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PubMed2004

Hepatic iron loading in patients with compound heterozygous HFE mutations.

AIM: To assess the severity of hepatic iron loading in patients with a compound heterozygous C282Y/H63D HFE genotype. METHODS: A total of 246 patients were referred to the Hepatology Clinic at a tertiary hospital for HFE genotyping and further assessment of elevated serum transferrin saturation and/or ferritin results, either with or without abnormal liver function tests. Subjects of the study were 19 patients compound heterozygous for HFE who had liver biopsy, quantitative liver iron estimation and liver histopathology. RESULTS: Mild iron overload [hepatic iron concentration between 30 and 100 micromol/g dry weight], was present in 16/19 compound heterozygous patients, three patients had values within the reference range. As well as the compound heterozygous HFE genotype, 18/19 patients were found to have had at least one additional risk factor for developing either iron loading or liver disease. CONCLUSION: Compound heterozygous patients show no more than mild liver iron loading. The decision whether or not to recommend liver biopsy in C282Y/H63D patients with abnormal serum iron indices and/or liver function tests should be based on the need to evaluate liver damage rather than solely to assess liver iron loading.

Adult↗
PubMed2004

Autosomal dominant iron overload due to a novel mutation of ferroportin1 associated with parenchymal iron loading and cirrhosis.

We report the identification of a novel mutation in ferroportin1 in an Australian family with autosomal dominant iron overload. The phenotype of iron overload in one member of this family is associated with high serum ferritin concentration and elevated transferrin saturation. The pattern of iron overload in the liver shows accumulation predominantly in parenchymal cells with some Kupffer cell iron loading. Although some cases of type 4 haemochromatosis have been associated with the development of liver fibrosis this is the first report of a patient with fully established cirrhosis at a relatively young age (32 years). The coexistence of sarcoidosis in this patient may contribute to the more severe phenotype. This report highlights the phenotypic variability that can occur in type 4 haemochromatosis. Some patients have predominant reticuloendothelial iron loading and normal transferrin saturation whereas others have predominant parenchymal iron loading and elevated transferrin saturation. The reasons for this variability remain to be determined. Interestingly this is the third mutation to affect asparagine 144, reinforcing the important role for this amino acid in the function of ferroportin1.

Adult↗
PubMed2001

Case study: rapid emergence of a cytomegalovirus UL97 mutant in a heart-transplant recipient on pre-emptive ganciclovir therapy.

A cytomegalovirus (CMV) strain containing a mutation in the UL97 gene (Leu595Ser), which is known to confer ganciclovir resistance, emerged rapidly in a heart-transplant recipient after 54 days of antigenaemia-guided ganciclovir therapy. The emergence of this viral mutant, while the patient was receiving oral ganciclovir 1000 mg three times daily, was associated with increasing CMV pp65 antigenaemia levels despite the re-instatement of intravenous ganciclovir 5 mg/kg twice daily. The antiviral regimen was then switched to intravenous foscarnet 90 mg/kg, administered either twice daily, once daily or every other day, which resulted in a rapid decrease of CMV antigenaemia levels and prevented the development of CMV-associated disease. Frequent monitoring of the CMV viral load and/or mutational studies are warranted in highly immunocompromised transplant recipients to prevent the development of CMV disease caused by ganciclovir-resistant strains.

Antiviral Agents↗
PubMed2006

Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy.

