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PubMed1998

Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations.

Blood samples from 125 unrelated families with classical type 2 neurofibromatosis (NF2) with bilateral vestibular schwannomas have been analysed for mutations in the NF2 gene. A further 17 families fulfilling modified criteria for NF2 have also been analysed. Causative mutations have been identified in 54 (43%) classical families and six (35%) of those fulfilling modified criteria. Forty-two cases from 38 families with truncating mutations had an average age at onset of symptoms of 19 years and diagnosis at 22.4 years. Fifty-one cases from 16 families with splice site mutations (15 from six), missense mutations (18 from six), and large deletions (18 from five) had an average age of onset of 27.8 years and at diagnosis of 33.4 years. Subjects with truncating mutations were significantly more likely to have symptoms before 20 years of age (p<0.001) and to develop at least two symptomatic CNS tumours in addition to vestibular schwannoma before 30 years (p<0.001). There were also significantly fewer multigenerational families with truncating mutations. Four further truncating mutations were in mosaic form and were associated with milder disease than other similar mutations. This large study has confirmed the previous impression that truncating mutations are associated with severe disease, but caution has to be exercised in using mutation type to predict disease course.

Adult↗
PubMed2003

Identification and functional analysis of truncated human glutamic acid decarboxylase 65.

Human brain glutamate decarboxylase 65 (hGAD65) was found to exist as full-length and truncated forms when the glutathione S-transferase-tagged hGAD65 fusion protein was subjected to factor Xa cleavage. The truncated form is produced by cleavage at arginine 69 based on N-terminal amino acid sequence analysis, and has a molecular weight of 58 kD. It is resistant to further factor Xa cleavage or mild trypsin treatment and is more active and more stable than the full-length form. Both the full-length and truncated forms of GAD are also observed in brain preparations in the presence of protease inhibitors. Furthermore, full-length GAD could be converted to the truncated form by endogenous proteases, suggesting that the conversion of full-length to truncated GAD mediated by endogenous protease may represent an important mechanism in the regulation of GABA biosynthesis in the brain.

Brain↗
PubMed2004

Morphological features of tail bud development in truncate mouse mutants.

A key malformation in the homozygous truncate mouse mutants is a partial lack of the notochord in the embryo tail. In order to analyze if tail bud development was affected by the truncate (tc) mutation, serial semithin sections of tails of the homozygous mutant embryos were compared to the wild-type controls. In the wild-type embryos morphologically uniform mesenchyme of the tail bud was continuous via the medullary cord to the secondary neural tube, and via the tail cord to the notochord and the gut. In truncate embryos the tail cord was not continuous to the notochord, but to the additional lumen of the tail gut resulting in tail gut duplication. Toward the base of the tail two tail guts subsequently fused together or the additional one disappeared. If present in the tip of the tail, the notochord in truncate embryos ended near the ventral border of the secondary neural tube. The rest of the tail notochord was fragmented and the posterior ends of the fragments were frequently adjacent or even continuous to the neural tube. We suggest that the improper regionalization of the tail bud, where notochord is associated with the neural tube rather than with the tail gut, is related to the subsequent segmental lack of the notochord in truncate mutants.

Animals↗
PubMed1996

Multicenter comparison of truncated biphasic shocks and standard damped sine wave monophasic shocks for transthoracic ventricular defibrillation. Transthoracic Investigators.

BACKGROUND: The most important factor for improving out-of-hospital ventricular fibrillation survival rates is early defibrillation. This can be achieved if small, lightweight, inexpensive automatic external defibrillators are widely disseminated. Because automatic external defibrillator size and cost are directly affected by defibrillation waveform shape and because of the favorable experience with truncated biphasic waveforms in implantable cardioverter-defibrillators, we compared the efficacy of a truncated biphasic waveform with that of a standard damped sine monophasic waveform for transthoracic defibrillation. METHODS AND RESULTS: The principal goal of this multicenter, prospective, randomized, blinded study was to compare the first-shock transthoracic defibrillation efficacy of a 130-J truncated biphasic waveform with that of a standard 200-J monophasic damped sine wave pulse using anterior thoracic pads in the course of implantable cardioverter-defibrillator testing. Pad-pad ECGs were also examined after transthoracic defibrillation. After the elimination of data for 24 patients who did not meet all protocol criteria, the results from 294 patients were analyzed. The 130-J truncated biphasic pulse and the 200-J damped sine wave monophasic pulse resulted in first-shock efficacy rates of 86% and 86%, respectively (P = .97). ST-segment levels measured 10 seconds after the shock in 151 patients in sinus rhythm were -0.26 +/- 1.58 and -1.86 +/- 1.93 mm for the 130- and 200-J shocks, respectively (P < .0001). CONCLUSIONS: We found that 130-J biphasic truncated transthoracic shocks defibrillate as well as the 200-J monophasic damped sine wave shocks that are traditionally used in standard transthoracic defibrillators and result in fewer ECG abnormalities after the shock.

