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PubMed1997

Localized frameshift mutation generates selective, high-frequency phase variation of a surface lipoprotein encoded by a mycoplasma ABC transporter operon.

The wall-less mycoplasmas have revealed unusual microbial strategies for adaptive variation of antigenic membrane proteins exposed during their surface colonization of host cells. In particular, high-frequency mutations affecting the expression of selected surface lipoproteins have been increasingly documented for this group of organisms. A novel manifestation of mutational phase variation is shown here to occur in Mycoplasma fermentans, a chronic human infectious agent and possible AIDS-associated pathogen. A putative ABC type transport operon encoding four gene products is identified. The 3' distal gene encoding P78, a known surface-exposed antigen and the proposed substrate-binding lipoprotein of the transporter, is subject to localized hypermutation in a short homopolymeric tract of adenine residues located in the N-terminal coding region of the mature product. High-frequency, reversible insertion/deletion frameshift mutations lead to selective phase variation in P78 expression, whereas the putative nucleotide-binding protein, P63, encoded by the most 5' gene of the operon, is continually expressed. Mutation-based phase variation in specific surface-exposed microbial transporter components may provide an adaptive advantage for immune evasion, while continued expression of other elements of the same transporter may preserve essential metabolic functions and confer alternative substrate specificity. These features could be critical in mycoplasmas, where limitations in both transcriptional regulators and transport systems may prevail. This study also documents that P63 contains an uncharacteristic hydrophobic sequence between predicted nucleotide binding motifs and displays an amphiphilic character in detergent fractionation. Both features are consistent with an evolutionary adaptation favoring integral association of this putative energy-transducing component with the single mycoplasma membrane.

ATP-Binding Cassette Transporters↗

PubMed2002

Comparative sequence analysis of the core protein and its frameshift product, the F protein, of hepatitis C virus subtype 1b strains obtained from patients with and without hepatocellular carcinoma.

The core protein of hepatitis C virus (HCV) has been implicated in hepatocarcinogenesis. In order to determine whether there is a correlation between mutations of the core protein and the development of hepatocellular carcinoma (HCC), the core protein-coding sequence of the viral genome of HCV subtype 1b (HCV-1b) obtained from patients with and without HCC was analyzed. We found that 12 (40.0%) of 30 HCV-1b isolates from patients with HCC but none of 29 isolates from patients without HCC had a point mutation(s) in an N-terminal region of 20 residues. Similarly, 10 (33.3%) of 30 isolates from patients with HCC had mutations in a limited region between residues 141 and 160, whereas only 2 (6.9%) of 29 isolates from patients without HCC did. The differences between the two groups were statistically significant. The mutations were found in isolates from both cancerous and adjacent noncancerous tissues of patients with HCC, suggesting that the mutations were present before the development of HCC. The other regions of the core protein of some isolates also had mutations, but no significant difference was observed between isolates from patients with HCC and those from patients without HCC. The F protein, a frameshift product that is still hypothetical for HCV-1b strains, showed more sequence diversity than the core protein among the isolates analyzed, but there were no significant differences in the mutation rates or positions between isolates from patients with HCC and isolates from patients without HCC, except for a short N-terminal sequence of approximately 11 residues that is shared with the core protein.

Amino Acid Sequence↗

PubMed1987

Complete nucleotide sequence of a milk-transmitted mouse mammary tumor virus: two frameshift suppression events are required for translation of gag and pol.

We sequenced two recombinant DNA clones constituting a single provirus of the milk-transmitted mouse mammary tumor virus characteristic of BR6 mice. The complete provirus is 9,901 base pairs long, flanked by 6 base-pair duplications of cellular DNA at the site of integration. Five extensive blocks of open reading frame corresponding to the gag gene, the presumed protease, the pol and env genes, and the open reading frame orf within the long terminal repeat of the provirus were readily discernible. Translation of gag, protease, and pol involved three different translational reading frames to produce the three overlapping polyprotein precursors Pr77, Pr110, and Pr160 found in virus-infected cells. Synthesis of the reverse transcriptase and endonuclease therefore required two separate frameshifts to suppress the termination codons at the ends of the Pr77 and Pr110 domains. Direct evidence is presented for translational readthrough of both stop codons in an in vitro protein synthesis system.

Amino Acid Sequence↗

PubMed1992

Translation of the rat LINE bicistronic RNAs in vitro involves ribosomal reinitiation instead of frameshifting.