OBJECTIVE: Peripheral neuropathy (PN) often complicates nucleoside reverse transcriptase inhibitor (NRTI) therapy of HIV infection and may involve mitochondrial dysfunction. Since iron deficiency is associated with some types of PN, and iron is essential for mitochondrial function, we tested the hypothesis that hemochromatosis (HFE) gene mutations influence susceptibility to NRTI-induced PN. DESIGN: Case-control study involving multicenter, AIDS Clinical Trials Group (ACTG) protocol 384 and ACTG Human DNA Repository specimens. METHODS: Study participants were randomized to receive three- or four-drug antiretroviral therapy with didanosine (ddI) plus stavudine (d4T) or zidovudine plus lamivudine, given with efavirenz, nelfinavir, or both, with up to three years of follow-up. PN was ascertained based on signs and symptoms. HFE C282Y and H63D genotypes were determined, and associations with PN were assessed using logistic regression. RESULTS: : Of 509 participants, 147 (29%) developed PN, 73% of whom had been randomized to receive ddI plus d4T. Among ddI/d4T-ever-treated individuals, HFE C282Y heterozygotes developed PN on ddI/d4T significantly less often than C282Y non-carriers, adjusting for age, CD4 lymphocyte count and viral load at baseline, and concomitant antiretroviral drugs [6% vs. 35%, respectively, in whites; adjusted odds ratio (OR), 0.17; 95% confidence interval (CI) 0.03-0.83; P = 0.021]. Regardless of race/ethnicity, ddI/d4T-associated PN was uncommon in C282Y heterozygotes [race-adjusted OR, 0.30; 95% CI 0.09-0.96); P = 0.042]. CONCLUSIONS: Iron-loading HFE mutations such as C282Y are associated with a decreased risk of PN during antiretroviral therapy. This finding has potential implications for the prediction and prevention of NRTI-associated PN, particularly in populations at risk of iron deficiency.

Adolescent↗
PubMed2024

Global quantification of off-target activity by base editors.

Base editors are engineered deaminases combined with CRISPR components. These engineered deaminases are designed to target specific sites within DNA or RNA to make a precise change in the molecule. In therapeutics, they hold promise for correcting mutations associated with genetic diseases. However, a key challenge is minimizing unintended edits at off-target sites, which could lead to harmful mutations. Researchers are actively addressing this concern through a variety of optimization efforts that aim to improve the precision of base editors and minimize off-target activity. Here, we examine the various types of off-target activity, and the methods used to evaluate them. Current methods for finding off-target activity focus on identifying similar sequences in the genome or in the transcriptome, assuming the guide RNA misdirects the editor. The main method presented here, that was originally developed to quantify editing levels mediated by the ADAR enzyme, takes a different approach, investigating the inherent activity of base editors themselves, which might lead to off-target edits beyond sequence similarity. The editing index tool quantifies global off-target editing, eliminates the need to detect individual off-target sites, and allows for assessment of the global load of mutations.

Gene Editing↗
PubMed2002

The impact of message mutation on the fitness of a genetic code.

The Standard Genetic Code is organized such that similar codons encode similar amino acids. One explanation suggested that the Standard Code is the result of natural selection to reduce the fitness "load" that derives from the mutation and mistranslation of protein-coding genes. We review the arguments against the mutational load-minimizing hypothesis and argue that they need to be reassessed. We review recent analyses of the organization of the Standard Code and conclude that under cautious interpretation they support the mutational load-minimizing hypothesis. We then present a deterministic asexual model with which we study the mode of selection for load minimization. In this model, individual fitness is determined by a protein phenotype resulting from the translation of a mutable set of protein-coding genes. We show that an equilibrium fitness may be associated with a population with the same genetic code and that genetic codes that assign similar codons to similar amino acids have a higher fitness. We also show that the number of mutant codons in each individual at equilibrium, which determines the strength of selection for load minimization, reflects a long-term evolutionary balance between mutations in messages and selection on proteins, rather than the number of mutations that occur in a single generation, as has been assumed by previous authors. We thereby establish that selection for mutational load minimization acts at the level of an individual in a single generation. We conclude with comments on the shortcomings and advantages of load minimization over other hypotheses for the origin of the Standard Code.

Amino Acids↗
PubMed2004

Prenatal diagnosis of a fetus harboring an intermediate load of the A3243G mtDNA mutation in a maternal carrier diagnosed with MELAS syndrome.