Adolescent↗
PubMed2003

Impaired neutrophil maturation in truncated murine G-CSF receptor-transgenic mice.

Severe congenital neutropenia (SCN) is a hematopoietic disorder characterized by neutropenia in peripheral blood and maturation arrest of neutrophil precursors in bone marrow. Patients with SCN may evolve to have myelodysplastic syndrome or acute myelocytic leukemia. In approximately 20% of SCN cases, a truncation mutation is found in the cytoplasmic region of the granulocyte colony-stimulating factor receptor (G-CSFR). We then generated mice carrying murine wild-type G-CSFR and its mutants equivalent to truncations at amino acids 718 and 731 in human G-CSFR, those were reported to be related to leukemic transformation of SCN. Although numbers of peripheral white blood cells, red blood cells, and platelets did not differ among mutant and wild-type G-CSFR transgenic (Tg) mice, both of the mutant receptor Tg mice had one third of peripheral neutrophil cell counts compared with wild-type receptor Tg mice. The mutant receptor Tg mice also showed impaired resistance to the infection with Staphylococcus aureus. Moreover, bone marrow of these Tg mice had an increased percentage of immature myeloid cells, a feature of SCN. This maturation arrest was also observed in in vitro cultures of bone marrow cells of truncated G-CSFR Tg mice under G-CSF stimulation. In addition, clonal culture of bone marrow cells of the truncated G-CSFR Tg mice showed the hypersensitivity to G-CSF in myeloid progenitors. Our Tg mice may be useful in the analysis of the role of truncated G-CSFR in SCN pathobiology.

Acute Disease↗
PubMed1994

Transit time indices derived from forced expiratory spirograms: repeatability and criteria for curve selection and truncation.

Transit time analysis applied to spirograms truncated with respect to volume, not time, could be informative in population surveys. The present paper asks the questions: How does averaging several forced expirations affect the within subject variability at different levels of truncation? If only one spirogram is analysed, how should it be chosen? Are the results likely to be influenced by prior bronchodilation? The subjects were 46 men, selected by stratified random sampling from a shipyard population. Spirograms were obtained in quintuplicate, on two occasions, an average of nine days apart. Using the three "best" spirograms, transit time indices were calculated from average moments and from single curves selected in eight different ways; the analyses were performed on complete expirations, and after truncation by volume at levels between 75-99% of forced vital capacity (FVC), and by time (at 6 s). Indices from averaged moments were found to be more reproducible and yielded higher intra-class correlations than indices from single curves. Of the latter, the curve selected as having the largest forced vital capacity also yielded acceptable results. Prior inhalation of a bronchodilator aerosol did not reduce the variability. The averaging procedure is recommended for respiratory surveys of working men. For this application, the optimal level of truncation appeared to be by volume at 90% FVC, but on theoretical grounds truncation at 75 and 99% of FVC could also be informative.

Adult↗
PubMed1994

Persistent expression of a truncated form of the luteinizing hormone receptor messenger ribonucleic acid in the rat testis after selective Leydig cell destruction by ethylene dimethane sulfonate.

