37 mutants examined (27% of the total). Among the 28 mutations in the coding sequence, base pair substitutions predominated (89%). With the exception of one base pair involved in a tandem mutation, all base pair substitutions resulted in alterations in the predicted amino acid sequence of the protein. In addition there were three frameshift mutations, consisting of the deletion of one or two base pairs. Although mutations occurred throughout the coding sequence, 50% (14/28) were found in the 5' portion of exon 3.

Base Sequence↗

PubMed1999

Novel exon skipping mutation in the fibrillin-1 gene: two 'hot spots' for the neonatal Marfan syndrome.

The Marfan syndrome is an autosomal dominant heritable disorder of connective tissue that involves principally the skeletal, ocular, and cardiovascular systems. The most severe end of the phenotypic spectrum, the neonatal Marfan syndrome (nMFS), is characterized by pronounced atrioventricular valve dysfunction, and death often occurs within the first year of life due to congestive heart failure. Mutations in the gene coding for fibrillin-1, FBN1, are known to cause Marfan syndrome, and have been identified in almost all exons of FBN1. Here, we describe a novel mutation affecting the invariant + 1 position of the splice donor site in intron 31, associated with skipping of exon 31, in a patient with nMFS. Published reports of nMFS are reviewed and a strict definition for nMFS is suggested. If this definition is used, all nMFS mutations reported to date lie in one of two hot spots, comprising mainly missense mutations in FBN1 exons 24-27 and mutations causing skipping of exon 31 or 32.

Exons↗

PubMed1995

Growth hormone binding to a circulating receptor fragment--the concept of receptor shedding and receptor splicing.

Recent advances in the understanding of circulating growth hormone binding proteins (GHBP) are reviewed. The high affinity GHBP represents the ectodomain of the GH receptor (GHR); it is either cleaved from membrane-bound GHRs (man, rabbit) or derived from an alternatively spliced GHR mRNA (rodents). Another circulating GHBP, of low affinity and not GHR-related, is only partially characterized. The GHBPs complex about half of the GH in human plasma. They act as a buffer regulating free and bound GH, prolong GH half-life, and modulate GH bioactivity through competition with GHRs for ligand. The plasma levels of both GHBPs are developmentally upregulated during childhood and remain relatively constant thereafter. Different species vary in their regulation of GHBP, with sexual dimorphism and large pregnancy-related changes in some but not all species. A variety of conditions associated with altered GH responsivity (resistance or hypersensitivity) are attended by altered levels of the high affinity GHBP. Generally, GH resistance is characterized by decreased GHBP levels, and the converse is true in GH hypersensitivity such as in obesity. It has been postulated that the plasma GHBP level reflects tissue concentrations of the GHR, but this remains to be proven. The high affinity GHBP appears to be positively, though imperfectly, linked to GH action. Soluble receptor isoforms analogous to the GHBP have been demonstrated for several members of the cytokine receptor family to which the GHR belongs. The ultimate biological role of these circulating receptor ectodomains remains to be fully defined.

Adult↗

PubMed1984

100 patient-years of ambulatory home total parenteral nutrition.

More than 100 patient-years' experience has been acquired in the treatment of 133 patients with ambulatory home total parenteral nutrition (TPN) between May 1974 and December 1983. Indications for chronic or permanent home TPN include short bowel syndrome, malabsorption, scleroderma, and vasoactive intestinal polypeptide syndrome. Indications for acute or temporary home TPN include Crohn's disease, malignancies, gastrointestinal fistulas, ulcerative colitis, anorexia nervosa, and numerous other disorders. Eighty-two patients in the acute group were treated primarily with percutaneously placed standard subclavian catheters and 51 patients in the chronic group have been treated thus far with implanted silicone rubber, Dacron-cuffed catheters for a cumulative total of 38,939 patient days. Of the 125 implanted catheters, 115 were placed in the superior vena cava and ten in the inferior vena cava for an average duration of 250 catheter-days, the longest single catheter remaining in situ for more than 8 1/2 years. Catheter-related sepsis occurred 33 times with the implanted catheters, or once every 2.6 catheter-years. One hundred and fourteen temporary catheters were placed percutaneously in the superior vena cava via a subclavian vein for an average duration of 68 days, the longest single catheter remaining in situ for 213 days. Catheter-related sepsis occurred seven times, equivalent to one episode per 3 catheter-years. Total catheter-related complications were quite infrequent and were directly related to duration of catheterization. They included venous thrombosis (12), clotted catheter (11), catheter failure or rupture (8), catheter compression (5) and inadvertent catheter removal (4). Twenty-six catheters were repaired or spliced in situ when the external segment was accidentally damaged or deteriorated secondary to long-term material fatigue. One remarkable patient has been maintained exclusively by TPN originally as an inpatient and subsequently as an outpatient for the entire 13 years of his life.

