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PubMed2003

Identification of novel genes with somatic frameshift mutations within coding mononucleotide repeats in colorectal tumors with high microsatellite instability.

We have systematically retrieved genes with coding mononucleotide repeats from sequence databases and analyzed them for mutations in tumors with high levels of microsatellite instability (MSI-H). We found somatic frameshift mutations in 7/13 genes previously not analyzed in MSI-H tumors. According to the frequency of mutations in MSI-H tumors, these genes could be divided into genes with high coding mononucleotide repeat instability (CMRI-H) and genes with low coding mononucleotide instability (CMRI-L). CMR-H genes were mutated in more than 9/38 and CMRI-L in less than 4/38 of MSI-H tumors. Four genes in our study were CMRI-H and could thus possibly play a role in the development of MSI-H tumors: TFE3 (9/38), TEF4 (12/38), RGS12 (11/38), and TCF1 (12/38). Our results suggest that systematic identification of genes with CMR in the sequence databases and determination of mutation frequency in MSI-H tumors might be a powerful tool for identification of new molecular targets in the development of MSI-H tumors.

Adenocarcinoma↗
PubMed1970

ICR-induced frameshift mutations in the histidine operon of Salmonella.

Both the acridine half-mustard, ICR191, and the nonalkylating azaacridine derivative, ICR364-OH, induce three classes of frameshift mutations in the histidine operon of Salmonella typhimurium. (i) One class is completely stable in reversion tests and is presumed to represent deletion of one or a few critical nucleotide pairs or two nearby frameshifts. One extended deletion was found out of 11 stable mutations. (ii) Of two spontaneously reverting classes which also are considered to predominantly involve base deletions, one is unaffected in reversion with ICR191, nitrosoguanidine, and diethylsulfate, and the other is induced to revert with ICR191. (iii) A third class, considered to predominantly involve base additions, responds in reversion tests with ICR191 as well as with nitrosoguanidine and diethylsulfate. Other investigators have shown that one mutant of this class is a "plus" frameshift and that nitrosoguanidine acts in reversion to delete a guanine plus cytosine base pair. Although such plus frameshifts are found with high frequency among mutations selected from acridine-treated bacteria or when strong selection pressure is applied for their detection in reversion tests, data from this laboratory indicate that this class of plus frameshifts is rare among mutations derived spontaneously or after treatment with a variety of other mutagens. Finally, we demonstrate that the alkylating ICR191 and the nonalkylating ICR364-OH preferentially cause mutations in different chromosome regions and that their spectra of activity only partially overlap that found for spontaneous frameshift mutations.

Acridines↗
PubMed1999

Frameshift mutations at mononucleotide repeats in caspase-5 and other target genes in endometrial and gastrointestinal cancer of the microsatellite mutator phenotype.

The majority of tumors from hereditary nonpolyposis colorectal cancer families and a subset of unselected gastrointestinal and endometrial tumors exhibit a microsatellite mutator phenotype (MMP) that leads to the accumulation of hundreds of thousands of clonal mutations in simple repeat sequences. The mutated genes with positive or negative roles in cell growth or survival in aneuploid gastrointestinal cancer (e.g., APC, K-ras, and p53) are less frequently mutated in near-diploid MMP gastrointestinal tumors. These tumors accumulate mutations in other genes, such as DNA mismatch repair hMSH3 and hMSH6, transforming growth factor-beta type II receptor, and BAX. All these genes carry, within their coding sequences, mononucleotide repeats that are preferred targets for the MMP. Endometrial carcinoma is the most common type of extracolonic neoplasia in the hereditary nonpolyposis colorectal cancer syndrome, but the spectrum of its target cancer genes is not well characterized. Here, we report that endometrial cancer of the MMP also accumulates mutations in genes that are typically mutated in gastrointestinal cancer of the mutator pathway, including BAX (55%), hMSH3 (28%), and hMSH6 (17%). We also report the detection of frameshift mutations in caspase-5, a member of the caspase family of proteases that has an (A)10 repeat within its coding region, in MMP tumors of the endometrium, colon, and stomach (28, 62, and 44%, respectively). We therefore suggest caspase-5 as a new target gene in the microsatellite mutator pathway for cancer.

Caspases↗
PubMed2003

Frameshift mutations in caspase-5 and other target genes in leukemia and lymphoma cell lines having microsatellite instability.

