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PubMed1999

Two novel frameshift mutations in the adrenoleukodystrophy gene in Italian patients.

Two novel frameshift adrenoleukodystrophy mutations in two families were identified: a complex dinucleotide deletion/tetranucleotide insertion at 1116 TC-->GAGA (codon 244 [serine]) and an AG deletion at nucleotide 1462 (codon 359 [glutamic acid]). Both mutations are predicted to cause premature termination of protein synthesis. The patients were affected by childhood cerebral adrenoleukodystrophy and by adrenomyeloneuropathy with mild Addison disease, respectively.

Adrenoleukodystrophy↗
PubMed1989

A frameshift mutation results in a truncated nonfunctional carboxyl-terminal pro alpha 1(I) propeptide of type I collagen in osteogenesis imperfecta.

A codon frameshift mutation caused by a single base (U) insertion after base pair 4088 of prepro alpha 1(I) mRNA of type I procollagen was identified in a baby with lethal perinatal osteogenesis imperfecta. The mutation was identified in fibroblast RNA by a new method that allows the direct detection of mismatched bases by chemical modification and cleavage in heteroduplexes formed between mRNA and control cDNA probes. The region of mismatches was specifically amplified by the polymerase chain reaction and sequenced. The heterozygous mutation in the amplified cDNA most likely resulted from a T insertion in exon 49 of COL1A1. The frameshift resulted in a truncated pro alpha 1(I) carboxyl-terminal propeptide in which the amino acid sequence was abnormal from Val1146 to the carboxyl terminus. The propeptide lacked Asn1187, which normally carries an N-linked oligosaccharide unit, and was more basic than the normal propeptide. The distribution of cysteines was altered and the mutant propeptide was unable to form normal interchain disulfide bonds. Some of the mutant pro alpha 1(I)' chains were incorporated into type I procollagen molecules but resulted in abnormal helix formation with over-hydroxylation of lysine residues, increased degradation, and poor secretion. Only normal type I collagen was incorporated into the extracellular matrix in vivo resulting in a tissue type I collagen content approximately 20% of that of control (Bateman, J. F., Chan, D., Mascara, T., Rogers, J. G., and Cole, W. G. (1986) Biochem. J. 240, 699-708).

Base Sequence↗
PubMed2002

Sinorhizobium fredii HH103 has a truncated nolO gene due to a -1 frameshift mutation that is conserved among other geographically distant S. fredii strains.

Strain SVQ121 is a mutant derivative of Sinorhizobium fredii HH103 carrying a transposon Tn5-lacZ insertion into the nolO-coding region. Sequence analysis of the wild-type gene revealed that it is homologous to that of Rhizobium sp. NGR234, which is involved in the 3 (or 4)-O-carbamoylation of the nonreducing terminus of Nod factors. Downstream of nolO, as in Rhizobium sp. NGR234, the noeI gene responsible for methylation of the fucose moiety of Nod factors was found. SVQ121 Nod factors showed lower levels of methylation into the fucosyl residue than those of HH103-suggesting a polar effect of the transposon insertion into nolO over the noel gene. A noeI HH103 mutant was constructed. This mutant, SVQ503, produced Nod factors devoid of methyl groups, confirming that the S. fredii noeI gene is functional. Neither the nolO nor the noeI mutation affected the ability of HH103 to nodulate several host plants, but both mutations reduced competitiveness to nodulate soybean. The Nod factors produced by strain HH103, like those of other S. fredii isolates, lack carbamoyl residues. By using specific polymerase chain reaction primers, we sequenced the nolO gene of S. fredii strains USDA192, USDA193, USDA257, and 042B(s). All the analyzed strains showed the same -1 frameshift mutation that is present in the HH103 nolO-coding region. From these results, it is concluded that, regardless of their geographical origin, S. fredii strains carry the nolO-coding region but that it is truncated by the same base-pair deletion.

Amino Acid Sequence↗
PubMed2004

A novel frameshift mutation of FOXC2 gene in a family with hereditary lymphedema-distichiasis syndrome associated with renal disease and diabetes mellitus.

Lymphedema-distichiasis (LD) syndrome is a clinically variable autosomal dominant disorder. The disorder is caused by mutations in the forkhead transcription factor FOXC2 gene on chromosome band 16q24.3. Here, we report the sequence of the FOXC2 gene in a German-Irish family with LD in six affected relatives over three generations and identify a single adenine base pair insertion at nt 1006--1007. This insertion creates a frameshift mutation that predicts a premature stop at codon 462. In addition to LD, four of the affected family members have renal disease and three have diabetes mellitus (DM), not usually seen in the LD syndrome. Polymorphisms of FOXC2 in diabetics have been studied in different populations. Our sequence analysis of the 5' untranslated region (UTR) C-512T shows the homozygous T allele in all family members tested. The sequencing data in this family suggests the possibility of a novel phenotype-haplotype. This novel phenotype, LD/renal disease/type 2 diabetes, might be the result of a combination of the nt 1006--1007 insA and the upstream UTR homozygous T polymorphism.