Adolescent↗

PubMed1992

Ontogeny of gonadotropin action in the rat ovary.

Specific binding of radiolabelled FSH and LH to rat ovaries was demonstrated at the age of 7 days. However, when the biological response to LH and FSH was monitored by cAMP production in vitro, the FSH response appeared earlier than that of LH, on days 4 and 7, respectively. Cholera toxin stimulated cAMP production even in fetal ovaries, suggesting the presence of functional post-receptor machinery of cAMP production. Hence, the appearance of the functional gonadotropin receptor probably plays a key role in the onset of postnatal ovarian steroidogenesis. To test the effect of gonadotropin suppression during postnatal ovarian development, a potent GnRH antagonist was administered to neonatal animals between days 1-6 or 1-9 of life. The ovarian responsiveness to FSH developed even in the absence of normal gonadotropin levels, but that to LH was suppressed after the longer antagonist treatment. The temporal relationship between the onset of LHR gene expression, i.e. transcription, and translation to functional receptor protein was thereafter investigated using the reverse transcriptase-polymerase chain reaction (RT-PCR) technique. The measurements revealed the existence only of truncated versions of LHR mRNA in the fetal ovary from day 17 of gestation up to day 7 of postnatal life. With the onset of the receptor function around day 7, also larger mRNA transcripts, corresponding to the full-length receptor protein appeared. Our findings suggest that the LHR gene may be constitutively expressed in the ovary and a change in the alternative splicing pattern may cause the onset of translation of a functional receptor protein.

Animals↗

PubMed2004

Exon skipping of cathepsin B: mitochondrial targeting of a lysosomal peptidase provokes cell death.

The alternatively spliced messenger RNA of the human cysteine peptidase cathepsin B missing exons 2 and 3 encodes a truncated form of the enzyme lacking the signal peptide and part of the inhibitory propeptide. This deletion results in a new N-terminal leader sequence characteristic of proteins predestined for transport into mitochondria. We determined enzyme targeting to intracellular organelles by transfecting HeLa cells with constructs containing segments of variable length of the N terminus of truncated cathepsin B fused to green fluorescent protein. Co-localization of the constructs with mitochondria and the endoplasmic reticulum was probed with specific markers. None of the chimeric products were found in the endoplasmic reticulum, showing that truncated cathepsin B is misrouted from its regular biosynthetic pathway and forced to enter the mitochondria instead of lysosomes as its final destination. The first 20 amino acids of the new N terminus were necessary and sufficient for mitochondrial targeting, but only cells expressing the complete truncated cathepsin B sequence died by nuclear fragmentation. This new and unexpected behavior draws attention to an additional extralysosomal role for a cysteine peptidase with several recognized important pathophysiological functions. Mitochondrial targeting of cathepsin B may have significant consequences on cell life in pathological or physiological situations characterized by excessive transcription of the cathepsin B message lacking exons 2 and 3, as observed for instance in osteoarthritic cartilage.

Alternative Splicing↗

PubMed2006

Novel HESX1 mutations associated with a life-threatening neonatal phenotype, pituitary aplasia, but normally located posterior pituitary and no optic nerve abnormalities.