Microsatellite instability (MSI) was examined in 49 lymphoid leukemia/lymphoma cell lines. Frameshift mutations within eight MSI target genes were analyzed in the 12 cell lines and nine childhood acute lymphoblastic leukemia (ALL) samples with MSI. Six cell lines (50%) showed mutations within the coding repeats of the BLM, caspase-5, TCF-4, and PTEN genes. No mutations were identified in the nine childhood ALL samples with MSI. This is the first report that describes mutations of these genes in hematological malignancies. Mutations, presumably caused by an abnormality of the DNA repair genes, may be selected for during the establishment of cell lines.

Adenosine Triphosphatases↗
PubMed1991

Two frameshift mutations in the cystic fibrosis gene.

Cystic fibrosis (CF) is a recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. We have identified in exon 7 two frameshift mutations, one caused by a two-nucleotide insertion and the other caused by a one-nucleotide deletion; these mutations--CF1154insTC and CF1213delT, respectively, are predicted to shift the reading frame of the protein and to introduce UAA(ochre) termination codons at residues 369 and 368.

Adolescent↗
PubMed1996

A common frameshift mutation in von Willebrand factor does not alter mRNA stability but interferes with normal propeptide processing.

Quantitative defects in von Willebrand factor (VWF) result in type 1 and type 3 von Willebrand disease (VWD). This study characterizes the defect in VWF expression resulting from a single nucleotide deletion in VWF exon 18, a mutation previously reported to be common among type 3 VWD patients. A severely affected (type 3) VWD patient in the current pedigree is homozygous for the mutation, whereas heterozygous individuals exhibit variable expression of type 1 VWD. In contrast to the previously reported high frequency of the exon 18 deletion in Sweden and Germany, this mutation appears to be infrequent among type 3 VWD patients in the United States. Although this frameshift mutation results in proximal premature termination of VWF translation, the abnormal VWF mRNA is stable. The mutant truncated recombinant VWF protein is retained within the transfected cell, and no propeptide processing is observed, suggesting a defect in protein folding. Cotransfection of mutant and wild-type recombinant VWF fails to demonstrate a dominant effect of the mutant on the normal allele. Consistent with these results, plasma VWF propeptide of the homozygous individual was markedly reduced whereas heterozygotes exhibited moderately reduced levels. In contrast to type 2A VWD (group 1), the misfolded mutant protein does not appear to exert a dominant-negative effect on normal VWF subunits expressed from the wild-type allele.

Exons↗
PubMed1992

Reading-frame restoration with an apolipoprotein B gene frameshift mutation.

We examined a mutant human apolipoprotein B (apoB) allele that causes hypobetalipoproteinemia and has a single cytosine deletion in exon 26. This frameshift mutation was associated with the synthesis of a truncated apoB protein of the predicted size; however, studies in human subjects and minigene expression studies in cultured cells indicated that the mutant allele also yielded a full-length apoB protein. The 1-base-pair deletion in the mutant apoB allele created a stretch of eight consecutive adenines. To understand the mechanism whereby the mutant apoB allele yielded a full-length apoB protein, the cDNA from cells transfected with the mutant apoB minigene expression vector was examined. Splicing of the mRNA was normal; however, 11% of the cDNA clones had an additional adenine within the stretch of eight adenines, yielding nine consecutive adenines. The insertion of the extra adenine, presumably during apoB gene transcription, is predicted to restore the correct apoB reading frame, thereby permitting the synthesis of a full-length apoB protein.

Alleles↗
PubMed1990

Induction of frameshift mutations by caffeine in Escherichia coli K12.

Caffeine induced reversions of five different frameshift mutations in Escherichia coli K12. Only those mutations which were very sensitive to reversion-induction by 9-amino-acridine (9AA) were also sensitive to caffeine. Caffeine mutagenesis was not due to inhibition of cellular repair functions, but to the production of replication errors, which were corrected very efficiently by mismatch repair. From the results reported here we conclude that the targets for caffeine mutagenesis are long runs of GC base pairs, and that this mutagen induces -1 frameshifts.

Aminoacridines↗
PubMed2002

A common frameshift mutation and other variants in GJB4 (connexin 30.3): Analysis of hearing impairment families.

