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PubMed1995

Isolation, characterization and chromosomal localization of a human pseudogene for hexokinase II.

A processed pseudogene for hexokinase II (HKII), the first such reported for a member of the hexokinase gene family, was isolated from a human genomic library by using a rat HKII cDNA as a probe. The pseudogene contains a region that is identical to the open reading frame of the human HKII cDNA at 97% of the nucleotide positions, but it contains several frameshift mutations, small deletions and insertions, and several stop codons. The human HKII pseudogene is located on the X chromosome and is integrated into a long interspersed nuclear repetitive DNA element (LINE). We estimate that this integration event occurred approximately 14-16 Myr (million years) ago.

Animals↗
PubMed1992

Requirement for ICR-like sequences in the replication of brome mosaic virus genomic RNA.

Previous studies using a brome mosaic virus (BMV) RNA-2 deletion mutant (pRNA-2 M/S) and additional derivatives as reporters established that viral sequences resembling internal control regions (ICRs) 1 and 2 of tRNA gene promoters are vital to (+)-strand replication in protoplasts. Transfer of these mutations to genomic RNA-2 and functional analysis in protoplast, local lesion, and systemic infections revealed a sequence-specific requirement for bases within the ICR2-like motif. Despite the low (generally less than 20% of wild-type) and sometimes undetectable levels of replication of these RNA-2 mutants, sufficient p2a protein was produced to support at least modest levels of RNA-1, -3 and -4 replication in protoplasts. However, only those RNA-2 ICR2 mutants supporting substantial replication of the viral genome in protoplasts were capable of establishing local lesions in Chenopodium hybridum and systemic infections in barley, further establishing the essential role of the ICR-like sequences in viral infectivity. Upon passage through a second set of barley plants, accumulation patterns for progeny from inocula containing certain RNA-2 mutants paralleled those from wild-type inocula, indicating repair of the introduced mutations. RNA stability and translatability were shown to be unaffected by the introduced mutations. BMV RNA-3 contains several ICR-like sequences, each of which was individually deleted. Whereas deletion of the 5'-terminal ICR2-like motif had little effect on RNA-3 accumulation in protoplasts or local lesion formation, it debilitated systemic spread in barley. Deletion of an internal ICR2-like motif at position 1100 decreased (+):(-) strand asymmetry from greater than 100:1 to 14:1, reduced RNA-3 replication in protoplasts to less than 15% of wild-type, and abolished local lesion and systemic infectivity.

Base Sequence↗
PubMed2003

Evolution of hepatitis B virus sequence from a liver transplant recipient with rapid breakthrough despite hepatitis B immune globulin prophylaxis and lamivudine therapy.

Recurrent hepatitis B virus (HBV) infection after liver transplantation can be prevented by prophylactic hepatitis B immune globulin (HBIG) and lamivudine therapy. However, reinfection may still occur due to the emergence of immune escape mutants and mutants of the YMDD motif. The full spectrum of mutations within the HBV genome during recurrent HBV infection remains to be documented. In this study, serial HBV isolates were characterized from a patient with lamivudine resistance prior to liver transplantation who developed recurrent HBV infection within 2 months of transplantation despite a high dose of HBIG and lamivudine therapy. Sequence analysis of full-length viral genome before transplantation revealed many point mutations as compared with a wild-type genotype C sequence, including the T1753G/A1762T/G1764A triple mutation in the basal core promoter and the G1896A nonsense mutation in the precore region. After transplantation and therapy, several point mutations in the HBV genome emerged or became dominant. These mutations caused L426I/L526M/M550I triple mutation (equivalent to L428I/L528M/M552I in previous reports) in the polymerase, and D144E mutation in the "a" determinant of HBsAg. Transfection experiments revealed that the D144E mutation reduced HBsAg affinity to anti-HBs, confirming its active role for immune escape. Our study suggests that mutations in the HBsAg (D144E) and the polymerase (L426I/L526M/M550I) of HBV genome may be responsible for viral breakthrough despite HBIG prophylaxis and lamivudine therapy.

Base Sequence↗
PubMed1992

The integration of molecular genetics into cancer management.