5' Untranslated Regions↗
PubMed2001

Infrequent frameshift mutations in the simple repeat sequences of hMLH3 in hereditary nonpolyposis colorectal cancers.

BACKGROUND: A recently identified mismatch repair gene, hMLH3, contains two simple repeat sequence regions, (A)9 and (A)8, in its coding region. To clarify the role of hMLH3 in hereditary nonpolyposis colorectal cancer (HNPCC), we searched for hMLH3 somatic and germline mutations, particularly in the repeat regions, in 41 HNPCC patient cells. METHODS: We analyzed the hMLH3 (A)9 and (A)8 repeats in 27 colorectal cancers with microsatellite instability (MSI) as well as in normal cells from 41 HNPCC patients by means of polymerase chain reaction-single-strand conformation polymorphism. hMSH3 (A)8 and hMSH6 (C)8 repeats were also examined in these cancers. RESULTS: Frameshift mutations in the hMLH3 (A)9 repeat were observed in 4/27 (14.8%) cancers with MSI, all of which showed the severe MSI phenotype. No mutations in the (A)8 repeat were found in any case. The mutation frequency of the hMLH3 (A)9 repeat was similar to that of the hMSH6 (C)8 repeat (5/26, 19.2%), but was significantly lower than that of the hMSH3 (A)8 repeat (16/27, 59.3%) (P < 0.001). All four cancers with hMLH3 mutations exhibited germline hMSH2 and/or somatic hMSH3 mutations. No germline mutation in the hMLH3 (A)9 or (A)8 repeat was detected in normal cells from the 41 HNPCC patients. CONCLUSION: hMLH3 mutations were infrequently observed in HNPCC cancers with MSI and they may be secondary to other mismatch repair gene mutations. Hence hMLH3 may only play a small role in HNPCC tumorigenesis.

Adult↗
PubMed1997

Identification of a frameshift mutation resulting in premature termination and loss of cell wall anchoring of the PAc antigen of Streptococcus mutans GS-5.

Most strains of Streptococcus mutans possess a 190-kDa protein antigen (PAc) on their cell surfaces, while strain GS-5 produces extracellularly a 155-kDa PAc protein. The pac gene of strain GS-5 consists of 3,477 bp and codes for a protein of 1,158 amino acids. One insertion of an adenine into the 3,469th, 3,470th, or 3,471st position from the start codon results in a frameshift mutation at codon 1157 with subsequent termination after 3 additional codons.

Amino Acid Sequence↗
PubMed2001

A novel frameshift mutation in exon 23 of ATP7A (MNK) results in occipital horn syndrome and not in Menkes disease.

Menkes disease and occipital horn syndrome (OHS) are allelic, X-linked recessive copper-deficiency disorders resulting from mutations in ATP7A, or MNK. Classic Menkes disease has a severe phenotype, with death in early childhood, whereas OHS has a milder phenotype, with, mainly, connective-tissue abnormalities. Data suggest that steady-state localization of ATP7A to the trans-Golgi network (TGN) is necessary for proper activity of lysyl oxidase, which is the predominant cuproenzyme whose activity is deficient in OHS and which is essential for maintenance of connective-tissue integrity. Recently, it was reported that ATP7A-transcript levels as low as 2%-5% of normal are sufficient to result in the milder phenotype, OHS, rather than the phenotype of Menkes disease. In contrast to previously reported cases of OHS, we describe a case of OHS in which, because of a frameshift mutation, no normal ATP7A is produced. Although abundant levels of mutant transcript are present, there are substantially reduced levels of the truncated protein, which lacks the key dileucine motif L1487L1488. It has been demonstrated that the dileucine motif L1487L1488 functions as an endocytic signal for ATP7A cycling between the TGN and the plasma membrane. The present report is the first to describe an ATP7A truncation that results in OHS rather than in Menkes disease. The data from the present report support the concepts that (1) OHS results from lower levels of functional ATP7A and (2) ATP7A does not require the dileucine motif to function in copper efflux.

Adenosine Triphosphatases↗
PubMed2007

Dendritic keratitis caused by an acyclovir-resistant herpes simplex virus with frameshift mutation.

