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PubMed1996

Molecular analysis of the cystinuria disease gene: identification of four new mutations, one large deletion, and one polymorphism.

A cystinuria disease gene (rBAT) has recently been identified, but evidence strongly suggests that only Type-I cystinuria is due to mutations in this gene. Sixteen point mutations and a large deletion causing the disease have so far been described in the rBAT gene sequence. To identify new mutated alleles, genomic DNA was analyzed, after the determination of the entire genomic structure of the rBAT gene, by RNA-single strand conformation polymorphism analysis, an accurate and sensitive method able to detect nucleotide changes. Four new point mutations, a large deletion, and a common intragenic polymorphism were detected. These new mutations increase to 22 the number of mutated alleles so far characterized in rBAT. In addition, the frequency of 21 mutations was assessed in a sample of accurately defined Type-I cystinuria chromosomes. They account for about 58% of all Type-I chromosomes, mutation M467T being the most common (0.26).

Alleles↗
PubMed1999

The mitochondrial DNA A3243G mutation in Portugal: clinical and molecular studies in 5 families.

Out of 90 Portuguese patients with mitochondrial cytopathy, six harbored the A3243G mutation in the mtDNA tRNA(Leu(UUR)) gene ('MELAS mutation'). They had heterogeneous clinical features, including myopathy with stroke-like episodes, progressive external ophthalmoparesis, diabetes mellitus, and subacute encephalopathy. Histochemical and biochemical analyses of muscle biopsies showed abundant ragged-red fibers reacting positively with the cytochrome oxidase stain, and decreased respiratory chain enzyme activities. On average, the proportion of mutated mtDNA was 67% (20-88%) in tissues from patients and 21% (0-49%) in blood from 20 maternal relatives. The proportion of mutated mitochondrial genomes in muscle did not correlate with clinical presentation or duration of disease. This study, the first in Portuguese patients, confirms the frequent occurrence of the A3243G mutation in patients with mitochondrial diseases, and emphasises the usefulness of genetic testing in reaching a correct diagnosis.

Adolescent↗
PubMed1989

Specificity and mechanism of error-prone replication by human immunodeficiency virus-1 reverse transcriptase.

DNA-dependent DNA synthesis in vitro by human immunodeficiency virus-1 reverse transcriptase is relatively error-prone. The enzyme, whether recombinant or from virus particles, produces errors while replicating M13mp2 DNA at a rate that, if operative in vivo, would produce about five mutations per genome per round of replication. Sequence analysis of mutants resulting from in vitro synthesis demonstrates that errors are nonrandomly distributed. Base substitution and one-base frameshift mutational hot spots are observed. The specificity and position of errors suggest that most of the frameshifts and many of the base substitutions are initiated by template-primer slippage. Processivity analysis for the enzyme on the M13mp2 DNA template reveals strong termination at specific sites. Termination sites within homopolymer sequences correlate with frameshift mutational hot spots. The results suggest that the formation and/or utilization of misaligned template-primers is increased during the dissociation-reinitiation phase of the reaction.

Base Sequence↗
PubMed1988

[The effect of mutations in recB and recC genes on the precise excision of Tn5 from pNM1 plasmid genome].

The affect of mutations in chromosomal genes determining the realization of RecBC and RecF pathways of recombination in E. coli K12 on the frequency of transposon Tn5 precise excision from the genome of the conjugative plasmid pNM1 has been demonstrated. The pNM1 plasmid is a derivative of R100.1 and differs from the latter in the presence of Tn5 inactivating the tet gene of transposon Tn10.

Conjugation, Genetic↗
PubMed1995

Detection of aberrations in androgen receptor gene by analysis of single-stranded conformation polymorphisms in polymerase chain reaction products.

Analysis of single-stranded conformation polymorphisms in polymerase chain reaction (PCR) products (PCR-SSCP) is a sensitive method for detecting point mutations in genomic DNA. To investigate its utility in examining the androgen receptor gene, we analyzed data on a patient with the testicular feminization syndrome (TFS) with a known point mutation in exon C. We detected mobility shifts of fragments of the corresponding region. Since examination of the subject's brother (legally sister), who also has TFS, revealed an identical shift pattern, we sequenced the exon C of the sibling and detected a mutation identical to that in the former. We conclude that PCR-SSCP is available for screening mutations of the androgen receptor gene.