Mutations in GJB1, GJB2, GJB3 and GJB6 are involved in hearing impairment. GJB2, GJB3 and GJB6 are also mutated in patients with hyperproliferative skin disorders. The human GJB4 gene has been deduced in silico and a mutation in a family with erythrokeratodermia variabilis has been reported. We describe here the analysis of the GJB4 gene in hearing impairment patients and control subjects. We have identified a common (4%) frameshift mutation (154del4) in GJB4 in both affected and hearing subjects, one patient being homozygous for the mutation. We have also detected five amino acid variants (R103C, R124Q, R160C, C169W and E204A) in individuals that have not skin disorders. While mutation 154del4 is not associated with hearing impairment the involvement of some of the amino acid variants detected here is uncertain. These GJB4 variants should help to define the putative role of connexin 30.3 in both skin disorders and hearing impairment.

Amino Acid Sequence↗
PubMed1991

Detection of three rare frameshift mutations in the cystic fibrosis gene in an African-American (CF444delA), an Italian (CF2522insC), and a Soviet (CF3821delT).

We have identified three new frameshift mutations in the CFTR gene in patients with cystic fibrosis (CF). The first one involves the deletion of an adenine nucleotide in exon 4 in an African-American patient (CF444delA), the second involves the insertion of a cytosine nucleotide in exon 13 in an Italian patient (CF2522insC), and the third results from the deletion of a thymidine nucleotide in exon 19 in a Soviet patient (CF3821delT). Each mutation is predicted to result in premature termination of the CFTR protein.

Adult↗
PubMed2003

Spectrum of mutations in the arylsulfatase A gene in a Canadian DNA collection including two novel frameshift mutations, a new missense mutation (C488R) and an MLD mutation (R84Q) in cis with a pseudodeficiency allele.

We describe three novel mutations in the human arylsulfatase A gene in three patients with MLD, an autosomal recessive lysosomal storage disorder. An insertion, 2590_2591insCCCC in exon 8 and a deletion, 752_758delGCCGGCC, in exon 3 will both result in frameshifts. A mutation in exon 8, 2566T-->C, results in a missense mutation C488R, disrupting an unusual cysteine-knot at the C-terminal end of the protein. All three mutations are heterozygous with previously documented mutations. A previously reported mutation, R84Q was identified on a pseudodeficiency allele. These mutations are part of a heterogeneous spectrum of mutations found in a collection of DNA samples from MLD patients from across Canada and the USA.

Adolescent↗
PubMed1997

Four frameshift mutations in neurofibromatosis type 1 caused by small insertions.

We have been using heteroduplex analysis to assay individual exons within the NF1 gene in an effort to identify disease causing constitutional mutations in neurofibromatosis type 1 patients. Here we report the identification and characterisation of four insertional NF1 frameshift mutations in an analysis of exons 28-39 in a set of 78 patients. These include three 1 base pair insertions and one 2 base pair insertion. Three of these mutations can be attributed to replication slippage errors, while the mechanism behind the fourth may be related to formation of secondary structure during replication. It may be of significance that a majority of the previously reported small insertions in NF1 also lie within exons 28-39.

Adult↗
PubMed1989

Suppression of a -1 frameshift mutation by a recessive tRNA suppressor which causes doublet decoding.

sufS was found to suppress the only known suppressible-1 frameshift mutation, trpE91, at a site identified as GGA and mapped within the single gene of the only tRNA that can decode GGA in Escherichia coli. It mapped to the same gene in Salmonella typhimurium. sufS alleles were recessive, and dominant alleles could not be isolated. This is in contrast to all other tRNA structural gene mutations identified thus far that cause frameshift suppression. The recessiveness implies that all sufS alleles are poor competitors against their wild-type tRNA(Gly2) counterparts. The base G immediately 5' of the GGA suppression site influenced the level but was not critical for suppression by sufS601. From this result, it is inferred that sufS601 causes frameshifting by doublet decoding.

Alleles↗
PubMed1998

Microsatellite instability and frameshift mutations in BAX and transforming growth factor-beta RII genes are very uncommon in acute lymphoblastic leukemia in vivo but not in cell lines.