Many of the phenotypes of cancer cells and tumors can now be traced to specific mutations in the genomes of these cells. These mutations may activate oncogenes, providing mitogenic stimulus to these cells. Alternatively, they may inactivate tumor-suppressor genes, relieving growth-inhibiting constraints placed on these cells. These genetic lesions together provide many of the explanations for the deregulated growth of tumor cells.

Cell Division↗
PubMed1994

Assessment of clinical parameters associated with increased frequency of mutant T cells in patients with systemic lupus erythematosus.

OBJECTIVE: To determine the clinical features that contribute to an increased frequency of mutant T cells (FMC) in patients with systemic lupus erythematosus (SLE). METHODS: During in vivo T cell division, there are errors in replication which give rise to mutations throughout the genome. An estimate of such mutations may be obtained by focusing on mutations in the hprt gene, which can be screened by assessing relative growth of T cell clones in the presence and absence of 6-thioguanine. In this study, peripheral blood T cell clones from 47 patients with SLE were assessed, and the frequency of mutant T cells (FMC) determined. An attempt was made to correlate the FMC with disease measures. RESULTS: Patients with SLE had a spectrum of FMC values, ranging from normal to almost 1,000 times normal. Total duration of active disease (rs = 0.94), past highest disease activity index (rs = 0.80), and number of lupus flares (rs = 0.76) correlated most strongly (P < 0.0001) with FMC by Spearman's rank order analysis. In contrast, current disease activity index and current anti-DNA level did not correlate with FMC. Similar correlations between FMC and cumulative past lupus disease activity were found by linear regression analysis (rp = 0.89 for the correlation between the natural logarithm of FMC and cumulative duration of active disease). By both statistical tests, therapy was found to be only a minor contributor to FMC. CONCLUSION: In our patient population, a high FMC value appears to reflect cumulative clinical lupus disease activity, involving both intensity and duration of past active disease.

Adult↗
PubMed1990

Common variable immunodeficiency and malignancy: a report of two cases and possible explanation for the association.

Two patients with common variable immunodeficiency (CVID) and malignant tumours are reported. The first patient developed myelogenous leukaemia soon after the myelodysplastic syndrome has been diagnosed. The undifferentiated gastric lymphoma found in the second patient suggests that an increased risk of gastrointestinal malignancies in CVID could partly be due to lymphomas. We hypothesize that the tissue- or site-specific risk of lymphomas and gastrointestinal cancer can be explained by an increased chromosomal or genomic instability with a higher mutation rate and genomic disorganization, and that this instability could be related to viral carcinogenesis. The primary immunodeficiency per se may not be responsible for the cancer susceptibility in CVID patients.

Adult↗
PubMed2004

A biological-based model that links genomic instability, bystander effects, and adaptive response.

This paper links genomic instability, bystander effects, and adaptive response in mammalian cell communities via a novel biological-based, dose-response model called NEOTRANS3. The model is an extension of the NEOTRANS2 model that addressed stochastic effects (genomic instability, mutations, and neoplastic transformation) associated with brief exposure to low radiation doses. With both models, ionizing radiation produces DNA damage in cells that can be associated with varying degrees of genomic instability. Cells with persistent problematic instability (PPI) are mutants that arise via misrepair of DNA damage. Progeny of PPI cells also have PPI and can undergo spontaneous neoplastic transformation. Unlike NEOTRANS2, with NEOTRANS3 newly induced mutant PPI cells and their neoplastically transformed progeny can be suppressed via our previously introduced protective apoptosis-mediated (PAM) process, which can be activated by low linear energy transfer (LET) radiation. However, with NEOTRANS3 (which like NEOTRANS2 involves cross-talk between nongenomically compromised [e.g., nontransformed, nonmutants] and genomically compromised [e.g., mutants, transformants, etc.] cells), it is assumed that PAM is only activated over a relatively narrow, dose-rate-dependent interval (D(PAM),D(off)); where D(PAM) is a small stochastic activation threshold, and D(off) is the stochastic dose above which PAM does not occur. PAM cooperates with activated normal DNA repair and with activated normal apoptosis in guarding against genomic instability. Normal repair involves both error-free repair and misrepair components. Normal apoptosis and the error-free component of normal repair protect mammals by preventing the occurrence of mutant cells. PAM selectively removes mutant cells arising via the misrepair component of normal repair, selectively removes existing neoplastically transformed cells, and probably selectively removes other genomically compromised cells when it is activated. PAM likely involves multiple pathways to apoptosis, with the selected pathway depending on the type of cell to be removed, its cellular environment, and on the nature of the genomic damage.