PURPOSE: To report a case of acyclovir-resistant herpes simplex virus (HSV) keratitis after long-term, inconsistent use of topical acyclovir and fluorometholone. METHODS: A 70-year-old man with dendritic keratitis caused by an acyclovir-resistant HSV strain was examined. The 50% inhibitory concentration of different antiviral agents against the isolated virus and the DNA sequence of viral thymidine kinase were determined. RESULTS: The 50% inhibitory concentration of acyclovir and trifluorothymidine for the isolated HSV strain was 13.75 and 0.28 microg/mL, respectively, indicating that the virus was resistant to acyclovir. DNA sequencing of the viral thymidine kinase revealed that this virus had a frameshift mutant with a G insertion in the 7Gs homopolymer. Topical trifluorothymidine was effective, and the epithelial lesion was completely resolved within 2 weeks. CONCLUSION: A typical form of dendritic keratitis was caused by an acyclovir-resistant HSV with frameshift mutation in a 7Gs homopolymer region.

Acyclovir↗
PubMed2005

Cloning and characterization of the glucosidase II alpha subunit gene of Trichoderma reesei: a frameshift mutation results in the aberrant glycosylation profile of the hypercellulolytic strain Rut-C30.

We describe isolation and characterization of the gene encoding the glucosidase II alpha subunit (GIIalpha) of the industrially important fungus Trichoderma reesei. This subunit is the catalytic part of the glucosidase II heterodimeric enzyme involved in the structural modification within the endoplasmic reticulum (ER) of N-linked oligosaccharides present on glycoproteins. The gene encoding GIIalpha (gls2alpha) in the hypercellulolytic strain Rut-C30 contains a frameshift mutation resulting in a truncated gene product. Based on the peculiar monoglucosylated N-glycan pattern on proteins produced by the strain, we concluded that the truncated protein can still hydrolyze the first alpha-1,3-linked glucose residue but not the innermost alpha-1,3-linked glucose residue from the Glc2Man9GlcNAc2 N-glycan ER structure. Transformation of the Rut-C30 strain with a repaired T. reesei gls2alpha gene changed the glycosylation profile significantly, decreasing the amount of monoglucosylated structures and increasing the amount of high-mannose N-glycans. Full conversion to high-mannose carbohydrates was not obtained, and this was probably due to competition between the endogenous mutant subunit and the introduced wild-type GIIalpha protein. Since glucosidase II is also involved in the ER quality control of nascent polypeptide chains, its transcriptional regulation was studied in a strain producing recombinant tissue plasminogen activator (tPA) and in cultures treated with the stress agents dithiothreitol (DTT) and brefeldin A (BFA), which are known to block protein transport and to induce the unfolded protein response. While the mRNA levels were clearly upregulated upon tPA production or BFA treatment, no such enhancement was observed after DTT addition.

Amino Acid Sequence↗
PubMed2003

Processive DNA synthesis observed in a polymerase crystal suggests a mechanism for the prevention of frameshift mutations.

DNA polymerases replicate DNA by adding nucleotides to a growing primer strand while avoiding frameshift and point mutations. Here we present a series of up to six successive replication events that were obtained by extension of a primed template directly in a crystal of the thermostable Bacillus DNA polymerase I. The 6-bp extension involves a 20-A translocation of the DNA duplex, representing the largest molecular movement observed in a protein crystal. In addition, we obtained the structure of a "closed" conformation of the enzyme with a bound triphosphate juxtaposed to a template and a dideoxy-terminated primer by constructing a point mutant that destroys a crystal lattice contact stabilizing the wild-type polymerase in an "open" conformation. Together, these observations allow many of the steps involved in DNA replication to be observed in the same enzyme at near atomic detail. The successive replication events observed directly by catalysis in the crystal confirm the general reaction sequence deduced from observations obtained by using several other polymerases and further refine critical aspects of the known reaction mechanism, and also allow us to propose new features that concern the regulated transfer of the template strand between a preinsertion site and an insertion site. We propose that such regulated transfer is an important element in the prevention of frameshift mutations in high-fidelity DNA polymerases. The ability to observe processive, high-fidelity replication directly in a crystal establishes this polymerase as a powerful model system for mechanistic studies in which the structural consequences of mismatches and DNA adducts are observed.

Bacillus↗
PubMed1999

Cutis laxa arising from frameshift mutations in exon 30 of the elastin gene (ELN).