Adult↗
PubMed2006

Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach.

The heterogeneity and instability of human tumors hamper straightforward identification of cancer-causing mutations through genomic approaches alone. Herein we describe a mouse model of liver cancer initiated from progenitor cells harboring defined cancer-predisposing lesions. Genome-wide analyses of tumors in this mouse model and in human hepatocellular carcinomas revealed a recurrent amplification at mouse chromosome 9qA1, the syntenic region of human chromosome 11q22. Gene-expression analyses delineated cIAP1, a known inhibitor of apoptosis, and Yap, a transcription factor, as candidate oncogenes in the amplicon. In the genetic context of their amplification, both cIAP1 and Yap accelerated tumorigenesis and were required to sustain rapid growth of amplicon-containing tumors. Furthermore, cIAP1 and Yap cooperated to promote tumorigenesis. Our results establish a tractable model of liver cancer, identify two oncogenes that cooperate by virtue of their coamplification in the same genomic locus, and suggest an efficient strategy for the annotation of human cancer genes.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Recurrent mutations in the vasopressin-neurophysin II gene cause autosomal dominant neurohypophyseal diabetes insipidus.

We examined the nucleotide sequence of the arginine vasopressin-neurophysin II gene in three kindreds with autosomal dominant neurohypophyseal diabetes insipidus. Each of the three different mutations identified represents a recurrence of a mutation previously described to cause this disease. These mutations are all transitions (C1761-->T, G1859-->A, and G279-->A) that encode amino acid substitutions Pro24-->Leu, Gly57-->Ser (both in neurophysin II), and Ala-->Thr (in the last amino acid at the C-terminus of the signal peptide). The presence of these mutations in genomic DNA was confirmed by alterations in restriction endonuclease recognition sites. A linkage map of distal chromosome 20 was constructed. To examine the possibility that these apparent recurrent mutations arose independently rather than by an ancestral founder mutation, we analyzed family origins, two polymorphic markers on chromosome 20 in close proximity with this gene (the oxytocin/XbaI restriction fragment length polymorphism and the D20S57 polymorphic CA repeat microsatellite), and/or the occurrence of a de novo mutation in our three families and in four additional families previously reported. Our results suggest that one of our families may share an ancestral founder mutation with one previously reported family, but that in the remainder of the families with identical mutations, these mutations probably arose independently.

Alleles↗
PubMed2025

Clinicopathologic and genomic analyses of SMARCA4-mutated non-small cell lung carcinoma implicate the needs for tailored treatment strategies.

BACKGROUND: The clinicopathologic and therapeutic significance of SMARCA4 mutation in non-small cell lung carcinoma (NSCLC) remains unclear. METHODS: We retrieved 575 NSCLC cases from the clinical target sequencing cohort (N = 2157) to compare the clinicopathologic characteristics of groups subclassified based on the presence of truncated or non-truncated SMARCA4 mutations (SMARCA4-truncated, SMARCA4-non-truncated, and SMARCA4-wild type [WT]). The differences in gene expression profiles between these groups were evaluated using the TCGA-LUAD dataset. RESULTS: Fifty (2.3%) SMARCA4-truncated and 63 (2.9%) SMARCA4-non-truncated NSCLCs were identified. The majority of SMARCA4-truncated NSCLCs were present in male smokers (94.0%) and pathologically diagnosed as adenocarcinoma (76.0%). The SMARCA4-truncated group showed rare targetable driver alterations with a higher tumor mutation burden than the SMARCA4-WT group. Gene expression profile analysis revealed that cancer/testis antigen (CTA) expression was enriched in the SMARCA4-truncated group, with up to 57% of the cases displaying immunoreactivities for MAGEA4, CT45A, and/or PRAME. The SMARCA4-non-truncated group showed heterogeneous clinicopathologic, genomic, and immunohistochemical features that fell between SMARCA4-truncated and WT groups. Both SMARCA4-truncated and non-truncated groups showed significantly poor prognosis with pemetrexed-platinum chemotherapy, yet there was no significant difference in survival following immune checkpoint inhibitor monotherapy. CONCLUSION: SMARCA4-truncated NSCLC represents a variant of driver-negative NSCLC, mainly occurring in male smokers with poorly differentiated adenocarcinoma histology. In contrast, SMARCA4-non-truncated NSCLC indicates a heterogeneous subpopulation, exhibiting intermediate characteristics between the SMARCA4-truncated and SMARCA4-WT groups. While showing poor response to pemetrexed-platinum chemotherapy, increased CTA expression could be a novel therapeutic target in SMARCA4-mutated NSCLCs.