Animals↗
PubMed2000

Ionizing radiation and genetic risks. XII. The concept of "potential recoverability correction factor" (PRCF) and its use for predicting the risk of radiation-inducible genetic disease in human live births.

Genetic risks of radiation exposure of humans are generally expressed as expected increases in the frequencies of genetic diseases over those that occur naturally in the population as a result of spontaneous mutations. Since human data on radiation-induced germ cell mutations and genetic diseases remain scanty, the rates derived from the induced frequencies of mutations in mouse genes are used for this purpose. Such an extrapolation from mouse data to the risk of genetic diseases will be valid only if the average rates of inducible mutations in human genes of interest and the average rates of induced mutations in mice are similar. Advances in knowledge of human genetic diseases and in molecular studies of radiation-induced mutations in experimental systems now question the validity of the above extrapolation. In fact, they (i) support the view that only in a limited number of genes in the human genome, induced mutations may be compatible with viability and hence recoverable in live births and (ii) suggest that the average rate of induced mutations in human genes of interest from the disease point of view will be lower than that assumed from mouse results. Since, at present, there is no alternative to the use of mouse data on induced mutation rates, there is a need to bridge the gap between these and the risk of potentially inducible genetic diseases in human live births. In this paper, we advance the concept of what we refer to here as "the potential recoverability correction factor" (PRCF) to bridge the above gap in risk estimation and present a method to estimate PRCF. In developing the concept of PRCF, we first used the available information on radiation-induced mutations recovered in experimental studies to define some criteria for assessing potential recoverability of induced mutations and then applied these to human genes on a gene-by-gene basis. The analysis permitted us to estimate unweighted PRCFs (i.e. the fraction of genes among the total studied that might contribute to recoverable induced mutations) and weighted PRCFs (i.e. PRCFs weighted by the incidences of the respective diseases). The estimates are: 0.15 (weighted) to 0.30 (unweighted) for autosomal dominant and X-linked diseases and 0.02 (weighted) to 0.09 (unweighted) for chronic multifactorial diseases. The PRCF calculations are unnecessary for autosomal recessive diseases since the risks projected for the first few generations even without using PRCFs are already very small. For congenital abnormalities, PRCFs cannot be reliably estimated. With the incorporation of PRCF into the equation used for predicting risk, the risk per unit dose becomes the product of four quantities (risk per unit dose=Px(1/DD)xMCxPRCF) where P is the baseline frequency of the genetic disease, 1/DD is the relative mutation risk per unit dose, MC is the mutation component and PRCF is the disease-class-specific potential recoverability correction factor instead of the first three (as has been the case thus far). Since PRCF is a fraction, it is obvious that the estimate of risk obtained with the revised risk equation will be smaller than previously calculated values.

Genetic Diseases, Inborn↗
PubMed1999

Definition of the mutation responsible for maple syrup urine disease in Poll Shorthorns and genotyping Poll Shorthorns and Poll Herefords for maple syrup urine disease alleles.