To correlate the process of ethylene dimethane sulfonate (EDS)-induced disappearance and repopulation of Leydig cells with LH receptor (LHR) expression, testicular messenger RNA (mRNA) and binding of LHR were analyzed in male rats, 5, 15, 20, and 40 days after treatment with 75 mg EDS/kg BW. Five and 15 days after EDS treatment, the serum testosterone level was reduced by 90% (P < 0.01) and testicular [125I]iodo-hCG binding was nearly undetectable (P < 0.01). Multiple splice variants of the LHR mRNA, with sizes of 6.8, 4.2, 2.7, and 1.8 kilobases, were detected in control testes upon Northern hybridization. Interestingly, 5 and 15 days after EDS injection, only the 1.8-kilobase band, previously reported to correspond to a truncated form of the LHR mRNA and encoding its extracellular part, remained, whereas the other mRNA species disappeared. On days 20 and 40 after EDS treatment, the pattern of hybridization gradually returned to that resembling the control pattern. To increase the sensitivity of mRNA detection, testicular RNA was reverse transcribed and amplified by polymerase chain reaction, using primers complementary to various parts of the LHR complementary DNA. The specificity of the complementary DNAs generated was verified by Southern hybridization with nested oligonucleotide primers. Five and 15 days after EDS treatment, only truncated mRNA forms, encoding regions of the extracellular part of the LHR, could be amplified. At 20 and 40 days, the pattern of amplification was similar to that in control testes, with amplification of the whole coding sequence. In situ hybridization was performed on day 5 after EDS treatment, when the interstitial space was devoid of morphologically discernible Leydig cells. An antisense complementary RNA probe, corresponding to the extracellular domain of the receptor, hybridized in the interstitial space to apparent precursor Leydig cells. Taken together, these results strongly suggest that the precursor Leydig cells, resistant to the cytotoxic action of EDS, express truncated forms of the LHR mRNA in the early stages of their differentiation. The full-length mRNA of LHR gradually appears when the functional Leydig cells recover and attain their differentiated functions. These data are analogous with our previous findings on testicular ontogeny; the fetal Leydig cell precursors constitutively express a truncated form of the LHR gene as well, and a similar change occurs in its alternative splicing during testicular maturation. Hence, the truncated form of the LHR mRNA is an early sign of Leydig cell differentiation, whether it occurs during ontogeny or in adulthood upon recovery from cytotoxic treatment.

Animals↗
PubMed2006

Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome.

BACKGROUND: Andermann syndrome (OMIM 218000) is an autosomal recessive motor-sensory neuropathy associated with developmental and neurodegenerative defects. The cerebral MRI reveals a variable degree of agenesis of the corpus callosum. Recently, truncating mutations of the KCC3 gene (also known as SLC12A6) have been associated with Andermann syndrome. METHODS: The authors assessed clinically and genetically three isolated cases from Germany and Turkey with symptoms consistent with Andermann syndrome. RESULTS: The authors detected four novel mutations within the KCC3 gene in their patients: two different truncating mutations in the first patient, a homozygous truncating mutation in the second, and a homozygous missense mutation in the third patient. In contrast to the classic phenotype of the Andermann syndrome linked to truncating KCC3 mutations the phenotype and the course of the disease linked to the missense mutation appeared to be different (i.e., showing additional features like diffuse and widespread white matter abnormalities). CONCLUSIONS: Not only truncating but also missense mutations of the KCC3 gene are associated with Andermann syndrome. Different types of KCC3 mutations may determine different clinical phenotypes.

Agenesis of Corpus Callosum↗
PubMed2004

Effects of truncation at the non-homologous region of a family 3 beta-glucosidase from Agrobacterium tumefaciens.

The function of the non-homologous region of a family 3 beta-glucosidase from Agrobacterium tumefaciens (Cbg1) was studied by analyzing the properties of mutant enzymes that have internal truncated amino acid sequences in the region. Five truncated mutants named Cbg1-d4, Cbg1-d31, Cbg1-d62, Cbg1-d89, and Cbg1-d119 having deletions of 4, 31, 62, 89, and 119 amino acid residues starting from Phe417, respectively, were expressed in Escherichia coli and purified. All the mutants exhibited beta-glucosidase activity, indicating that the non-homologous region was not essential for the activity. The truncation caused thermal instability, decrease in pK(a) of the proton donor residue (Glu616), and deficient transglycosylation activity. The thermal stability and the pK(a) of Glu616 were partially recovered with longer truncation, suggesting that the truncation perturbed the structure and that their presence in the region was not essential. The main role of the non-homologous region could be formation of a hydrophobic atmosphere at the acceptor site to make the enzyme suitable for hydrolyzing hydrophobic glucosides.