Congenital cutis laxa, a rare syndrome with marked skin laxity and pulmonary and cardiovascular compromise, is due to defective elastic fiber formation. In several cases, skin fibroblast tropoelastin production is markedly reduced yet reversed in vitro by transforming growth factor-beta treatment. We previously showed that this reversal was due to elastin mRNA stabilization in one cell strain, and here this behavior was confirmed in skin fibroblasts from two generations of a second family. cDNA sequencing and heteroduplex analysis of elastin gene transcripts from three fibroblast strains in two kindreds now identify two frameshift mutations (2012DeltaG and 2039DeltaC) in elastin gene exon 30, thus leading to missense C termini. No other mutations were present in the ELN cDNA sequences of all three affected individuals. Transcripts from both alleles in each kindred were unstable and responsive to transforming growth factor-beta. Exons 22, 23, 26A, and 32 were always absent. Since exon 30 underwent alternative splicing in fibroblasts, we speculate that a differential splicing pattern could conceivably lead to phenotypic rescue. These two dominant-acting, apparently de novo mutations in the elastin gene appear to be responsible for qualitative and quantitative defects in elastin, resulting in the cutis laxa phenotype.

Alleles↗
PubMed2000

Non-erythroid form of acute intermittent porphyria caused by promoter and frameshift mutations distant from the coding sequence of exon 1 of the HMBS gene.

Acute intermittent porphyria (AIP) is a low-penetrant, autosomal dominant disorder caused by mutations in the HMBS gene. The gene is transcribed from two promoters to produce ubiquitous and erythroid isoforms of porphobilinogen deaminase, which differ only at their NH2 ends. In the classical form of AIP, both isoforms are deficient, but about 5% of families have the non-erythroid variant in which only the ubiquitous isoform is affected. Previously identified mutations in this variant have been within or close to the coding region of exon 1 of the HMBS gene, the only exon that is expressed solely in the ubiquitous isoform. Here, we describe mutations in the ubiquitous promoter (-154delG) and in exon 3 (41delA) that cause the non-erythroid variant. Reporter gene and electrophoretic mobility shift assays show that the G nucleotide at position -154, the most 5' of several transcription-initiation sites in the ubiquitous HMBS promoter, which lies immediately 3' to a transcription-factor IIB binding motif, is essential for normal transcription. The frameshift mutation in exon 3 introduces a stop codon into mRNA for the ubiquitous isoform only. Our investigations identify two new mechanisms for production of the non-erythroid variant of AIP and demonstrate that mutational analysis for diagnosis of this variant needs to include wider regions of the HMBS gene than indicated by previous reports. Furthermore, they show that deletion of one of several transcription initiation sites in the promoter of a housekeeping gene that lacks both TATA and initiator elements can produce disease.

Adolescent↗
PubMed1994

Congenital adrenal hyperplasia caused by a novel homozygous frameshift mutation 273 delta AA in type II 3 beta-hydroxysteroid dehydrogenase gene (HSD3B2) in three male patients of Afghan/Pakistani origin.

Classical 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency is an autosomal recessive form of congenital adrenal hyperplasia caused by mutations in the type II 3 beta-HSD (HSD3B2) gene. The sequence of the type II 3 beta-HSD gene was determined by direct sequencing of asymmetric PCR products in three male infants suffering from a severe salt-losing form of 3 beta-HSD deficiency and belonging to three families originating from Afghanistan and Pakistan. The three patients were homozygous for the frameshift mutation 273 delta AA resulting from deletion of two adenosines at codon 273, thus leading to a premature termination codon at position 279. This mutation was detected in the heterozygous state in all the relatives studied. The observation that all three patients share the same haplotype for HSD3B1A, HSD3B1C, HSD3B2A, and the microsatellite marker D1S252 indicates that a founder effect is responsible for the severe form of 3 beta-HSD deficiency found in these three families.

3-Hydroxysteroid Dehydrogenases↗
PubMed1991

Phase variation of gonococcal pili by frameshift mutation in pilC, a novel gene for pilus assembly.

Pili prepared from Neisseria gonorrhoeae contain minor amounts of a 110 kd outer membrane protein denoted PilC. The corresponding gene exists in two copies, pilC1 and pilC2, in most strains of N.gonorrhoeae. In the piliated strain MS11(P+), only one of the genes, pilC2, was expressed. Inactivation of pilC2 by a mTnCm insertion resulted in a nonpiliated phenotype, while a mTnCm insertion in pilC1 had no effect on piliation. Expression of pilC was found to be controlled at the translational level by frameshift mutations in a run of G residues positioned in the region encoding the signal peptide. Nonpilated (P-), pilin expressing colony variants that did not express detectable levels of PilC were selected; all P+ backswitchers from these P-, PilC- clones were found to be PilC+. The structural gene for pilin, pilE, was sequenced and found to be identical in one P-, PilC- and P+, PilC+ pair. Most PilC- cells were completely bald whereas the PilC+ backswitcher had 10-40 pili per cell. Thus, a turn ON and turn OFF in the expression of PilC results in gonococcal pili phase variation. These results suggest that PilC is required for pilus assembly and/or translocation across the gonococcal outer membrane.