We prenatally diagnosed MELAS syndrome in a fetus whose mother and older brother had the MELAS-specific A3243G mutation. The mutant mtDNA level of the amniotic fluid cells was not significantly different from that of the postnatal peripheral blood and hair follicle samples. The obstetrical course was uncomplicated except for transient exacerbation of the mother's diabetes, which required insulin control. At term, the infant was macrosomic, and the delivery was complicated by shoulder dystocia. MELAS syndrome in itself does not influence either the prenatal course of the mother or the fetal outcome. In contrast to the fulminating clinical course of this mother's first child, MELAS symptoms did not develop in her second child until age four, despite similar high tissue levels of mutant mtDNA. The phenotypic diversity in two offspring with similar higher levels of mutant mtDNA suggests that prenatal genetic diagnosis of cultured amniotic cells may yield results that are poor prognosticators of fetal outcome.

Adult↗
PubMed2006

Genomic instability of the DYZ1 repeat in patients with Y chromosome anomalies and males exposed to natural background radiation.

We assessed genomic instability of 3.4 kb DYZ1 repeat arrays in patients encompassing prostate cancer (PC), cases of repeated abortion (RA) and males exposed to natural background radiation (NBR) using real-time PCR and fluorescence in situ hybridization (FISH). Normal males showed DYZ1 copies ranging from 3000 to 4300, RA, 0-2237; PC, 550; and males exposed to NBR, 1577-5700. FISH showed organizational variation of DYZ1 in these samples substantiating the data obtained from real-time PCR. Of the 10 RA samples, 7 were found to be affected of which, 5 showed deletion of 265 bp from nt 25 to 290 and 773 bp from 1347 to 2119 and 2 showed deletion of 275 bp from nt 3128 to 3402. Copy number variation of DYZ1 in these males correlated with genetic constrains/anomalies. Although precise mechanisms of genomic instability of DYZ1 remains unclear, we construe that this repeat plays a critical role in maintaining the structural integrity of the Y chromosome, possibly by absorbing the load of mutations. This may be used as a marker system to analyze genetic integrity of the DYZ1 repeat array(s) across the spectrum of patients.

Abortion, Induced↗
PubMed2026

High levels of mitotic gene conversion are needed to effectively purge deleterious mutations in asexual organisms.

Self-fertilisation and asexual reproduction are both hypothesised to cause long-term extinction due to inefficient selection against deleterious mutations. Self-fertilisation can counter these effects through creating homozygous genotypes and purging deleterious mutations. Although complete asexuality lacks meiotic gene exchange, mitotic gene conversion creates homozygous regions that could limit deleterious mutation accumulation in an analogous manner. We compare mutation accumulation in self-fertilising and facultative sexual populations subject to mitotic gene conversion, and quantify the efficacy of purging in the latter. We first show analytically that purging is most effective with high levels of asexuality and gene conversion, and when deleterious mutations are recessive. We further show using simulations that, when mitotic gene conversion becomes sufficiently high in obligate asexuals, there is a reduction in the mutation count and a jump in homozygosity, reflecting purging. However, this mechanism is not necessarily as efficient at purging under high self-fertilisation, and elevated rates of mitotic gene conversion seem to be needed for widespread purging compared to empirical estimates. If gene conversion rates are allowed to evolve, then elevated rates that increase mean fitness can arise, but only if there is sufficient variance in the gene conversion rate. Conversely, if gene conversion rates are already high and rates are not constrained then they will slightly decrease, reducing mean fitness.

Self-fertilisation↗
PubMed2025

Compensatory Evolution Following Deleterious Episodes of GC-biased Gene Conversion in Rodents.

GC-biased gene conversion (gBGC) is a widespread evolutionary force associated with meiotic recombination that favors the accumulation of deleterious AT to GC substitutions in proteins, moving them away from their fitness optimum. In many mammals, recombination hotspots have a rapid turnover, leading to episodic gBGC, with the accumulation of deleterious mutations stopping when the recombination hotspot dies. Selection is therefore expected to act to repair the damage caused by gBGC episodes through compensatory evolution. However, this process has never been studied or quantified so far. Here, we analyzed the nucleotide substitution pattern in coding sequences of a highly diversified group of Murinae rodents. Using phylogenetic analyses of about 70,000 coding exons, we identified numerous exon-specific, lineage-specific gBGC episodes, characterized by a clustering of synonymous AT to GC substitutions and by an increasing rate of nonsynonymous AT to GC substitutions, many of which are potentially deleterious. Analyzing the molecular evolution of the affected exons in downstream lineages, we found evidence for pervasive compensatory evolution after deleterious gBGC episodes. Compensation appears to occur rapidly after the end of the episode and to be driven by the standing genetic variation rather than new mutations. Our results demonstrate the impact of gBGC on the evolution of amino-acid sequences and underline the key role of epistasis in protein adaptation. This study contributes to a growing body of literature emphasizing that adaptive mutations, which arise in response to environmental changes, are just 1 subset of beneficial mutations, alongside mutations resulting from oscillations around the fitness optimum.