Agrobacterium tumefaciens↗
PubMed2003

Immunohistochemical localization of truncated midkine in developing human bile ducts.

Midkine (MK) is a heparin-binding growth factor whose gene has been identified in embryonal carcinoma cells in early stages of retinoic acid-induced differentiation. In the present study, we investigated the developmental localization of truncated MK protein in human bile ducts. Thirty specimens of the livers from 25 fetuses (from 9 to 40 gestational weeks) and from five neonates less than 4 weeks old were examined. Immunohistochemical analysis was performed using a mouse IgG2b monoclonal antibody against recombinant-truncated MK. Truncated MK was expressed moderately in the fetal liver from 9 to 15 gestational weeks. The immunoreactivities were found in the primitive hepatocytes, ductal plates, migrating biliary cells and immature bile ducts. The reaction products were localized in the cytoplasm heterogeneously. The intensity of immunostaining was weak from 15 gestational weeks to 26 gestational weeks. After 27 gestational weeks, truncated MK was not detected in the fetal livers. It was suggested that primitive hepatocytes, ductal plates and immature bile ducts produced truncated MK transiently during human bile ducts development.

Bile Ducts↗
PubMed2002

Physico-chemical properties of the N-terminally truncated L68Q cystatin C found in amyloid deposits of brain haemorrhage patients.

Cystatin C, a major extracellular cysteine proteinase inhibitor, is deposited as amyloid in brain haemorrhage patients with hereditary cystatin C amyloid angiopathy (HCCAA). A disease-causing mutation on the genetic level results in the substitution Leu68-->Gln (L68Q) in cystatin C, which causes protein instability. Besides carrying the L68Q substitution, cystatin C in amyloid deposits isolated from patients is N-terminally truncated by 10 amino acids. To elucidate the role of the N-terminal truncation for protein stability and aggregation properties, (delta1-10,L68Q)-cystatin C was produced in an Escherichia coli expression system and characterised. Unlike wild-type cystatin C, this variant rapidly dimerised under physiological conditions. Two unfolding intermediates of (delta1-10,L68Q)-cystatin C were identified, under the same pH and ionic strength conditions as required to form intermediates of full-length L68Q cystatin C. No evidence was found that the N-terminal truncation per se alters protein stability and leads to higher forms of aggregation. Monomeric as well as dimeric L68Q cystatin C incubated with neutrophil elastase was truncated as in HCCAA patients' amyloid. A protein variant with a thrombin cleavage site placed in front of residue Gly11 in L68Q cystatin C was constructed and used to confirm that the N-terminal segment is similarly accessible to proteinases in the monomeric and dimeric states of L68Q cystatin C. Thus, the N-terminal segment of L68Q cystatin C is exposed to proteolytic attack and does not seem to be involved in intramolecular contacts leading to dimerisation or higher-order aggregation. We conclude that the N-terminal truncation likely is an event secondary to amyloid formation, and of no relevance for the development of HCCAA.

Cerebral Amyloid Angiopathy, Familial↗
PubMed1988

Characteristic features of MR truncation artifacts.

Truncation artifacts occur in MR imaging because Fourier transforms are used to process MR signal data. These artifacts may alter the intensity, shape, and anatomic detail of structures in the spine. Ring artifacts (Gibb phenomenon) occurring near highly contrasting interfaces represent but one manifestation of truncation artifacts visible on MR images. We review truncation phenomena by providing graphic and phantom models. Ways in which truncation artifacts alter the MR appearance of the spine are discussed. We found that truncation phenomena are reduced most effectively by using a 256 x 256 matrix whenever feasible.

Computer Simulation↗
PubMed1999

Expression of normal and truncated forms of human endoglin.