The genomic structure of the rat LINE (L1Rn) DNA element contains two overlapping open reading frames (ORFs) and apparently has a potential to code for a DNA/RNA-binding protein (in ORF1) and a reverse transcriptase (in ORF2). We have characterized a 1,630-bp L1Rn cDNA clone encompassing the overlapping ORFs and a 600-bp genomic fragment derived from a full-length L1Rn member and containing the beginning of ORF1. These DNAs were used to restore in part the ORF1-ORF2 organization of L1Rn after being cloned into the pSP65 vector under the control of SP6 polymerase promoter. To test whether L1Rn ORF1 and ORF2 are expressed as a fusion protein, a series of capped RNAs with progressive truncations containing one or both ORFs were prepared and translated in the rabbit reticulocyte lysate. Our analysis indicates that the expression of a putative reverse transcriptase-encoded L1Rn ORF2 in vitro is regulated by reinitiation or internal initiation of translation but not by ribosomal frameshifting.

Amino Acid Sequence↗

PubMed1985

Frameshift suppressor mutations outside the anticodon in yeast proline tRNAs containing an intervening sequence.

Extragenic suppressors of +1 frameshift mutations in proline codons map in genes encoding two major proline tRNA isoacceptors. We have shown previously that one isoacceptor encoded by the SUF2 gene (chromosome 3) contains no intervening sequence. SUF2 suppressor mutations result from the base insertion of a G within a 3'-GGA-5' anticodon, allowing the tRNA to read a 4-base code word. In this communication we describe suppressor mutations in genes encoding a second proline tRNA isoacceptor (wild-type anticodon 3'-GGU-5') that result in a novel mechanism for translation of a 4-base genetic code word. The genes that encode this isoacceptor include SUF7 (chromosome 13), SUF8 (chromosome 8), trn1 (chromosome 1), and at least two additional unmapped genes, all of which contain an intervening sequence. We show that suppressor mutations in the SUF7 and SUF8 genes result in G-to-U base substitutions at position 39 that disrupted the normal G . C base pairing in the last base pair of the anticodon stem adjacent to the anticodon loop. These anticodon stem mutations might alter the size of the anticodon loop and permit the use of a 3'-GGGU-5' sequence within the loop to read 4-base proline codons. Uncertainty regarding the exact structure of the mature suppressor tRNAs results from the possibility that anticodon stem mutations might affect sites of intervening sequence removal. The possible role of the intervening sequence in the generation of mature suppressor tRNA is discussed. Besides an analysis of suppressor tRNA genes, we have extended previous observations of the apparent relationship between tRNA genes and repetitive delta sequences found as solo elements or in association with the transposable element TY1. Hybridization studies and a computer analysis of the DNA sequence surrounding the SUF7 gene revealed two incomplete, inverted delta sequences that form a stem and loop structure located 165 base pairs from the 5' end of the tRNA gene. In addition, sequences beginning 164 base pairs from the 5' end of the trn1 gene also exhibit partial homology to delta. These observations provide further evidence for a nonrandom association between tRNA genes and delta sequences.

Anticodon↗

PubMed2002

Origins of spontaneous mutations: specificity and directionality of base-substitution, frameshift, and sequence-substitution mutageneses.

Spontaneous mutations are derived from various sources, including errors made during replication of undamaged template DNA, mutagenic nucleotide substrates, and endogenous DNA lesions. These sources vary in their frequencies and resultant mutations, and are differently affected by the DNA sequence, DNA transactions, and cellular metabolism. Organisms possess a variety of cellular functions to suppress spontaneous mutagenesis, and the specificity and effectiveness of each function strongly affect the pattern of spontaneous mutations. Base substitutions and single-base frameshifts, two major classes of spontaneous mutations, occur non-randomly throughout the genome. Within target DNA sequences there are hotspots for particular types of spontaneous mutations; outside of the hotspots, spontaneous mutations occur more randomly and much less frequently. Hotspot mutations are attributable more to endogenous DNA lesions than to replication errors. Recently, a novel class of mutagenic pathway that depends on short inverted repeats was identified as another important source of hotspot mutagenesis.

Base Sequence↗

PubMed1994

A truncated thyroxine-binding globulin due to a frameshift mutation is retained within the rough endoplasmic reticulum: a possible mechanism of complete thyroxine-binding globulin deficiency in Japanese.

