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PubMedDate not supplied

Preliminary characterization of cis interactions between mutations of poliovirus genome.

The effects of three distinct point mutations in the P3 genomic region of poliovirus type 1 (Mahoney strain) have previously been analysed. A U to C change at position 5658, which modifies the proteinase 3C, is responsible for a small plaque phenotype and defective RNA replication. An A to G change at position 7256, which modifies the replicase 3D, is responsible for temperature sensitivity. A C to U change at position 7348, which is silent at the protein level, has no apparent phenotypic effect. These three mutations were introduced into a single poliovirus genome by recombinant cDNA techniques. The resulting plurimutant virus, vHA507, was temperature-sensitive and exhibited a small plaque phenotype. Both these characters were accentuated compared to those of the viruses in which the mutations were on separate genomes. Spontaneous ts+ revertants of vHA507 arose by true reversion of the replicase mutation. The small plaque phenotype and defective RNA replication were partially suppressed in the case of these revertants, despite the fact that the proteinase mutation was still present on their genomes. This suppression was assumed to be due to the presence of the silent mutation at position 7348. This system provides a simple model of cis interactions within the poliovirus genome.

DNA-Directed RNA Polymerases↗
PubMed1994

Cancers beget mutations versus mutations beget cancers.

Despite the plethora of "oncogenes" and "tumor suppressor genes," the hypothesis that cancer is usually the result of genomic mutations may be wrong. We should at least examine the alternative hypothesis, for which there is considerable evidence, that mutations do not commonly beget cancer, but rather that cancer phenotypes result from confused or aberrant patterns of normal-gene expression; the abnormal patterns are postulated to result from epigenetic mechanisms rather than from mutations. The epigenetic hypothesis that I am proposing suggests that cancers may exhibit mutations primarily because replicative errors at inactive sites in the cancer genome may be repaired slowly or not at all, but the mutations so produced, occurring at already inactivated sites in the genome, may have limited biological significance. Thus, it may be more correct to say that cancers beget mutations than it is to say that mutations beget cancers.

Animals↗
PubMed2000

Genotyping in HIV drug resistance mutations: epidemiology in 145 patients.

The epidemiology of HIV-1 genomic mutations causing antiretroviral drug resistance, in 145 HIV-1 infected patients were obtained using a new sequencing technique. All patients were in a follow up treatment for at least 4 months with all drugs available in clinical practice in accordance to international guidelines. The percentage of the mutations were calculated both on the number of all participants and on the number of patients who received the drugs selecting for that specific resistance. It was possible then to evaluate patients who showed the mutation without receiving the drug. We consider this new sequencing method reliable and hopeful in clinical practice, giving the opportunity for a guided therapy for the single patient and in detecting and monitoring the antiretroviral drug resistance mutations in the pertinent geographic area following a periodic surveillance program.

Adult↗
PubMed1997

Evidence for a selectively favourable reduction in the mutation rate of the X chromosome.

The equilibrium per-genome mutation rate in sexual species is thought to result from a trade-off between the benefits of reducing the deleterious mutation rate and the costs of increasing fidelity. We propose that selection will often favour a lower mutation rate on the X chromosome than on autosomes, owing to the exposure of deleterious recessive mutations on hemizygous chromosomes. We tested this hypothesis by examining 33 X-linked genes that have been sequenced in both mouse and rat, and compared their rate of evolution against 238 autosomal genes. The X-linked genes were found to have a significantly lower rate of synonymous substitution than the autosomal genes. Neither the supposed higher mutation rate in males nor stronger purifying selection against slightly deleterious mutations on the X chromosome can account for the low value. The most parsimonious explanation is that rodents have a lower mutation rate on the X chromosome than on autosomes. It is therefore likely that previous indirect estimates of the excess male mutation rate are inaccurate. Indeed, after correction we find no evidence for a male-biased mutation rate in rodents. Furthermore, the rate of synonymous substitution in Y-linked genes is not significantly different from that in autosomal ones. The extent to which enhanced male mutation rates are problematic for the mutational deterministic model of the evolution of sex must, in turn, be questioned.

Animals↗
PubMed2025

ProgModule: A novel computational framework to identify mutation driver modules for predicting cancer prognosis and immunotherapy response.