Humans↗
PubMed2004

Chaotic genomes make chaotic cells: the mutator phenotype theory of carcinogenesis applied to clinicopathological relationships of solid tumors.

Abnormalities of cell morphology and chromosomes have been identified as features of the pathology of tumors for more than 100 years. However, no theory of carcinogenesis until recently has provided a basis for relating them either to each other or to the clinical behavior of individual tumors in many patients. The mutator phenotype theory is based on large numbers of mutations occurring chaotically (randomly, unpredictably, and variably from cell to cell) in individual tumors. Chaotic mutation clearly parallels both the often-observed chaotic morphology of tumors and the frequently unpredictable relationship of these morphologies to clinical behavior. Possible implications of this concept for staging, grading, multifocality, and therapy of cancers are discussed.

Cell Transformation, Neoplastic↗
PubMed2006

Mitochondrial tRNA sequences as unusual replication origins: pathogenic implications for Homo sapiens.

The heavy strand of vertebrate mitochondrial genomes accumulates deaminations proportionally to the time it spends single-stranded during replication. A previous study showed that the strength of genome-wide deamination gradients originating from tRNA gene's locations increases with their capacities to form secondary structures resembling mitochondrial origins of light strand replication (OL), suggesting an alternative function for tRNA sequences. We hypothesize that this function is frequently pathogenic for those tRNA genes that normally do not form OL-like structures, because this could cause excess mutations in genome regions unadapted to tolerate them. In human mitochondrial genomes, pathogenic tRNA variants usually form less OL-like structures than non-pathogenic ones in cases where the normal non-pathogenic tRNA variant can function as OL, as evolutionary analyses reveal. For tRNAs lacking the putative OL-like functioning capacity, pathogenic variants form more OL-like secondary structures, particularly structures that might invoke bi-directional replication (true for 14 among 21 tRNA species, p<0.05, sign test; significantly at p<0.05 (1 tailed test) for 7 tRNA species), but not more unidirectional replication invoking structures. Accounting for the functional cloverleaf-like structure-forming capacities of tRNAs yields similar results. Rare, non-pathogenic tRNA mutants tend to form more OL-like structures than the common, non-pathogenic ones, suggesting weak directional selection also among non-pathogenic variants. The duration spent single stranded by a region of the heavy strand (D(ssH)) during replication, estimated by integrating over all regions that can function as OL in Homo sapiens mitochondrial genomes, increases with distance of that region from the Dloop. This suggests convergence of single-strandedness during replication and transcription, and explains conserved locations of tRNA species in mitochondrial genomes and bacterial operons. These locations minimize deamination costs only in anticodons and not in other tRNA regions, during replication and transcription. Therefore, putative functioning as OLs by tRNA sequences is normal at some locations and pathogenic at others.

Aging↗
PubMed1987

Spontaneous reversion of a C/T transition mutation in the adenovirus endoproteinase gene.