CONTEXT: Hesx1 is one of the earliest homeodomain transcription factors expressed during pituitary development. Very few HESX1 mutations have been identified in humans; although in those cases the disease phenotype shows considerable variability, all but one of the patients display an ectopic posterior pituitary and/or optic nerve abnormalities. OBJECTIVE: The objectives of the study were to describe the complex phenotype associated with the panhypopituitarism of two unrelated Italian patients who, at birth, presented with hypoglycemic seizures and respiratory distress complicated by shock, in a familial context of neonatal death in one family and spontaneous miscarriage in both families and to identify the molecular basis of this unusual syndrome. MAIN OUTCOME MEASURES: Magnetic resonance imaging of the pituitary region, study of HESX1 gene and transcripts, and assessment of the ability of mutated HESX1 proteins to repress transcription were measured. RESULTS: Magnetic resonance imaging examination showed an anterior pituitary aplasia in a flat sella turcica and a normally located posterior pituitary in both patients. A constellation of extrapituitary developmental defects were found in the two patients, but without any optic nerve abnormalities. Sequencing of HESX1 exons and their flanking intronic regions revealed two different homozygous mutations. A frameshift (c.449_450delAC) was identified in one case, whereas the other patient carried a splice defect (c.357 + 2Tb > C) confirmed by the study of HESX1 transcripts. If translated, these mutations would lead to the synthesis of truncated proteins partly or entirely lacking the homeodomain, with no transcriptional repression, as shown by their inability to inhibit PROP1 activity. CONCLUSIONS: These observations reveal two novel HESX1 mutations in a so-far-undescribed disease phenotype characterized by a life-threatening neonatal condition associated with anterior pituitary aplasia, in the absence of ectopic posterior pituitary and optic nerve abnormalities, two features classically associated with HESX1 defects.

Cells, Cultured↗

PubMed2001

Carbamoyl phosphate synthetase I deficiency: molecular genetic findings and prenatal diagnosis.

We report a Japanese boy who died at Day 28 of life because of severe carbamoyl phosphate synthetase I (CPS1) deficiency that was proven by enzyme assay. By analysis of cDNA and genomic DNA, he was shown to be a compound heterozygote with two point mutations of the CPS1 gene, 840G>C leading to an aberrant splicing and 1123C>T (predicting Q375X). The 840G>C was a mutation described in another Japanese family. Since his parents carried each mutation heterozygously, we performed prenatal diagnosis at 16 weeks of his mother's next gestation by multiplex PCR and melting curve analysis in a single capillary containing two-color fluorescent (LC-Red 640 and LC-Red 705) probes on LightCycler. We analyzed genomic DNA extracted from amniotic cells and found that the fetus was homozygous for the wild-type alleles. At term a healthy girl was born without hyperammonemia.

Carbamoyl-Phosphate Synthase I Deficiency Disease↗

PubMed1996

Production and characterization of high-titer stocks of rev-defective HIV-1.

High-titer stocks of rev-defective HIV-1 virions have been produced and characterized. To produce these stocks, CEM cells transduced with a murine retroviral vector that expresses Rev were used to support the growth of an HIV-1 genome containing four inactivating mutations in the rev gene. The resulting viral stocks were of high-titer when used to infect CEM cells that expressed Rev, but had no measurable titer when used to infect parental CEM cells; replication-competent virus was not detected. As expected, these rev-defective viruses established early gene expression in parental CEM cells as demonstrated by the accumulation of viral mRNAs and Nef protein. The expression of late genes was impaired as demonstrated by the inability of these viruses to direct the accumulation of singly spliced mRNA or p24 antigen. These defective viruses did not interfere with replication of the wild-type virus, although they were produced at low levels during coinfection experiments. This experimental system may be useful for the study of early events during the HIV-1 life cycle. In addition, this system represents a simple method of gene transfer into CD4-positive cells using replication-defective but transcriptionally active HIV-1.

Base Sequence↗

PubMed1997

Overexpression of the FosB2 gene in thymocytes causes aberrant development of T cells and thymic epithelial cells.