Gene Conversion↗
PubMed2006

Introduction to chronic hepatitis B infection.

Chronic hepatitis B virus (HBV) infection affects over 350 million people worldwide and over 1 million die annually of HBV-related chronic liver disease. Although many individuals eventually achieve a state of nonreplicative infection, the prolonged immunologic response to infection leads to the development of cirrhosis, liver failure, or hepatocellular carcinoma (HCC) in up to 40% of patients. In endemic areas, where carrier rates are >5%, most individuals are infected perinatally, by vertical transmission, or in early childhood. In the United States, where prevalence is low except in particular areas and populations (e.g., Alaskan natives, immigrants from highly endemic areas), transmission is generally horizontal, percutaneous, or via sexual contact in adulthood. A variety of host (age at infection, gender, immune status); viral (viral load, genotype, mutation); and external (concurrent viral infections, alcohol consumption, chemotherapy) factors influence disease progression. Several variables (age at infection, gender, ethnicity, immune status) also influence the risk of chronic infection. Perinatal transmission, the most common mode of infection worldwide, can be reduced by appropriate prophylaxis (vaccination of the infant at birth together with hepatitis B immune globulin); anti-viral therapy in late pregnancy may also be beneficial. Five drugs are now FDA-approved for the treatment of HBV (interferon, lamivudine, adefovir, entecavir, and peginterferon alfa-2a), and suppressive anti-viral therapy improves the natural history of HBV. Patients with decompensated cirrhosis or HCC are highly likely to die unless they successfully undergo liver transplantation. While novel anti-viral drugs have improved the management of cirrhosis, strategies to prevent and treat HCC remain inadequate.

Antiviral Agents↗
PubMed2000

[Tuberculosis and the human immunodeficiency virus infection].

HIV-1 infection is a major cause of worldwide epidemic of tuberculosis. HIV-1 infection, even in its early stages, markedly reduces effective immune response to M. tuberculosis. In Japan, the cumulative number of the patients reported is 131 by the end of 1999 with 10 to 20 annual new cases. Most of Japanese cases are advanced AIDS patients with low CD4 number less than 100/ml. The peak of Japanese patient age is 40 to 60 years old, whereas that of foreigners is 20-30 years old, suggesting that most Japanese cases are recurrent tuberculosis. There is increasing clinical evidence that coinfection with M. tuberculosis accelerates progression of AIDS. We found that, in vivo, HIV-1 load and mutation increase in involved lung segments in patients with pulmonary tuberculosis. The promotion of HIV-1 production is not only due to activated translocation of a nuclear factor. NF-kB, but also due to reduced inhibitory factor, C/EBPb 16 kD which binds to HIV LTR and represses the transcription of HIV-1.

Acquired Immunodeficiency Syndrome↗
PubMed2000

[Tuberculosis in patients with acquired immune deficiency syndrome].