The organisation of the E1alpha subunit of bovine branched-chain alpha-keto acid dehydrogenase gene was established. c DNA was cloned from Poll Shorthorn x Poll Hereford calves affected with Maple Syrup Urine Disease to identify the mutation responsible for the disease in Poll Shorthorns. Clones containing the c DNA sequences inherited from the Poll Shorthorn sire of the affected calves were identified. Paternal clones were sequenced and a cytidine to thymidine transition was found at nucleotide 1380. The mutation is predicted to substitute leucine in place of a highly conserved proline at codon 372. A polymerase chain reaction procedure was developed for detection of the 1380C-->T mutation in genomic DNA. Three Poll Shorthorn parents of affected calves and three affected Poll Shorthorn x Poll Hereford calves were heterozygous and an affected Poll Shorthorn calf was homozygous for this mutation. An improved polymerase chain reaction procedure was also devised to genotype Poll Herefords for the 248C-->T mutation. The procedures will facilitate disease prevention programs and assist in differential diagnosis of conditions in new-born calves that present with a rapid onset of progressive neurological disease and are characterised histologically by 'status spongiosus'. Maple Syrup Urine Disease (MSUD) is an autosomal recessive defect reported in humans (Danner and Elsas 1989), and in Poll Hereford (PH) and Poll Shorthorn (PS) calves (Harper et al 1986, Healy et al 1992). The clinical, biochemical and pathological manifestations of the disease are identical in the two breeds of cattle, and are characterised by the rapid onset of progressive neurological disease, leading to death within a few days of birth. The disease is caused by a deficiency of activity of the mitochondrial enzyme branched-chain alpha-keto acid dehydrogenase (BCKADH). This deficiency leads to elevated concentrations, in blood and tissues, of branched chain alpha-keto acids and their precursors, the branched chain amino acids, valine, leucine and isoleucine. BCKADH consists of four subunits E1alpha, E1beta, E2 and E3 that are encoded by separate genes, and MSUD may result from deficiency of any of the subunits. In PH s, the disease in caused by premature termination of translation, of the E1alpha subunit, that is induced by a cytidine to thymidine transition exon 2 (248C-->T), that converts the glutamine codon -6 to a stop codon (Q-6ST; Zhang et al 1990). We have shown that MSUD -affected PSxPH calves are heterozygous at the PH locus, illustrating molecular heterogeneity exists for bovine MSUD (Healy and Dennis 1994a). The fact that these crossbred calves are affected, indicates the PS, like the PH mutation, resides in the E1alpha subunit.

Alleles↗
PubMed1988

Base substitutions, frameshifts, and small deletions constitute ionizing radiation-induced point mutations in mammalian cells.

The relative role of point mutations and large genomic rearrangements in ionizing radiation-induced mutagenesis has been an issue of long-standing interest. Recent studies using Southern blotting analysis permit the partitioning of ionizing radiation-induced mutagenesis in mammalian cells into detectable deletions and major genomic rearrangements and into point mutations. The molecular nature of these point mutations has been left unresolved; they may include base substitutions as well as small deletions, insertions, and frame-shifts below the level of resolution of Southern blotting analysis. In this investigation, we have characterized a collection of ionizing radiation-induced point mutations at the endogenous adenine phosphoribosyltransferase (aprt) locus of Chinese hamster ovary cells at the DNA sequence level. Base substitutions represented approximately equal to 2/3 of the point mutations analyzed. Although the collection of mutants is relatively small, every possible type of base substitution event has been recovered. These mutations are well distributed throughout the coding sequence with only one multiple occurrence. Small deletions represented the remainder of characterized mutants; no insertions have been observed. Sequence-directed mechanisms mediated by direct repeats could account for some of the observed deletions, while others appear to be directly attributable to radiation-induced strand breakage.

Adenine Phosphoribosyltransferase↗
PubMed2007

Theory of lethal mutagenesis for viruses.

Mutation is the basis of adaptation. Yet, most mutations are detrimental, and elevating mutation rates will impair a population's fitness in the short term. The latter realization has led to the concept of lethal mutagenesis for curing viral infections, and work with drugs such as ribavirin has supported this perspective. As yet, there is no formal theory of lethal mutagenesis, although reference is commonly made to Eigen's error catastrophe theory. Here, we propose a theory of lethal mutagenesis. With an obvious parallel to the epidemiological threshold for eradication of a disease, a sufficient condition for lethal mutagenesis is that each viral genotype produces, on average, less than one progeny virus that goes on to infect a new cell. The extinction threshold involves an evolutionary component based on the mutation rate, but it also includes an ecological component, so the threshold cannot be calculated from the mutation rate alone. The genetic evolution of a large population undergoing mutagenesis is independent of whether the population is declining or stable, so there is no runaway accumulation of mutations or genetic signature for lethal mutagenesis that distinguishes it from a level of mutagenesis under which the population is maintained. To detect lethal mutagenesis, accurate measurements of the genome-wide mutation rate and the number of progeny per infected cell that go on to infect new cells are needed. We discuss three methods for estimating the former. Estimating the latter is more challenging, but broad limits to this estimate may be feasible.