We have examined the role of the AP-1 transcription factor on thymocyte maturation and thymus architecture by overexpressing FosB2 in transgenic mice. FosB2 is a naturally occurring splice variant of the FosB2 gene, encoding a truncated protein which lacks two domains necessary for transcriptional activation. The expression of FosB2 in the thymocytes severely affected their maturation and the structure of the whole thymus: the phenotype developed slowly during the first months of life, resulting in a progressive expansion of the medulla and concomitant reduction of the cortex. CD4+ thymocytes represented the major thymocyte population, whereas the CD4+ 8+ thymocytes were virtually absent. This phenotype appeared to be an intrinsic property of bone marrow derived cells, as it could be reproduced in bone marrow chimaeric mice. This pathology was very reminiscent to that observed in mice overexpressing c-Fos in thymic epithelium: also in that case the thymus underwent with age a progressive expansion of the epithelium and major changes in the ratio of thymocyte subsets, but the phenotype appeared to be an intrinsic property of the epithelial cells since it could not be reproduced by transgenic bone marrow transplantation. We speculate that both overexpression of FosB2 in thymocytes and overexpression of c-Fos in thymic epithelium results in aberrant signaling between thymocytes and stroma, that ultimately alters the thymic micromilieu, leading to this severe pathology.

Age Factors↗

PubMed1986

The trypanosome spliced leader small RNA gene family: stage-specific modification of one of several similar dispersed genes.

Diverse mRNAs of Trypanosoma brucei possess the same 5' terminal 35 nucleotides, termed the spliced leader (SL), which appears to be derived from a separate 135 nucleotide transcript. This small SL RNA is encoded within a 1.4 kb unit of DNA which is tandemly reiterated in the genome. In addition, there are at least 4 orphon elements containing SL sequences dispersed from the tandem array. Here we show that during the trypanosome life cycle one of the SL orphons undergoes a stage-specific modification that prevents cleavage of an EcoRV site and we further demonstrate that although only one orphon is modified, three of the SL orphons are flanked by very similar sequences. Each of these contains SL reiteration units including the non-transcribed spacer DNA, suggesting that they did not originate through an RNA intermediate. In addition no evidence of direct repeats at the junction of 1.4 kb and non-1.4 kb DNA was observed. Finally, a phylogenetic survey indicates that while many trypanosomatid species possess similarly organized SL-like sequences, only the SL orphons of closely related subspecies of the T. brucei - T. evansi complex share similar flanking regions.

Animals↗

PubMed1996

A unique U5-->A substitution in the Physarum polycephalum U1 snRNA: evidence at the RNA and gene levels.

The 5' terminal sequence of U1 snRNA that base-pairs with the intron 5' splice site in the course of spliceosome assembly was considered to be universally conserved. A study of the P polycephalum U1 snRNA at both RNA and gene levels shows that there are exceptions to this rule: the P polycephalum U1 snRNA has a U to A substitution at position 5, that is partially compensated by a high frequency of T residue at position +4 of introns. In contrast to the yeast genome, the P polycephalum genome contains several U1 snRNA coding sequences (about 20). They either encode the U1A snRNA expressed in microplasmodia or correspond to the previously cloned U1B coding sequence. Both coding sequences show the U5A substitution. The ratio of U1A versus U1B coding sequences is of about 3. A U1A gene was cloned. The 60 nt region upstream of the coding sequence has the same sequence as in the U1B gene. The U1B gene is probably expressed at another stage of the P polycephalum life cycle.

Amino Acid Sequence↗

PubMedDate not supplied

Propionic acidemia: mutation update and functional and structural effects of the variant alleles.

Mutations in the PCCA or PCCB genes, encoding both subunits of propionyl-CoA carboxylase, result in propionic acidemia, a life-threatening inborn error of metabolism with autosomal recessive inheritance. To date, 41 mutations in the PCCA gene and 54 in the PCCB gene have been reported, most of them single base substitutions causing amino acid replacements, and a variety of small insertions and deletions and splicing defects. A greater heterogeneity is observed in the PCCA gene, specially in Caucasians, with no prevalent mutations, while in the Japanese population three mutations account for more than half of the alleles studied. For the PCCB gene a limited number of mutations is responsible for the majority of the alleles characterized in both Caucasian and Oriental populations. These two populations show a different mutational spectrum, only sharing some involving CpG dinucleotides probably as recurrent mutational events. Functional characterization of the mutant missense alleles has been accomplished using different prokaryotic and eukaryotic systems, and the structural consequences have been analyzed in the available crystal models. For the PCCA gene, the main molecular effect of the expressed mutations is related to protein instability, except two mutations in the active site predictably affecting ATP binding. In the PCCB gene the majority of the analyzed mutations are predicted to alter the active site conformation resulting in diminished activity. A few carboxy-terminal PCCB mutations affect the interaction between subunits and the assembly with PCCA to form a functional PCC oligomer. The amount of normal transcripts resulting from some PCCA and PCCB splicing mutations has also been analyzed. Overall, the data generated from the expression analysis reveal potential genotype-phenotype correlations for this clinically heterogeneous disorder.