BACKGROUND: Cancer originates from dysregulated cell proliferation driven by driver gene mutations. Despite numerous algorithms developed to identify genomic mutational signatures, they often suffer from high computational complexity and limited clinical applicability. METHODS: Here, we presented ProgModule, an advanced computational framework designed to identify mutation driver modules for cancer prognosis and immunotherapy response prediction. In ProgModule, we introduced the Prognosis-Related Mutually Exclusive Mutation (PRMEM) score, which optimizes the balance between exclusive mutation coverage and the incorporation of mutation combination mechanisms critical for cancer prognosis. RESULTS: Applying to BLCA and HNSC cohorts, ProgModule successfully identified driver modules that stratify patients into distinct prognostic subgroups, and the combination of these modules could serve as an effective prognostic biomarker. Extending our method to diverse cancers, ProgModule presented robust prognostic performance and stability across model parameters, including stopping criteria and network topology. Moreover, our analysis suggested that driver modules can predict immunotherapeutic benefit more effectively than existing signatures. Further analyses based on published CRISPR data indicated that genes within these modules may serve as potential therapeutic targets. CONCLUSIONS: Altogether, ProgModule emerges as a powerful tool for identifying mutation driver modules as prognostic and immunotherapy response biomarkers, and genes within these modules may be used as potential therapeutic targets for cancer, offering new insights into precision oncology.

Humans↗
PubMed2004

Characterization of Hprt mutations in cDNA and genomic DNA of T-cell mutants from control and 1,3-butadiene-exposed male B6C3F1 mice and F344 rats.

A multiplex PCR procedure for analysis of genomic DNA mutations in the mouse hypoxanthine-guanine phosphoribosyltransferase (Hprt) gene was developed and then used with other established methods for the coincident identification of large- and small-scale genetic alterations in the Hprt gene of mutant T-cell isolates propagated from sham- and 1,3-butadiene (BD)-exposed mice and rats. The spectra data for RT-PCR/cDNA analysis and multiplex PCR of genomic DNA from Hprt mutants were combined, and statistical analyses of the mutant fractions for the classes of mutations identified in control versus exposed animals were conducted. Under the assumption that the mutant fractions are distributed as Poisson variates, BD exposure of mice significantly increased the frequencies of (1) nearly all types of base substitutions; (2) single-base deletions and insertions; and (3) all subcategories of deletions. Significantly elevated fractions of G:C-->C:G and A:T-->T:A transversions in the Hprt gene of BD-exposed mice were consistent with the occurrence of these substitutions as the predominant ras gene mutations in multiple tumor types increased in incidence in carcinogenicity studies of BD in mice. BD exposure of rats produced significant increases in (1) base substitutions only at A:T base pairs; (2) single-base insertions; (3) complex mutations; and (4) deletions (mainly 5' partial and complete gene deletions). Future coincident analyses of large- and small-scale mutations in rodents exposed to specific BD metabolites should help identify species differences in the sources of deletion mutations and other types of mutations induced by BD exposures in mice versus rats.

Animals↗
PubMedDate not supplied

Biophysical and genetic evidence for transformation in plants.

In thiamine mutants of Arabiodopsis, genetic corrections have been obtained by treatment with DNA bearing a thiamine information. When correction is attempted under selective conditions, about 0.7% of the treated plants grow and set fruit. Their progeny and the following ones, obtained by selfing, behave as homozygotes. Segregation of characters is found only when correction is attempted under nonselective conditions or when the correcting genes were of plasmidian origin. The correction is hereditary; results of backcrosses and test crosses indicate that it is dominant, nuclear, and strongly bound to the genome. The corrective factor appears to be added to the mutated genome and not substituted for the mutation, as it can be suppressed by outcrossing with the wild type or with a plant corrected by another DNA.

DNA, Bacterial↗
PubMedDate not supplied

Point mutation of the mitochondrial genome in Japanese deaf-mutism.

Recently, a number of hearing-impaired individuals with mitochondrial genome (mtDNA) mutations have been reported, and it is well known that the mtDNA mutations are responsible for the hearing disorder. We have demonstrated that the mtDNA mutation A3243G is responsible for adult-onset sensorineural hearing loss (SNHL). At the same time, a case in which SNHL occurred within 2 years from birth has been reported. The mtDNA mutations may be possible causes of prelingual deafness. In the present study, the mtDNA fragments from the deaf-mute persons were amplified by polymerase chain reaction, followed by a restriction enzyme fragment length polymorphism method and direct sequencing. We failed to find A3243G involvement in 46 deaf-mutes but found that 8.7% of them had A1555G which is an important cause of prelingual deafness, no less than autosomal recessive inheritance, in Japan.