Mutations in the DNA mismatch repair (MMR) system lead to an instability of simple repetitive DNA sequences involved in several cancer types. This instability is reflected in a high mutation rate of microsatellites, and recent studies in colon cancer indicate that defects in MMR result in frequent frameshift mutations in mononucleotide repeats located in the coding regions of BAX and transforming growth factor-beta (TGF-beta) receptor genes. Circumstantial evidence suggests that the MMR defect may be involved in some lymphoid malignancies, although several allelotype analyses have concluded on the low level of microsatellite instability in acute lymphoblastic leukemias. To further evaluate the implication of MMR defects in leukemogenesis, we have studied a series of 98 children with acute lymphoblastic leukemia and 14 leukemic cell lines using several indicators of MMR defects. Microsatellite markers were compared between blast and normal DNA from the same patients and mutations were sought in mononucleotide repeat sequences of BAX and TGF-beta receptor II (TGF-beta RII). The absence of microsatellite instability (MI) and the absence of mutations in the genes examined from patient's leukemic cells contrasted with the observation that half of the cell lines displayed a high degree of MI and that three of seven of these mutator cell lines harbored mutations in BAX and/or TGF-beta RII. From these results we conclude that MMR defects are very uncommon in freshly isolated blasts but are likely to be selected for during the establishment of cell lines.

Biomarkers, Tumor↗
PubMed1999

Deficiency of human complement protein C4 due to identical frameshift mutations in the C4A and C4B genes.

The complement protein C4, encoded by two genes (C4A and C4B) on chromosome 6p, is the most polymorphic among the MHC III gene products. We investigated the molecular basis of C4 deficiency in a Finnish woman with systemic lupus erythematosus. C4-specific mRNA was present at low concentrations in C4-deficient (C4D) patient fibroblasts, but no pro-C4 protein was detected. This defect in C4 expression was specific in that synthesis of two other complement proteins was normal. Analysis of genomic DNA showed that the proposita had both deleted and nonexpressed C4 genes. Each of her nonexpressed genes, a C4A null gene inherited from the mother, a C4A null gene, and a C4B null gene inherited from the father, all contained an identical 2-bp insertion (TC) after nucleotide 5880 in exon 29, providing the first confirmatory proof of the C4B pseudogene. This mutation has been previously found only in C4A null genes. Although the exon 29/30 junction is spliced accurately, this frameshift mutation generates a premature stop at codon 3 in exon 30. These truncated C4A and C4B gene products were confirmed through RT-PCR and sequence analysis. Among the possible genetic mechanisms that produce identical mutations is both genes, the most likely is a mutation in C4A followed by a gene conversion to generate the mutated C4B allele.

Adult↗
PubMed2000

N-terminal RAG1 frameshift mutations in Omenn's syndrome: internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains.

Omenn's syndrome is an autosomal recessive primary immunodeficiency characterized by variable numbers of T lymphocytes of limited clonality, hypereosinophilia, and high IgE levels with a paradoxical absence of circulating B lymphocytes. We have previously attributed this disorder to missense mutations that render the RAG1/RAG2 recombinase only partially active. Here we report seven Omenn's patients with a novel class of genetic lesions: frameshift mutations within the 5' coding region of RAG1. Interestingly, we demonstrate in transient expression experiments that these frameshift deletion alleles remain partially functional for both deletional and inversional recombination and can hence explain the partial rearrangement phenotype observed in these patients. The rearrangement activity is mediated by truncated RAG1 proteins that are generated by alternative ATG usage 3' to the frameshift deletion and that demonstrate improper cellular localization. Taken together, our results suggest a novel mechanism for the development of immunodeficiency in a subset of Omenn's syndrome patients.

Alleles↗
PubMed2006

Novel homozygous frameshift mutation of EVER1 gene in an epidermodysplasia verruciformis patient.

Epidermodysplasia verruciformis (EV) is a rare genetic skin disease with an autosomal recessive trait, and the patients have susceptibility to a specific group of human papillomavirus genotypes. Recently germline mutations in EVER1/2 genes have been detected in EV patients with different ethnic origins. In this study, we have applied PCR, single-stranded conformational polymorphism analysis, and sequencing as well as restriction fragment length polymorphism analysis for identifying potential mutation(s) of EVER genes in an EV patient and in the parents of Pakistani origin. A novel homozygous frameshift mutation (T base deletion at nucleotide position 968 of DNA) has been detected in the EVER1 gene of the patient. The parents carried this mutated allele in a heterozygous form. This is the third report on the presence of EVER1 mutations in an EV patient, and this result supports better understanding, diagnosis, and genetic counseling of EV patients.

Adult↗