Alleles↗

PubMedDate not supplied

Mutations in exon 14 of dihydropyrimidine dehydrogenase and 5-Fluorouracil toxicity in Portuguese colorectal cancer patients.

PURPOSE: Dihydropyrimidine dehydrogenase is a critical enzyme in the catabolism of 5-Fluorouracil, a drug frequently used in cancer therapy. Patients with deficient dihydropyrimidine dehydrogenase activity are at risk of developing severe 5-Fluorouracil-associated toxicity. Genetic analysis of the gene coding for dihydropyrimidine dehydrogenase has shown that mutations in exon 14, especially the splice-site mutation IVS14+1G-->A, were associated with dihydropyrimidine dehydrogenase enzymatic deficiency. METHODS: We evaluated the frequency of mutations in exon 14 of dihydropyrimidine dehydrogenase (DPYD) gene in 73 unselected colorectal cancer patients treated with 5-Fluorouracil after surgery at a Portuguese Cancer Institute. RESULTS: Sequencing the entire exon 14 allowed the detection of mutations in two of the 73 patients (2.7%), namely two of the eight (25%) patients who presented grade 3-4 toxicity after 5-Fluorouracil chemotherapy. One patient was heterozygous for the splice-site mutation IVS14+1G-->A, whereas the second patient was heterozygous for a novel missense mutation 1845G-->T (E615D) in exon 14 of DPYD gene. CONCLUSION: We conclude that mutations in exon 14 of DPYD gene are responsible for a significant proportion of life-threatening toxicity to 5-Fluorouracil, and should therefore be excluded before its administration to cancer patients.

Adult↗

PubMed2006

Multiple, non-allelic, intein-coding sequences in eukaryotic RNA polymerase genes.

BACKGROUND: Inteins are self-splicing protein elements. They are translated as inserts within host proteins that excise themselves and ligate the flanking portions of the host protein (exteins) with a peptide bond. They are encoded as in-frame insertions within the genes for the host proteins. Inteins are found in all three domains of life and in viruses, but have a very sporadic distribution. Only a small number of intein coding sequences have been identified in eukaryotic nuclear genes, and all of these are from ascomycete or basidiomycete fungi. RESULTS: We identified seven intein coding sequences within nuclear genes coding for the second largest subunits of RNA polymerase. These sequences were found in diverse eukaryotes: one is in the second largest subunit of RNA polymerase I (RPA2) from the ascomycete fungus Phaeosphaeria nodorum, one is in the RNA polymerase III (RPC2) of the slime mould Dictyostelium discoideum and four intein coding sequences are in RNA polymerase II genes (RPB2), one each from the green alga Chlamydomonas reinhardtii, the zygomycete fungus Spiromyces aspiralis and the chytrid fungi Batrachochytrium dendrobatidis and Coelomomyces stegomyiae. The remaining intein coding sequence is in a viral relic embedded within the genome of the oomycete Phytophthora ramorum. The Chlamydomonas and Dictyostelium inteins are the first nuclear-encoded inteins found outside of the fungi. These new inteins represent a unique dataset: they are found in homologous proteins that form a paralogous group. Although these paralogues diverged early in eukaryotic evolution, their sequences can be aligned over most of their length. The inteins are inserted at multiple distinct sites, each of which corresponds to a highly conserved region of RNA polymerase. This dataset supports earlier work suggesting that inteins preferentially occur in highly conserved regions of their host proteins. CONCLUSION: The identification of these new inteins increases the known host range of intein sequences in eukaryotes, and provides fresh insights into their origins and evolution. We conclude that inteins are ancient eukaryote elements once found widely among microbial eukaryotes. They persist as rarities in the genomes of a sporadic array of microorganisms, occupying highly conserved sites in diverse proteins.