HIV-1 infection is a major cause of worldwide epidemic of tuberculosis. In Japan, the cumulative number of the patients reported is 131 by the end of 1999 with 10 to 20 annual new cases. Most of Japanese cases are advanced AIDS patients with low CD4 number less than 100/microliter. The peak age of Japanese patient is 40 to 60 years old, whereas that of foreigners is 20-30 years old, suggesting that most Japanese cases are recurrent tuberculosis. There is increasing clinical evidence that coinfection with M. tuberculosis accelerates progression of AIDS. We found that, in vivo, HIV-1 load and mutation increase in involved lung segments in patients with pulmonary tuberculosis. We also reported that Mycobacterium tuberculosis stimulates HIV-1 replication by enhancing transcription on the 5' LTR in a macrophage cell line, THP-1, in vitro. In contrast, HIV-1 replication is suppressed by M. tuberculosis infection of monocytes derived macrophages (MDM) or differentiated monocytic THP-1 cells. We observed that HIV-1 5' LTR function was repressed in PMA differentiated THP-1 cells after co-infection with M. tuberculosis. Point mutations in C/EBP-beta binding domains of the HIV-1 LTR negative regulatory element (NRE) abolished promoter repression. Monocyte-derived macrophages and differentiated THP-1 cells increased expression of the 16 kDa inhibitory from of C/EBP-beta after M. tuberculosis coinfection. Bronchoalveolar lavage cells obtained from normal controls and alveolar macrophages from uninflamed lung of tuberculosis patients also expressed the 16 kDa inhibitory form of C/EBP-beta. However, alveolar macrophages from lung segments involved with pulmonary tuberculosis had markedly reduced C/EBP-beta expression. These data suggest that 16 kDa isoform of C/EBP-beta plays an important role for the control of HIV-1 replication in macrophages. We propose derepression of HIV-1 LTR mediated transcription as one mechanism for enhanced HIV-1 replication observed in pulmonary tuberculosis.

AIDS-Related Opportunistic Infections↗
PubMed2004

[Molecular pathogenesis in tuberculosis complicated with AIDS].

HIV-1 infection is a major cause of worldwide epidemic of tuberculosis. There is increasing clinical evidence that coinfection with M. tuberculosis accelerates progression of AIDS. We found that, in vivo, HIV-1 load and mutation increase in involved lung segments in patients with pulmonary tuberculosis. We also reported that Mycobacterium tuberculosis stimulates HIV-1 replication by enhancing transcription on the 5' LTR in a macrophage cell line, THP-1, in vitro. In contrast, HIV-1 replication is suppressed by M. tuberculosis infection of monocytes derived macrophages (MDM) or differentiated monocytic THP-1 cells. We observed that HIV-1 5' LTR function was repressed in PMA differentiated THP-1 cells after co-infection with M. tuberculosis. Point mutations in C/EBP beta binding domains of the HIV-1 LTR negative regulatory element (NRE) abolished promoter repression. Monocyte-derived macrophages and differentiated THP-1 cells increased expression of the 16kDa inhibitory form of C/EBP after M. tuberculosis co-infection. Bronchoalveolar lavage cells obtained from normal controls and alveolar macrophages from uninflamed lung of tuberculosis patients also expressed the 16kDa inhibitory form of C/EBP. However, alveolar macrophages from lung segments involved with pulmonary tuberculosis had markedly reduced C/EBP expression. These data suggest that 16kDa isoform of C/EBP plays an important role for the control of HIV-1 replication in macrophages. We propose derepression of HIV-1 LTR mediated transcription as one mechanism for enhanced HIV-1 replication observed in pulmonary tuberculosis. Since the cellular immune response in pulmonary tuberculosis requires lymphocyte/macrophage interaction, a model system was developed in which lymphocytes were added to AM. Contact between lymphocytes and AM reduced inhibitory C/EBP beta, activated NF-kappaB and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBP beta expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-kappaB was activated. Antibodies which cross-linked macrophage expressed B-7, VCAM and CD-40 were used mimic lymphocyte contact. Cross-linking antibodies abolished inhibitory C/EBP beta expression; however, the HIV-1 LTR was not maximally stimulated and NF-kappaB was not activated. Maximal HIV-1 LTR stimulation required both lymphocyte derived soluble factors and cross-linking of macrophage expressed co-stimulatory molecules. These results demonstrate that neither contact nor soluble factor(s) are sufficient to maximally enhance HIV-1 LTR activity in macrophages. Contact between activated lymphocytes and macrophages is necessary to downregulate inhibitory C/EBP beta, thereby derepressing the HIV-1 LTR. Lymphocyte derived soluble factor(s) activate NF-kappaB, further enhancing the HIV-1 LTR.

AIDS-Related Opportunistic Infections↗
PubMed1994

Mutagenesis of the H-ras protooncogene and the p53 tumor suppressor gene.