Amino Acid Sequence↗
PubMed1989

A frameshift mutation prevents Kunitz trypsin inhibitor mRNA accumulation in soybean embryos.

We investigated the molecular basis of a soybean Kunitz trypsin inhibitor (KTi) gene mutation that prevents the accumulation of Kunitz trypsin inhibitor protein during seed development. We found that mRNA encoding the major Kunitz trypsin inhibitor protein (KTi3 mRNA) is reduced at least 100-fold in null (KTi-) embryos but that KTi3 gene transcriptional activity is similar in Kunitz trypsin inhibitor producing embryos (KTi+) and in KTi- embryos. We sequenced the Kunitz trypsin inhibitor KTi3 gene from both KTi3+ and KTi3- lines and found that these genes differ by only three nucleotides (+481, +486, and +487) within the KTi3 coding region. Alteration of these nucleotides results in a frameshift within the KTi3- gene that causes premature termination during translation. Our results suggest that the KTi3- frameshift mutation results in KTi3- mRNA destabilization and leads to a drastic reduction in KTi3 mRNA prevalence.

Amino Acid Sequence↗
PubMed1990

Activity of carcinogens that bind to the C8 position of guanine residues in an assay specific for the detection of -2 frameshift mutations in a defined hot spot.

In this paper we describe a reversion assay specific for the detection of -2 frameshift mutations occurring within short stretches of alternating GC sequences. We have compared a series of chemical carcinogens that all bind covalently to the C8 position of guanine residues for their potency in inducing revertants in this assay. Large variations in potency are found within the list of compounds that were tested. The most potent chemicals tested induce the reversion frequency by a factor of 10(5) over background, whereas others only increase it by two orders of magnitude. These differences are discussed in terms of the conformational changes that the different C8-guanine adducts induce in DNA.

Base Sequence↗
PubMed2001

Molecular analysis of endogenous retrovirus HRES-1: identification of frameshift mutations in region encoding putative 28-kDa autoantigen.

A possible involvement of HTLV-1-related endogenous sequence 1 (HRES-1) in autoimmune diseases has been recently reported. In primate cells, PCRs and RT-PCRs using specific primers reveal the presence and the transcription of gag-related sequences. However antisera generated against selected HRES-1 peptides failed to detect a 28-kDa protein deduced from the translated gag ORF and described previously. Such discordant results led us to perform DNA cloning and sequencing of LTR- and gag-related nucleotidic fragments. Repeated sequence analyses on distinct samples revealed frameshift mutations in the gag and LTR ORFs. Our sequence analyses detected a stop codon in the gag-related ORF, which is inconsistent with the expression of a 28-kDa protein. Instead of the two ORFs previously found, our gag-related region contained three ORFs. One of them demonstrated higher nucleotidic and peptidic homologies with the p19 gag of HTLV-I. However, the molecular analyses of our new sequence did not show evidence of potent translation capacities.

Amino Acid Sequence↗
PubMed1999

Frameshift mutations and a length polymorphism in the hMSH3 gene and the spectrum of microsatellite instability in sporadic colon cancer.

Mutations in the hMVSH3 gene in sporadic colon cancer with microsatellite instability (MSI) were investigated, since several mismatch repair genes were known to be mutated in cancers with MSI, but only deletions in the (A)8 region in the hMSH3 gene have been reported. We also analyzed the relationships between hMSH3 mutations and the spectrum of MSI. We screened MSI in 79 sporadic colon cancer samples using mono- and dinucleotide repeat markers and the samples with MSI were further analyzed for tri- and tetranucleotide repeat instability and mutations in the hMSH3 gene by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. Five (6%) out of 79 tumors were MSI-H and 15 (19%) were MSI-L. Two MSI-H tumors showed insertion in the (C)8 region in the hMSH6 gene and one tumor showed insertion and deletion in the (A)8 region in the hMSH3 gene, and two of the three above tumors showed MSI in tri-and tetranucleotide repeats. One MSI-L tumor showed somatic alteration in a 9-bp repeat sequence in hMSH3. No frameshift mutations were found in the (A)7 and (A)6 regions in hMSH3. Thus, we confirmed that the (A)8 region in hMSH3 is a hot spot and mutations in the (A)7 and (A)6 regions in hMSH3 are not common. The hMSH3 mutation may enhance genomic instability in some colorectal cancers.

Base Pair Mismatch↗