Adult↗
PubMed1997

Gene dosage effect in one family with myoclonic epilepsy and ragged-red fibers (MERRF).

OBJECTIVES: We analyzed the percentage of mitochondrial DNA (mtDNA) heteroplasmy in blood samples of 13 individuals belonging to a three family generation of myoclonic epilepsy with ragged-red fibers (MERRF) and compared the 5 affected patients and the 8 unaffected relatives. MATERIAL AND METHODS: DNA was extracted from blood and muscle of the proband and from blood of 12 maternal relatives. A PCR restriction analysis method was used to detect the mutation. RESULTS: The proband had the complete MERRF phenotype. The phenotype in three other individuals in the maternal lineage was consistent with the MERRF syndrome. The remaining were asymptomatic. The np 8344 mutation was observed in muscle and blood of the proband, and in blood from every one of 12 maternal relatives, ranging from 44% to 83% of mutated genomes. Symptomatic individuals had higher levels (P < 0.001) of mutated mtDNA than asymptomatic maternal relatives. However, high proportions of mutant genomes (up to 63%) were found in asymptomatic relatives. CONCLUSIONS: Although there seems to be a gene dosage effect in MERRF, we found no absolute relationship between the relative proportion of mutant genomes in blood and clinical severity. Factors other than gene dosage in blood may account for the differences in clinical phenotype.

Adult↗
PubMed1997

The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2.

The activin receptor-like kinase 1 gene (ALK-1) is the second locus for the autosomal dominant vascular disease hereditary hemorrhagic telangiectasia (HHT). In this paper we present the genomic structure of the ALK-1 gene, a type I serine-threonine kinase receptor expressed predominantly in endothelial cells. The coding region is contained within nine exons, spanning < 15 kb of genomic DNA. All introns follow the GT-AG rule, except for intron 6, which has a TAG/gcaag 5' splice junction. The positions of introns in the intracellular domain are almost identical to those of the mouse serine-threonine kinase receptor TSK-7L. By sequencing ALK-1 from genomic DNA, mutations were found in six of six families with HHT either shown to link to chromosome 12q13 or in which linkage of HHT to chromosome 9q33 had been excluded. Mutations were also found in three of six patients from families in which available linkage data were insufficient to allow certainty with regard to the locus involved. The high rate of detection of mutations by genomic sequencing of ALK-1 suggests that this will be a useful diagnostic test for HHT2, particularly where preliminary linkage to chromosome 12q13 can be established. In two cases in which premature termination codons were found in genomic DNA, the mutant mRNA was either not present or present at barely detectable levels. These data suggest that mutations in ALK-1 are functionally null alleles.

Activin Receptors↗
PubMed1994

Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase.

Mutations in the gene for Bruton's tyrosine kinase (Btk) are responsible for X-linked agammaglobulinemia (XLA). Thus far, mutations in this gene have been identified based on alterations in Southern or Northern blot analysis or cDNA sequence. To permit detection of mutations in genomic DNA, we designed PCR primers to flank each of the 19 exons of Btk with splice sites. Two overlapping PCR products were employed for exons longer than 230 base pairs. Single strand conformation polymorphism (SSCP) analysis was used to screen PCR products from 30 unrelated families presumed to carry a Btk mutation. It was possible to amplify DNA in every reaction from every patient, indicating that large deletions in Btk are uncommon. Twenty three different mutations were found in 25 unrelated families, including one family in whom DNA was available from a carrier but not an affected patient. Seven mutations were single base pair substitutions resulting in premature stop codons scattered throughout the gene. Small insertions or deletions causing frameshifts and secondary premature stop codons constituted an additional seven mutations. One patient had a point mutation in the start codon and one patient had a mutation in a splice donor site. Point mutations resulting in amino acid substitutions were seen in nine patients. Northern blot analysis of RNA from three patients with premature stop codons showed an absence of Btk transcript whereas four patients with amino acid substitutions had normal amounts of transcript of normal size. These studies document the considerable variability in the Btk mutations causing XLA and they demonstrate an approach that will be useful for carrier detection as well as mutation identification.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1987

Obese (ob/ob) and diabetes (db/db) mutations: two factors modulating brain and peripheral tissue accumulation of estradiol in C57BL/KsJ mice.