Point mutations in ras protooncogenes and in the p53 tumor suppressor gene are common in many forms of human cancer. The identification of carcinogens which are responsible for their induction in humans is of great interest because it may suggest measures for disease prevention. Furthermore, the load of somatic mutations in cancer-related genes in premalignant tissues may become a useful parameter for risk assessment. For the measurement of such mutations, highly sensitive genotypic mutation systems are required which avoid the selection and clonal expansion of cells on the basis of a mutated phenotype. We have developed the restriction fragment length polymorphism/polymerase chain reaction method for genotypic mutation analysis and applied it to the study of the mutability of hot-spot codons in c-H-ras1 and p53 genes with human carcinogens. In particular, we studied the mutability of codons 247-250 of p53 with the mycotoxin aflatoxin B1 (AFB1) in human hepatocytes. AFB1 preferentially induced the transversion of guanosine to thymidine in the third position of codon 249, generating the same mutation which is found in a large fraction of hepatocellular carcinomas from regions of the world with AFB1-contaminated food. Our results are in support of AFB1 as an etiological factor for hepatocellular carcinoma in AFB1-contaminated areas. In an ongoing study we are comparing the load of mutations in hot-spot codon 12 of c-H-ras1 in urinary bladder carcinoma and in normal tissue, by restriction fragment length polymorphism/polymerase chain reaction. We observed moderately elevated abundances of guanosine to thymidine transversions in the middle position of codon 12 in tumor DNA. These results may reflect a mutator phenotype of the tumor tissue or they could be the consequence of the heterogeneity of the biopsies which were analyzed.

Aflatoxin B1↗
PubMed2001

The -48 C/T polymorphism in the presenilin 1 promoter is associated with an increased risk of developing Alzheimer's disease and an increased Abeta load in brain.

Mutations in the presenilin 1 gene (PS1) account for the majority of early onset, familial, autosomal dominant forms of Alzheimer's disease (AD), whereas its role in other late onset forms of AD remains unclear. A -48 C/T polymorphism in the PS1 promoter has been associated with an increased genetic risk in early onset complex AD and moreover has been shown to influence the expression of the PS1 gene. This raises the possibility that previous conflicting findings from association studies with homozygosity for the PS1 intron 8 polymorphism might be the result of linkage disequilibrium with the -48 CC genotype. Here we provide further evidence of increased risk of AD associated with homozygosity for the -48 CC genotype (odds ratio=1.6). We also report a phenotypic correlation with Abeta(40), Abeta(42(43)), and total Abeta load in AD brains. The -48 CC genotype was associated with 47% greater total Abeta load (p<0.003) compared to CT + TT genotype bearers. These results suggest that the -48 C/T polymorphism in the PS1 promoter may increase the risk of AD, perhaps by altering PS1 gene expression and thereby influencing Abeta load.

Age of Onset↗
PubMed1999

A single mutation, RecB(D1080A,) eliminates RecA protein loading but not Chi recognition by RecBCD enzyme.

Homologous recombination and double-stranded DNA break repair in Escherichia coli are initiated by the multifunctional RecBCD enzyme. After binding to a double-stranded DNA end, the RecBCD enzyme unwinds and degrades the DNA processively. This processing is regulated by the recombination hot spot, Chi (chi: 5'-GCTGGTGG-3'), which induces a switch in the polarity of DNA degradation and activates RecBCD enzyme to coordinate the loading of the DNA strand exchange protein, RecA, onto the single-stranded DNA products of unwinding. Recently, a single mutation in RecB, Asp-1080 --> Ala, was shown to create an enzyme (RecB(D1080A)CD) that is a processive helicase but not a nuclease. Here we show that the RecB(D1080A)CD enzyme is also unable to coordinate the loading of the RecA protein, regardless of whether chi sites are present in the DNA. However, the RecB(D1080A)CD enzyme does respond to chi sites by inactivating in a chi-dependent manner. These data define a locus of the RecBCD enzyme that is essential not only for nuclease function but also for the coordination of RecA protein loading.

DNA Helicases↗