A temperature-sensitive mutation (H2ts1) that abolishes the viral endoproteinase activity at the nonpermissive temperature has been mapped by marker rescue between map coordinates 59.8 and 61.9 on the adenovirus type 2 genome. The mutation has been identified by sequencing to be a C/T transition at coordinate 61.1 changing a proline residue to a leucine residue and eliminating a HaeIII restriction enzyme cleavage site (L. Yeh-Kai, G. Akusjarvi, P. Alestrom, U. Pettersson, M. Tremblay, and J. Weber, 1983, J. Mol. Biol. 167, 217-222). This feature of the mutation offered a convenient assay to distinguish between true revertants and suppressor mutations among phenotypic revertants of H2ts1. Seventeen spontaneous revertants were isolated in three independent experiments by picking plaques at 39 degrees after three passages of H2ts1 at 39 degrees in HEp2 cells. All revertants grew like wild-type virus and regained normal endoproteinase activity. The Ncol fragment encompassing the H2ts1 region was terminally labeled and subcleaved with HaeIII to determine the presence or absence of the HaeIII site at 61.1 for each revertant. All revertants had regained the HaeIII site by true reversion. We conclude that the H2ts1 mutation probably lies in a critical domain of the enzyme and is therefore not suppressible, and that the C/T transition at coordinate 61.1 is the sole cause of the H2ts1 phenotype.

Adenoviruses, Human↗
PubMed2000

p53 mutations in hairy cell leukemia.

We have studied the frequency of p53 mutations in genomic DNA extracted from peripheral blood or the spleen of 61 patients with hairy cell leukemia using PCR-SSCP and automated cycle sequencing. We identified exon 5-8 mutations in 17 cases, corresponding to a frequency of 28%. In four cases, mutations were localized in exon 5; one patient with atypical HCL had a mutation in exon 6 at the 3' boundary; five cases showed mutations in exon 7, while exon 8 was found to be mutated in seven cases. The mutations found could be divided into three major categories: structural (n=9), inactivating (n= 6), and neutral (n= 2) mutations. None of the three transitions found occurred at CpG dinucleotides. The rate of p53 mutations found in this large cohort of HCL patients is unexpectedly high as in other non-Hodgkin lymphomas p53 mutations predict for poor treatment outcome. The character of the mutations we have found is entirely different from that described in other hematologic malignancies.

Adult↗
PubMed1994

Obesity, diabetes, and neoplasia in yellow A(vy)/- mice: ectopic expression of the agouti gene.

The viable yellow A(vy) mutation results in a mottled yellow mouse that is obese, slightly larger than its nonyellow sibs, and more susceptible to tumor formation in those tissues sensitized by the strain genome. The mutation exhibits variable expressivity resulting in a continuum of coat color phenotypes, from clear yellow to pseudoagouti. The mouse agouti protein is a paracrine signaling molecule that induces hair follicle melanocytes to switch from the synthesis of black pigment to yellow pigment. Molecular cloning studies indicate that the obesity and growth effects of the A(vy) mutation result from ectopic expression of the normal agouti gene product. This review seeks to summarize the current state of knowledge regarding the obesity, stimulation of somatic growth, and enhancement of tumor formation caused by the A(vy) mutation, and to interpret these pleiotropic effects in terms of the normal function of the agouti protein.

Agouti Signaling Protein↗
PubMed1988

Herpes simplex virus virion host shutoff function.

Herpes simplex virus (HSV) virions contain one or more functions which mediate the shutoff of host protein synthesis and the degradation of host mRNA. HSV type 1 (HSV-1) mutants deficient in the virion shutoff of host protein synthesis (vhs mutants) were isolated and were found to be defective in their ability to degrade host mRNA. Furthermore, it was found that viral mRNAs in cells infected with the vhs 1 mutant have a significantly longer functional half-life than viral mRNAs in wild-type virus-infected cells. In the present study we have mapped the vhs1 mutation affecting the virion shutoff of host protein synthesis to a 265-base-pair NruI-XmaIII fragment spanning map coordinates 0.604 to 0.606 of the HSV-1 genome. The mutation(s) affecting the functional half-lives of host mRNA as well as the alpha (immediate-early), beta (early), and gamma (late) viral mRNAs were also mapped within this 265-base-pair fragment. Thus, the shutoff of host protein synthesis is most likely mediated by the same function which decreases the half-life of viral mRNA. The shorter half-life of infected-cell mRNAs may allow a more rapid modulation of viral gene expression in response to changes in the transcription of viral genes. Interestingly, the vhs1 mutation of HSV-1 maps within a region which overlaps the Bg/II-N sequences of HSV-2 DNA shown previously to transform cells in culture. The possible relationship between the transformation and host shutoff functions are discussed.

Animals↗
PubMed2004

[Mutational analysis of three Chinese pedigrees with adrenoleukodystrophy].