The effect of two mutant genes for obesity (ob/ob) and diabetes (db/db) on the accumulation rate of radiolabeled estradiol was examined in female C57BL/KsJ mice. Mutant mice were match-paired with normal (+/?) animals at 16 weeks of age. All ob/ob and db/db mice exhibited overt obesity and hyperglycemia relative to normals. The distribution and uptake of the radiolabeled estradiol was subsequently examined in specified CNS and peripheral tissues. In all cases, the db/db and ob/ob mutant conditions resulted in a depressed cellular accumulation of radiolabeled estradiol in both CNS and peripheral tissues relative to normal mice. The ob/ob mutation resulted in a more severe depression of tissue estradiol uptake than did the db/db mutation. These studies indicate that the abnormal metabolic and hormonal states induced by the mutations, and not the mere presence of the genomic mutation itself, probably accounts for the depressed cellular affinity for gonadal steroids in these murine models.

Animals↗
PubMedDate not supplied

Assessing the relative incidence of mitochondrial DNA A3243G in migraine without aura with maternal inheritance.

OBJECTIVE: To determine whether patients with migraine without aura with maternal "inheritance" are affected by a monosymptomatic form of the MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) or carry the most common mitochondrial DNA (mtDNA) mutation associated with MELAS, namely the A3243G transition in the transfer RNA (tRNA)Leu(UUR) gene. BACKGROUND: The association between migraine and abnormal mitochondrial function has been suggested on clinical, biochemical, and neuroradiological grounds. Migraine attacks with vomiting and cerebral infarctions, most often in the posterior cerebral regions, which are reminiscent of complicated migraine, are typical features of MELAS. The observation that migrainous patients have affected mothers more often than affected fathers suggests a possible role for maternally transmitted genetic factors. METHODS: We studied 25 patients with migraine with aura whose mothers were also affected. A sensitive polymerase chain reaction restriction fragment length polymorphism analysis was used to detect mutated genomes. CONCLUSIONS: We failed to detect the MELAS mutation, but migraine may still be associated with point mutations of mtDNA other than A3243G or with as-yet-unidentified nuclear DNA factors related to mitochondrial function.

Adolescent↗
PubMed2002

Computational model of the modulation of gene expression following DNA damage.

High linear energy transfer (LET) radiation, such as heavy ions or neutrons, has an increased biological effectiveness compared to X rays for gene mutation, genomic instability, and carcinogenesis. In the traditional paradigm, mutations or chromosomal aberrations are causative of late effects. However, in recent years experimental evidence has demonstrated the important role of the description of the modification of gene expression by radiation in understanding the mechanisms of radiation action. In this report, approaches are discussed to the mathematical description of mRNA and protein expression kinetics following DNA damage. Several hypotheses for models of radiation modulation of protein expression are discussed including possible non-linear processes that evolve from the linear dose responses that follow the initial DNA damage produced by radiation.

Cell Division↗
PubMed1993

Retinitis pigmentosa, ataxia, and mental retardation associated with mitochondrial DNA mutation in an Italian family.

An Italian pedigree including two sisters and their mother affected by a neuro-ophthalmic disease characterised by retinitis pigmentosa, ataxia, and psychomotor retardation is reported. Molecular analysis of mitochondrial DNA showed the presence of heteroplasmic 8993 point mutation in the subunit 6 of the ATPase gene. The clinical features and genetic findings in this family were comparable with those recently described in an English family. The mitochondrial DNA analysis of the family showed a correlation between the amount of mutated DNA and the disease severity in the probands, and indicated the presence of a threshold amount of mutated genome inducing ophthalmic defects. Moreover, the comparative analysis of blood, hairs, muscle, and urinary tract epithelia of two probands revealed an essentially similar distribution of mutated and wild type mitochondrial genomes. Our results suggest that the 8993 mitochondrial DNA mutation characterises a disease with similar clinical features in different populations.

Adolescent↗
PubMed1998

Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations.