Endoglin is a transmembrane glycoprotein 633 residues in length expressed at the surface of endothelial cells as a disulphide-linked homodimer; the specific cysteine residues involved in endoglin dimerization are unknown. Mutations in the coding region of the endoglin gene are responsible for hereditary haemorrhagic telangiectasia type 1 (HHT1), a dominantly inherited vascular disorder. Many of these mutations, if translated, would lead to truncated forms of the protein. It is therefore of interest to assess the protein expression of different truncated forms of endoglin. Infections in vitro or in vivo with recombinant vaccinia virus, as well as transient transfections with expression vectors, were used to express normal and truncated forms of endoglin. Truncated mutants could be classified into three different groups: (1) those that did not produce stable transcripts; (2) those that produced stable transcripts but did not secrete the protein; and (3) those that secreted a soluble dimeric protein. This is the first time that a recombinant truncated form of endoglin has been found to be expressed in a soluble form. Because a chimaeric construct encoding the N-terminal sequence of platelet/endothelial cell adhesion molecule (PECAM-1) antigen fused to residues Ile281-Ala658 of endoglin also yielded a dimeric surface protein, these results suggest that cysteine residues contained within the fragment Cys330-Cys412 are involved in disulphide bond formation. Infection with vaccinia recombinants encoding an HHT1 mutation did not affect the expression of the normal endoglin, and did not reveal an association of the recombinant soluble form with the transmembrane endoglin, supporting a haploinsufficiency model for HHT1.

Animals↗
PubMed2000

Screening a human population sample for DNA repair gene deficiencies utilizing the protein truncation test.

A significant fraction of human cancers are thought to have a genetic component and several lines of evidence suggest that deficiencies in DNA repair may be a contributing factor. Little is known, however, about the frequency and distribution of variants of DNA repair genes in the general human population. The protein truncation test (PTT) was used to screen 136 healthy volunteers for protein-truncating variants of 10 DNA repair genes: APE, CDK7, ERCC1, WAF1, HOGG1, MGMT, POLB, UNG, HAAG, and CCNH. This sample consisted of 41males (30%) and 95 females (70%) with an average age of 25.3 years, ranging from 17 to 60 years of age. No truncating mutations were found in the 10 genes examined in any of the subjects. The 95% confidence interval for a proportion of 0 over the 272 alleles examined per locus is 0-0.01. The calculated frequency of truncating mutations in each of these genes, among the general population, is thus less than 1%. Among the 10 genes tested in 136 people, a single sample had no PCR product for HAAG, even though PCR products were obtained on all other genes. Total RNA dot hybridization confirmed the presence of HAAG mRNA transcripts in this sample. Despite identification of this single DNA repair variant, these results indicate a low frequency of truncating mutations in DNA repair genes in the general population.

Base Sequence↗
PubMed1975

Estimates of fecundability from a truncated distribution of conception times.

A population consisting of women who have conceived before a time t ignores all women whose conception time exceeds t. Such a population is considered as a truncated population, and the samples are called truncated samples. Under the assumption that fecundability among women varies according to a Beta distribution (with parameters a and b), the distribution of conception times in a truncated population can be considered as truncated Type I geometric. This paper presents an algorithm to obtain the moment and maximum likelihood estimates of a and b from the truncated samples. Large sample properties of the estimators are also studied. Examples using the Hutterite and the Princeton Fertility Survey data are given.

Female↗
PubMed2002

Expression of wild-type and truncated myocilins in trabecular meshwork cells: their subcellular localizations and cytotoxicities.

PURPOSE: To investigate the subcellular localizations and potential cytotoxicities of wild-type and truncated (Q368X) myocilin in cultured human trabecular meshwork (TM) cells. METHODS: Full-length wild-type myocilin, truncated myocilin, and stromelysin were expressed as green fluorescence (GFP) or DsRed fusion proteins in TM cells by using adenoviral vectors, and their secretory properties and cytopathic effects were evaluated by Western blot analysis and cell proliferation assay, respectively. To determine the subcellular localizations of myocilins, the cellular organelles of the infected TM cells were stained with organelle-specific antibodies or fluorescent indicators and examined under a confocal microscope. RESULTS: Wild-type myocilin was expressed mainly in the perinuclear region of TM cells and was localized preferentially in endoplasmic reticulum (ER), but not in actin, microtubules, or mitochondria. Truncated myocilin was also localized in ER, and its expression was found to be potentially toxic to TM cells, leading to deformed cellular morphology and diminished cell proliferation, but it had no effect on the secretion of stromelysin. The truncated myocilin was also found to be colocalized with and appeared to aggregate with wild-type myocilin when the proteins were coexpressed. CONCLUSIONS: TM cells participating in the turnover of trabecular extracellular matrix (ECM) components are important in regulating aqueous outflow. The truncated myocilin, colocalized and coaggregated with wild-type myocilin, is believed to cause a dysfunction of the cells, resulting in alterations in structural compartmentalization of trabecular ECM and obstruction of aqueous outflow.