Alleles↗

PubMed2005

Expression of alternative transcripts of ferroportin-1 during human erythroid differentiation.

BACKGROUND AND OBJECTIVES: Ferroportin-1 (FPN1) is expressed in various types of cells that play critical roles in mammalian iron metabolism and appears to act as an iron exporter in these tissues. The aim of this study was to investigate whether erythroid cells possess specific mechanisms for iron export. DESIGN AND METHODS: The expression of FPN1 during human erythroid differentiation, the characterization of alternative transcripts, the modulation by iron and the subcellular localization of this protein were studied. RESULTS: FPN1 mRNA and protein are highly expressed during human erythroid differentiation. The iron-responsive element (IRE) in the 5'- untranslated region (UTR) of FPN1 mRNA is functional but, in spite of that, FPN1 protein expression, as well as mRNA level and half-life, seem not to be affected by iron. To explain these apparenthy discordant results we searched for alternative transcripts of FPN1 and found at least three different types of transcripts, displaying alternative 5' ends. Most of the FPN1 transcripts code for the canonical protein, but only half of them contain an IRE in the 5'-UTR and have the potential to be translationally regulated by iron. Expression analysis shows that alternative FPN1 transcripts are differentially expressed during erythroid differentiation. Finally, sustained expression of alternative FPN1 transcripts is apparently observed only in erythroid cells. INTERPRETATION AND CONCLUSIONS: This is the first report describing the presence of FPN1 in erythroid cells at all stages of differentiation, providing evidence that erythroid cells possess specific mechanisms of iron export. The existence of multiple FPN1 transcripts indicates a complex regulation of the FPN1 gene in erythroid cells.

5' Untranslated Regions↗

PubMed2006

The rise and falls of introns.

There has been a lively debate over the evolution of eukaryote introns: at what point in the tree of life did they appear and from where, and what has been their subsequent pattern of loss and gain? A diverse range of recent research papers is relevant to this debate, and it is timely to bring them together. The absence of introns that are not self-splicing in prokaryotes and several other lines of evidence suggest an ancient eukaryotic origin for these introns, and the subsequent gain and loss of introns appears to be an ongoing process in many organisms. Some introns are now functionally important and there have been suggestions that invoke natural selection for the ancient and recent gain of introns, but it is also possible that fixation and loss of introns can occur in the absence of positive selection.

Eukaryotic Cells↗

PubMed1991

A novel subpopulation of CD45RA+ CD4+ T cells expressing IL-2 receptor alpha-chain (CD25) and having a functionally transitional nature into memory cells.

Differential expression of various isoforms of leukocyte common antigen (CD45), which arises from alternate mRNA splicing, identifies naive and memory populations of human T cells. Some memory (CD45RO+ CD45RA-) populations of CD4+ T cells from adult individuals express IL-2 receptor (IL-2R) alpha-chain (CD25), but naive (CD45RO- CD45RA+) CD4+ T cells only do so to a small degree. We found that a small but significant fraction of CD4+ T cells in neonatal blood expressed CD25, although most generally exhibited the phenotype of naive cells. It was demonstrated that purified neonatal CD25+ CD4+ T cells expressed mRNA for the IL-2R alpha-chain. Two-color immunofluorescence analysis disclosed that a CD25+ population of neonatal CD4+ T cells had the naive (CD45RA+ CD45RO-) phenotypes. These CD25+ CD4+ T cells from newborns could express mRNA for some specified lymphokines such as IL-4, IL-5, and interferon-gamma on activation in a similar manner to CD45RO+ (memory) CD4+ T cells from adults. Notably, polymerase chain reaction analysis demonstrated that neonatal CD45RA+ CD4+ T cells expressing CD25 contained spliced mRNA transcripts possibly encoding CD45RO in addition to CD45RA-associated transcripts, seemingly indicating that this population might be in the recently antigen-primed states. Such a small population of CD45RA+ CD4+ T cells expressing CD25 appeared to be present in the blood throughout human life. The results suggest that CD4+ T cells with the naive (CD45RA+) phenotype expressing IL-2R alpha-chain (CD25) represent the novel transitional population in the maturation process of naive into memory CD4+ T cells.

Adult↗