To facilitate the evaluation of ATM heterozygotes for susceptibility to other diseases, such as breast cancer, we have attempted to define the most common mutations and their frequencies in ataxia-telangiectasia (A-T) homozygotes from 10 ethnic populations. Both genomic mutations and their effects on cDNA were characterized. Protein-truncation testing of the entire ATM cDNA detected 92 (66%) truncating mutations in 140 mutant alleles screened. The haplotyping of patients with identical mutations indicates that almost all of these represent common ancestry and that very few spontaneously recurring ATM mutations exist. Assays requiring minimal amounts of genomic DNA were designed to allow rapid screening for common ethnic mutations. These rapid assays detected mutations in 76% of Costa Rican patients (3), 50% of Norwegian patients (1), 25% of Polish patients (4), and 14% of Italian patients (1), as well as in patients of Amish/Mennonite and Irish English backgrounds. Additional mutations were observed in Japanese, Utah Mormon, and African American patients. These assays should facilitate screening for A-T heterozygotes in the populations studied.

Ataxia Telangiectasia↗
PubMed1999

Cloning of multiple keratin 16 genes facilitates prenatal diagnosis of pachyonychia congenita type 1.

Pachyonychia congenita type 1 (PC-1) is an autosomal dominant ectodermal dysplasia characterized by severe nail dystrophy, focal non-epidermolytic palmoplantar keratoderma (FNEPPK) and oral lesions. We have previously shown that mutations in keratin K16 cause fragility of specific epithelia resulting in phenotypes of PC-1 or FNEPPK alone. These earlier analyses employed an RT-PCR approach to avoid amplification of K16-like pseudogenes. Here, we have cloned the K16 gene (KRT16A) and two homologous pseudogenes (psiKRT16B and psiKRT16C), allowing development of a genomic mutation detection strategy based on a long-range PCR, which is specific for the functional K16 gene. We report a novel heterozygous 3 bp deletion mutation (388del3) in K16 in a sporadic case of PC-1. The mutation was detected in genomic DNA and confirmed at the mRNA level by RT-PCR, showing that our genomic PCR system is reliable for K16 mutation detection. Using this system, we carried out the first prenatal diagnosis for PC-1 using CVS material, correctly predicting a normal fetus. This work will greatly improve K16 mutation analysis and allow predictive testing for PC-1 and the related phenotype of FNEPPK.

Abnormalities, Multiple↗
PubMed1996

Accumulation of deletions and point mutations in mitochondrial genome in degenerative diseases.

Accumulation of various mutations in the mitochondrial genome is proposed as an important contributor to aging and degenerative diseases. Extensive fragmentation of mtDNA was detected in association with increased 8-hydroxydeoxyguanosine content in the heart mitochondrial DNA (mtDNA) from a patient with premature aging and mitochondrial cardiomyopathy, who carried a mutation within the mitochondrial tRNA(Asp) gene. This result suggests that damage to mtDNA by hydroxyl radical and accumulation of deleted mtDNA can be accelerated by a specific mitochondrial genotype. Similarly, extensive fragmentation of mtDNA was also detected in cultured cells exposed to a high oxygen concentration atmosphere, implying that mtDNA is vulnerable to reactive oxygen species. To clarify the role of point mutations accumulated in mtDNA, we examined the sequence heterogeneity of mtDNA in the skeletal muscle of a MELAS patient who carried a mutation within the mitochondrial tRNA(leu)(UUR) gene. The analysis revealed that the frequency of mutant clones in the MELAS muscle was significantly higher than those in an age-matched control muscle and a control placenta. Some of these nucleotide substitutions were missense and nonsense mutations, which potentially have deleterious effects on the mitochondrial function. The frequency of nucleotide substitutions in the striatum of three patients with Parkinson's disease was also significantly higher than that in control tissues. We also observed increased protein modification by 4-hydroxy-2-nonenal, a lipid peroxidation by-product, in Parkinson's disease. These results suggests that a vicious cycle contributes to the progression of degenerative process. In this cycle, first a primary mitochondrial mutation(s) induces a mitochondrial respiratory defect, which increases the leakage of reactive oxygen species (ROS) from the respiratory chain. Then the ROS would trigger accumulation of secondary mtDNA mutations in postmitotic cells, leading to further aggravation of mitochondrial respiratory defects and increased production of ROS and lipid peroxides from mitochondria, and thus resulting in degeneration of cellular components.

Aged↗