Adenoviridae↗
PubMed1992

A truncated recombinant alpha subunit of Gi3 with a reduced affinity for beta gamma dimers and altered guanosine 5'-3-O-(thio)triphosphate binding.

The baculovirus-based expression system was adapted to express alpha subunits of the complete (alpha i3) and an amino-terminally truncated (alpha i3') form of Gi3 and of two complete forms of Gs (alpha s-L and alpha s-S). Subunits encoded in full length cDNAs were obtained with yields of 40-60 mg of recombinant protein/liter of cells, of which alpha i3 was between 30 and 50% soluble, but alpha s subunits were only 5-10% soluble. Only the complete alpha i3 was myristoylated. alpha i3 was purified in four steps. The purified protein bound 0.8-0.9 mol of guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) per mol of protein and had one predominant contaminant which was identified as a truncated form that begins with methionine 18 instead of methionine 1. Both the full length alpha i3 and the truncated alpha i3' formed trimers with human erythrocyte beta gamma as seen by their migration in sucrose density gradients and by an increased rate of ADP ribosylation by pertussis toxin, but compared to alpha i3, alpha i3' interacted with beta gamma with a reduced affinity and dissociated upon warming. At 32 degrees C, only full length alpha i3 was ADP-ribosylated; at 4 degrees C, alpha i3 and alpha i3' were both ADP-ribosylated, with the truncated form requiring approximately 200-fold higher concentrations of beta gamma. A genetically engineered alpha i3' (alpha i3[18-354]) was also expressed in Sf9 cells. Yields, assessed as saturable GTP gamma S binding sites, were 3-5 mg per liter. Scatchard analysis showed that truncation of the amino terminus interferes with the ability of Mg2+ to promote high affinity binding of GTP gamma S. We conclude that the G protein alpha subunit amino terminus is not essential for interaction with beta gamma dimers, but rather is important in determining the affinity of the alpha subunit for both the beta gamma dimers and guanine nucleotide.

Amino Acid Sequence↗
PubMed1992

Assembly of the oligomeric membrane pore formed by Staphylococcal alpha-hemolysin examined by truncation mutagenesis.

The alpha-hemolysin (alpha HL) from Staphylococcus aureus causes the lysis of susceptible cells such as rabbit erythrocytes (rRBCs). Lysis is associated with the formation of a hexameric pore in the plasma membrane. Here we show that truncation mutants of alpha HL missing 2 to 22 N-terminal amino acids form oligomers on the surfaces of rRBCs but fail to lyse the cells. By contrast, mutants missing 3 or 5 amino acids at the C terminus are very inefficient at oligomerization but do lyse rRBCs, albeit extremely slowly. The C-terminal truncation mutants, retarded as monomers on the cell surface, undergo a conformational change in which the protease-sensitive loop located near the midpoint of the polypeptide chain becomes occluded. Judged by this criterion, polypeptides truncated at the N terminus, frozen as nonlytic oligomers, are in a similar conformation. A second proteolytic site near the N terminus of the polypeptide becomes inaccessible in the lytic pore formed by the wild-type polypeptide, supporting the idea that a second conformational change occurs upon pore formation. These findings suggest a pathway for assembly of the lytic pore in which alpha HL first binds to target cells as a monomer, which is converted to a nonlytic oligomeric intermediate before formation of the pore. In keeping with this model, an N-terminal truncation mutant blocks the slow lysis induced by a C-terminal truncation mutant, presumably by diverting the weakly lytic subunits into inactive oligomers.

Amino Acid Sequence↗