OBJECTIVE: To identify the mutational genotype of three Chinese families with X-linked adrenoleukodystrophy (X-ALD: MIM#300100). METHODS: Total RNA was extracted from the peripheral blood leukocytes of patients 1, 2 and the mother of patient 3, using RNA blood Mini kit (QIAGEN). After reverse transcription, cDNA was amplified in four overlapping segments. The PCR products were purified and directly sequenced. To confirm the mutations, the genomic DNA was isolated from the patients and their family members using DNA blood isolation kit (MO-BIO) and analyzed by PCR-restrictive digestion or amplification refractory mutation system. RESULTS: Three distinct mutations were detected in the ABCD1 gene of the three pedigrees. A mutation of CCC-->CGC was detected at codon 534 of the ABCD1 gene from patient 1, resulting in the arginine for proline substitution. A change of GGG-->AGG was found at codon 266 of the second patient's gene, accompanied with the replacement of glycine by arginine. A mutation of CGC-->GGC was found at codon 617 in one ABCD1 allele of the third patient's mother, leading to the glycine for arginine substitution. The three mutations were confirmed through restriction analysis or amplification refractory mutation system. CONCLUSION: Three ABCD1 gene missense mutations were detected in three unrelated Chinese families with X-linked adrenoleukodystrophy, one of which, the mutation (P534R), is novel in Chinese with ALD, and the other two G266R and R617G mutations, have been reported outside China.

ATP Binding Cassette Transporter, Subfamily D, Mem↗
PubMed1996

Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome.

Apert syndrome is a distinctive human malformation characterized by craniosynostosis and severe syndactyly of the hands and feet. It is caused by specific missense substitutions involving adjacent amino acids (Ser252Trp or Pro253Arg) in the linker between the second and third extracellular immunoglobulin domains of fibroblast growth factor receptor 2 (FGFR2). We have developed a simple PCR assay for these mutations in genomic DNA, based on the creation of novel (SfiI) and (BstUI) restriction sites. Analysis of DNA from 70 unrelated patients with Apert syndrome showed that 45 had the Ser252Trp mutation and 25 had the Pro253Arg mutation. Phenotypic differences between these two groups of patients were investigated. Significant differences were found for severity of syndactyly and presence of cleft palate. The syndactyly was more severe with the Pro253Arg mutation, for both the hands and the feet. In contrast, cleft palate was significantly more common in the Ser252Trp patients. No convincing differences were found in the prevalence of other malformations associated with Apert syndrome. We conclude that, although the phenotype attributable to the two mutations is very similar, there are subtle differences. The opposite trends for severity of syndactyly and cleft palate in relation to the two mutations may relate to the varying patterns of temporal and tissue-specific expression of different fibroblast growth factors, the ligands for FGFR2.

Acrocephalosyndactylia↗
PubMed2002

A new mutation delivery system for genome-scale approaches in Bacillus subtilis.

In Bacillus subtilis, although many genetic tools have been developed, gene replacement remains labour-intensive and not compatible with large-scale approaches. We have developed a new one-step gene replacement procedure that allows rapid alteration of any gene sequence or multiple gene sequences in B. subtilis without altering the chromosome in any other way. This novel approach relies on the use of upp, which encodes uracil phosphoribosyl-transferase, as a counter-selectable marker. We fused the upp gene to an antibiotic-resistance gene to create an 'upp-cassette'. A polymerase chain reaction (PCR)-generated fragment, consisting of the target gene with the desired mutation joined to the upp-cassette, was integrated into the chromosome by homologous recombination, using positive selection for antibiotic resistance. Then, the eviction of the upp-cassette from the chromosome by recombination between short repeated chromosomal sequences, included in the design of the transforming DNA molecule, was achieved by counter-selection of upp. This procedure was successfully used to deliver a point mutation, to generate in-frame deletions with reduced polar effects, and to combine deletions in three paralogous genes encoding two-component sensor kinases. Also, two chromosome regions carrying previously unrecognized essential functions were identified, and large deletions in two dispensable regions were combined. This work outlines a strategy for identifying essential functions that could be used at genome scale.

Amino Acid Sequence↗