We have previously reported six unrelated Japanese families having the same mutation in the TBG gene and manifesting complete TBG deficiency (TBG-CDJ). The deficiency consists of a single nucleotide deletion resulting in the production of C-terminal truncation due to a frameshift and premature termination. However, the reason for the failure to detect TBG in the serum of subjects harboring this mutation remains unknown. In this communication we investigated the mechanism of the TBG deficiency associated with TBG-CDJ. The complementary DNAs of TBG-CDJ and normal TBG (TBG-N) were expressed in COS-1 cells. Pulse-chase experiments revealed a complete absence of secretion of TBG-CDJ, whereas TBG-N was already present in the medium at time 0 and was almost entirely secreted by 3 h. In cell lysates, TBG-CDJ had a smaller molecular mass [52 kilodalton (kDa)] than TBG-N (54 kDa) and gradually decreased during the chase. Thus, failure of TBG-CDJ secretion accounts for the complete TBG deficiency. The molecular mass of TBG-CDJ (42 kDa) was also smaller than that of TBG-N (44 kDa) when synthesized in the presence of tunicamycin. These findings are consistent with the premature termination of the TBG-CDJ molecule deduced from the nucleotide sequence analysis. Intracellular TBG-N was resistant to endoglycosidase H but not TBG-CDJ, suggesting the retention of TBG-CDJ within the rough endoplasmic reticulum. Indeed, subcellular fractionation revealed that most of TBG-CDJ was located in the rough endoplasmic reticulum compartment, and TBG-N was distributed in the Golgi fractions. Our results suggested that the lack of intracellular transport of the truncated TBG molecule is the cause for the absence of immunoreactive TBG in the serum of subjects harboring the TBG-CDJ variant.

Animals↗

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↗

PubMed1984

Hb Wayne, the frameshift variant with extended alpha chains observed in a Caucasian family from Alabama.

The presence of the alpha-globin frameshift mutant, Hb Wayne, in three generations of a second family is described. The data include a hematological evaluation of the four heterozygotes, structural characterization of the variant, the use of HPLC for the separation of tryptic and chymotryptic peptides, functional analyses of the isolated variant showing high affinity for oxygen and the (near) absence of a Bohr effect, and alpha chain gene organization analyses with restriction endonuclease technology suggesting that the Hb Wayne heterozygote has a full complement of four alpha globin genes.

Adult↗

PubMed1989

Frameshift codon 5 [Fsc-5 (-CT)] thalassemia; a novel mutation detected in a Greek patient.

Sequence analysis and dot-blot hybridization of DNA from a Greek patient with a transfusion dependent thalassemia revealed the combination of a beta IVS-I-1 G----A mutation (beta(0) -thalassemia) and a hitherto undescribed frameshift mutation; the latter concerns the absence of a CT dinucleotide from codon 5 and results in a termination signal at the new codon 21 (also a beta (0)-thalassemia).

Adolescent↗

PubMed1993

The beta-thalassemia frameshift at codon 8 (-AA) observed in four Chinese of the Uygur nationality.

During a survey for beta-thalassemia in Kashi City, Xinjiang Province, P.R. China, four unrelated Uygur students were identified as heterozygotes for the beta-thalassemia frameshift at codon 8 (-AA). Detection was with the polymerase chain reaction combined with allele-specific oligonucleotide hybridization. This beta-thalassemia allele has not been observed in the Chinese population before and might be rather specific for the Uygur nationality.

Asian People↗

PubMed2006

Frameshift proteins in Alzheimer's disease and in other conformational disorders: time for the ubiquitin-proteasome system.

Neuronal homeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the ubiquitin-proteasome system (UPS) and discovered a frameshift protein for ubiquitin (UBB+1), that accumulates in the neuritic plaques and tangles in patients with Alzheimer's disease (AD). UBB+1, unable to tag proteins to be degraded, has been shown to be a substrate for ubiquitination and subsequent proteasomal degradation. If UBB+1 is accumulated, it inhibits the proteasome, which may result in neuronal death. We showed that UB+1 is also present in other tauopathies (e.g. Pick's disease) and in several polyglutamine diseases, but remarkably not in synucleinopathies (e.g. Parkinson's disease). Accumulation of UBB+1-being a reporter for proteasomal dysfunctioning- thus differentiates between these conformational diseases. The accumulation of UBB+1 causes a dysfunctional UPS in these multifactorial neurodegenerative diseases. Novel transgenic mouse models and large-scale expression profiling and functional analyses of enzymes of the UPS compounds - enabling us to identify the targets of the UPS in these conformational diseases - may now pave the way for intervention and treatment of AD.

Alzheimer Disease↗

PubMed1990

Frameshift and nonsense mutations in a human genomic sequence homologous to a murine UDP-Gal:beta-D-Gal(1,4)-D-GlcNAc alpha(1,3)-galactosyltransferase cDNA.