Antiviral Agents↗
PubMed2006

Activation of human long interspersed nuclear element 1 retrotransposition by benzo(a)pyrene, an ubiquitous environmental carcinogen.

Long interspersed nuclear elements [LINE-1 (L1)] are abundant retrotransposons in mammalian genomes that remain silent under most conditions. Cellular stress signals activate L1, but the molecular mechanisms controlling L1 activation remain unclear. Evidence is presented here that benzo(a)pyrene (BaP), an environmental hydrocarbon metabolized by mammalian cytochrome P450s to reactive carcinogenic intermediates, increases L1 retrotransposition in HeLa cells. Increased retrotransposition is mediated by up-regulation of L1 RNA levels, increased L1 cDNA synthesis, and stable genomic integration. Activation of L1 is dependent on the ability of BaP to cause DNA damage because it is absent in HeLa cells challenged with nongenotoxic hydrocarbon carcinogens. Thus, the mutations and genomic instability observed in human populations exposed to genotoxic environmental hydrocarbons may involve epigenetic activation of mobile elements dispersed throughout the human genome.

Benzo(a)pyrene↗
PubMed2000

Nonsense mutations in the human beta-globin gene lead to unexpected levels of cytoplasmic mRNA accumulation.

Generally, nonsense codons 50 bp or more upstream of the 3'-most intron of the human beta-globin gene reduce mRNA abundance. In contrast, dominantly inherited beta-thalassemia is frequently associated with nonsense mutations in the last exon. In this work, murine erythroleukemia (MEL) cells were stably transfected with human beta-globin genes mutated within each of the 3 exons, namely at codons 15 (TGG-->TGA), 39 (C-->T), or 127 (C-->T). Primer extension analysis after erythroid differentiation induction showed codon 127 (C-->T) mRNA accumulated in the cytoplasm at approximately 20% of the normal mRNA level. Codon 39 (C-->T) mutation did not result in significant mRNA accumulation. Unexpectedly, codon 15 (TGG-->TGA) mRNA accumulated at approximately 90%. Concordant results were obtained when reticulocyte mRNA from 2 carriers for this mutation was studied. High mRNA accumulation of codon 15 nonsense-mutated gene was revealed to be independent of the type of nonsense mutation and the genomic background in which this mutation occurs. To investigate the effects of other nonsense mutations located in the first exon on the mRNA level, nonsense mutations at codons 5, 17, and 26 were also cloned and stably transfected into MEL cells. After erythroid differentiation induction, mRNAs with a mutation at codon 5 or 17 were detected at high levels, whereas the mutation at codon 26 led to low mRNA levels. These findings suggest that nonsense-mediated mRNA decay is not exclusively dependent on the localization of mutations relative to the 3'-most intron. Other factors may also contribute to determine the cytoplasmic nonsense-mutated mRNA level in erythroid cells. (Blood. 2000;96:2895-2901)

Animals↗
PubMed1992

[Medium chain acyl-CoA dehydrogenase (MCAD) deficiency: a life-threatening defect of fatty acid oxidation].

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a potentially fatal metabolic disease, which is characterized by non-ketotic hypoglycemia and lethargy. The disease manifests itself by periodic attacks in connection with infections and periods of fasting, or suddenly as unexpected child death or "near miss". Characterization of a prevalent disease-causing mutation (G985) in the MCAD gene has increased the diagnostic possibilities, since 75% of all patients with MCAD deficiency are homozygous for the mutation. Analysis for this mutation in genomic DNA from a bloodspot on a PKU-card constitute today a certain and specific diagnosis for the disease in 75% of all cases. In the remaining 25% the mutation analysis is supplemented with urine metabolite studies by gas chromatography/mass spectrometry, and with measurements of enzyme activities in cultured skin fibroblasts. The disease is today considered more common than previously anticipated, since the incidence of patients with MCAD enzyme deficiency in Denmark is estimated to 1/27,000 newborns, or two new cases annually. The relationship between the enzyme defect (gene defect) and the clinical expression of the disease is a main subject for the clinical research in the disease at present, because less than 10% of all patients with the gene defect are diagnosed. This applies not only to Denmark but also to other countries.

Acyl-CoA Dehydrogenases↗
PubMed2005

[Studies on exogenous and endogenous factors associated with various ocular diseases].

The exact cause and nature of various ocular diseases are still unknown. In accordance with the progress of modern medical science, technology for research investigations has greatly developed and a variety of new results have recently been produced. However, they were mostly about exogenous factors such as bacteria or parasites. On the other hand, molecular biology has markedly progressed in the second half of the 20th century and has been applied to medical science. As for the exogenous factors, molecular techniques have been introduced to the diagnosis of infectious diseases, and their diagnosis has become much easier and much more exact than before. Similarly, in the field of immunogenetics, molecular genetics has greatly developed, and disease susceptibility or disease resistance has been investigated at the DNA or molecular level. Regarding the exogenous disease mechanisms, most infectious diseases occur when the microorganisms are transmitted to some individuals. In this case, endogenous factors play almost no or very little role. Adenovirus keratoconjunctivitis is one example. Human adenovirus (HAdV) is a DNA virus. Although HAdVs are classified into 51 different serotypes, only 7 of them such as HAdV-3, -4, -7, -8, -11, -19, and -37 usually develop acute keratoconjunctivitis. The genome of HAdV develops constant mutation, and new genome types often cause epidemics of nosocomial infections. Recent studies showed that most of the keratoconjunctivitis cases are caused by HAdV-37 in Japan. With regard to the endogenous disease mechanisms, only 30 years have passed since the recent molecular genetic studies on disease susceptibility started. Before that, genetic disease mechanisms were studied only in hereditary diseases such as color vision defects, which follow the modes of Mendelian inheritance. Therefore, the presence of disease susceptibility was not clearly understood in the so-called nonhereditary diseases. However, after our initial findings of the close association between Behçet's disease and HL-A 5 (later HLA-B 5 or HLA-B 51) in 1973, there were many reports on the presence of genetic predisposition to certain non-hereditary diseases. One example is Vogt-Koyanagi-Harada's (VKH) disease which has a close association with HLA-DRB 1*0405 in Japanese patients, as also was the case with sympathetic ophthalmia. These studies indicate that Behçet's disease may be called "a disease of the Yayoi people" and Vogt-Koyanagi-Harada's disease as "a disease of the Jomon people" when analyze the associated genetic factors. On the other hand, the human genome project has been successfully completed and it is now possible for us to investigate any genetic factor associated with certain diseases either on 22 pairs of autosomal chromosomes or on one pair of sex chromosomes. Our collaborative team has adopted the microsatellite methods utilizing the pooled DNA PCR method, and started investigation of any genetic association with ocular diseases, in addition to the HLA system on the short arm of autosomal chromosome 6. In the first screening of 100 DNA samples of Behçet's disease patients, for example, 9 % of microsatellite markers on the autosomal chromosomes 1, 6, 17, and 19 showed significant positive association. The same studies are now in progress by our collaborative team on inflammatory diseases such as sarcoidosis, and on noninflammatory conditions like hypertension or high myopia. These results suggest that exogenous environmental factors such as infections which may trigger the occurrence of the disease or conditions, and endogenous genetic factors which may predispose someone to contracting a disease, are both significantly associated with various ocular diseases, and construct intricate disease mechanisms. Therefore, in future studies of diagnosis, treatment, and prevention of various ocular diseases, both exogenous factors and endogenous factors have to be carefully analyzed and investigated.

Adenoviridae↗
PubMed1996

[Oncoproteins and anti-oncoproteins in blood serum as biomarkers of early health effects induced by occupational and environmental carcinogens].

Over a whole life-span a genetic machinery of human cells is exposed to carcinogenic effect of various chemical, physical and biological factors leading to cellular changes in the genome like point mutation and translocation or amplification of genes. Together with growing an ageing of the human organism, the number and heterogeneity of mutated cells increase. Thus, the presence or absence of the neoplastic process may depend on the length of life, efficiency of the immunological system, cumulation of adverse affects of environmental factors or inherited susceptibility to a disease. There is no doubt that neoplasms which develop due to inheritance of different genetic defects or due to direct environmental effect progress in line with similar mutations, resulting finally in the genome destabilisation and disturbances in the balance between proliferation and differentiation processes. The knowledge as to how far environmental carcinogens affect cellular genome is still limited. Nevertheless, data collected to date help to understand the mechanisms by which environmental carcinogens may initiate the process of transforming normal cells into neoplastic ones. It is most likely that activation of some oncoproteins and deactivation of some suppressive genes and related qualitative and quantitative changes in oncoproteins and anti-oncoproteins participating in the growth control and cellular division, are the essential mechanisms which are involved in this process. The discovery that activation of oncoproteins and related emergence of oncoprotein in cells, increased in the number of changed, can be monitored in easily available biological fluids, such as blood or urine, has become of great importance for occupational medicine and environmental health. That has provided new diagnostic measures for evaluating carcinogenic effects of the working and living environments. The fact, that the emergence of oncoproteins in biological fluids may precede by many months or even years clinical manifestations of neoplastic disease should greatly contribute to undertaking more effective preventive measures.

Antibodies, Neoplasm↗
PubMed1993

Protective protein gene mutations in galactosialidosis.

Four different protective protein cDNA mutations, 146A-->G (Q49R), 193T-->C (W65R), 268-269TC-->CT (S90L), and 1184A-->G (Y395C), were identified in six Japanese galactosialidosis patients with various phenotypic manifestations, and another mutation, 746T-->A (Y249N), in a patient of French-German origin with an atypical clinical course. Y395C was a common mutation in four Japanese patients in infancy and childhood; two juvenile patients were compound heterozygotes of Y395C and another common mutation, SpDEx7, and the other two infants were compound heterozygotes of Y395C and mutant alleles other than SpDEx7. We confirmed these mutations in genomic DNA by direct-sequence analysis or restriction-site analysis. The mutant cDNA clones, transiently expressed in a transformed galactosialidosis cell line, did not restore the secondarily deficient beta-galactosidase or alpha-neuraminidase activity except for the Y249N mutation that expressed some carboxypeptidase activity and restored the two lysosomal enzyme activities. Pulse-chase analysis detected a small amount of the mature form, as well as the precursor, in the cells transfected with the Y249N cDNA. Only precursor proteins were detected, mature proteins not appearing for the other mutant cDNAs.

Adolescent↗
PubMed1994

Direct detection of a common inversion mutation in the genetic diagnosis of severe hemophilia A.

Two recent reports suggest that approximately 50% of the cases of severe hemophilia A (factor VIII:C < 0.01 U/mL) may be caused by a gross rearrangement of the factor VIII gene. The mutation involves genomic sequence from exon 1 to within intron 22 of the gene in an inversion event. This rearrangement can be detected on a Southern blot using a probe that is complementary to sequence from within intron 22. In this report, we describe the analysis of 71 severe hemophilia A patients for the presence of this mutation. Thirty-two of the patients (45%) showed evidence of the rearrangement, a figure that confirms the initial reports on 28 patients. Five different patterns of rearrangement have been noted, although two of these patterns (pattern 1 [70%] and pattern 2 [16%]) account for the majority of cases. The other patterns of rearrangement appear to be confined to individual families and may represent the result of additional sequence variation within the region of the genome to which the proximal 22 exons of factor VIII are translocated. Analysis of this patient population for the factor VIII inversion mutation has been extremely useful in a molecular diagnostic sense. In 23 of the cases studied (72%), the affected individual was the only documented hemophiliac in the family and, thus, previous linkage analysis had been limited to the provision of exclusion testing only. In conclusion, it appears that testing for the factor VIII inversion mutation will be positive in approximately 45% of severe hemophiliacs and as such should constitute the initial stage in the genetic testing protocol for these patients' families.

Chromosome Inversion↗