We have previously isolated a murine UDP-Gal:beta-D-Gal(1,4)-D-GlcNAc alpha(1,3)-galactosyltransferase (alpha(1,3)-GT) cDNA (Larsen, R. D., Rajan, V. P., Ruff, M. M., Kukowska-Latallo, J., Cummings, R. D., and Lowe, J. B. (1989) Proc. Natl. Acad. Sci. U. S. A. 86, 8227-8231). This enzyme constructs the terminal alpha(1,3)-galactosyl linkage within the epitope Gal alpha 1----3Gal. This epitope is expressed by New World monkeys and many nonprimate mammals but generally not by Old World primates, anthropoid apes, or man. To investigate the molecular basis for the apparent species-specific absence of this enzyme and its oligosaccharide product, we have sequenced a human genomic DNA fragment homologous to the murine alpha(1,3)-GT cDNA. This fragment contains a 703-nucleotide region that shares 82% identity with a region of the murine cDNA encoding part of the enzyme's catalytic domain. The human sequence, however, has suffered deletion of single nucleotides at two separate positions, relative to the murine sequence. These frameshift mutations disrupt the translational reading frame that would otherwise maintain a 76% amino acid sequence identity between the human sequence and the murine alpha(1,3)-GT. Moreover, nonsense mutations exist within this disrupted reading frame that would truncate the human polypeptide, relative to the murine enzyme. We therefore propose that this human sequence represents a pseudogene and cannot determine expression of Gal alpha 1----3Gal epitopes on human cells.

Amino Acid Sequence↗

PubMed1989

The 3-methylcholanthrene-inducible UDP-glucuronosyltransferase deficiency in the hyperbilirubinemic rat (Gunn rat) is caused by a -1 frameshift mutation.

The Gunn rat is a mutant strain of Wistar rat which has unconjugated hyperbilirubinemia as a result of the absence of hepatic UDP-glucuronosyltransferase (UDPGT) activity toward bilirubin. The Gunn rat is also deficient in a 3-methylcholanthrene (MC)-inducible UDPGT isoenzyme that has high activity toward phenolic substrates. We have isolated and sequenced a cDNA, designated 4-NP UDPGT, which encodes an MC-inducible UDPGT from normal Wistar rat livers (Iyanagi, T., Haniu, M., Sogawa, F., Fujii-Kuriyama, Y., Watanabe, S., Shively, J.E., and Anan, K.F. (1986) J. Biol. Chem. 261, 15607-15614). In the present study, we found that this cDNA detected MC-inducible UDPGT mRNA in the MC-treated homozygous Gunn rat liver. The level of this mRNA, however, was significantly lower than that of normal Wistar livers. The size of mRNA in Gunn rats was identical to that of the functionally mature UDPGT mRNA in Wistar rats, but the MC-inducible UDPGT protein was absent from homozygous Gunn rat microsomes. We therefore made a cDNA library from MC-treated Gunn rat liver mRNA and isolated cDNA clones, using the 4-NP UDPGT cDNA as a probe. Sequencing analysis of these cDNA clones revealed a single base deletion in the coding region. Northern blot analysis of mRNAs from normal Wistar and heterozygous and homozygous Gunn rats livers was performed using specific oligonucleotide probes, and the results confirmed the presence of mRNA containing the single base deletion in heterozygous and homozygous Gunn rats. These data suggested that the defect of the MC-inducible isoenzyme in Gunn rats arises from a -1 frameshift mutation that removes 115 amino acids from the COOH terminus.

Animals↗

PubMed1989

A frameshift mutation in a patient with Tay-Sachs disease causes premature termination and defective intracellular transport of the alpha-subunit of beta-hexosaminidase.

Mutations of the gene encoding the alpha-subunit of the lysosomal enzyme, beta-hexosaminidase, are the cause of Tay-Sachs disease. We previously showed that fibroblasts from one patient (WG1051) synthesized an unstable alpha-subunit that was smaller than normal and appeared to be trapped in an early biosynthetic compartment (Zokaeem, G., Bayleran, J., Kaplan, P., Hechtman, P., and Neufeld, E. F. (1987) Am. J. Hum. Genet. 40, 537-547). We now have identified the mutation as a deletion of cytosine at position 1510 of the coding sequence. We first determined that the structural abnormality was at the carboxyl terminus of the protein and then sequenced the corresponding regions of the cDNA and genomic DNA after amplification by the polymerase chain reaction. The frameshift mutation, which is present on both alleles, causes premature termination four codons downstream, and the loss of a very hydrophilic stretch of 22 amino acids. Expression of alpha-subunit cDNA with the cytosine deletion in Cos-1 cells reproduced the WG1051 phenotype, i.e. a truncated alpha-subunit that was retained and degraded in an early compartment, presumably the endoplasmic reticulum. Loss of the cysteine residue at position 522 was not the sole cause of instability and defective transport.

Amino Acid Sequence↗

PubMed1988

Dysfunctional alpha-globin gene in hemoglobin H disease in blacks. A dinucleotide deletion produces a frameshift and a termination codon.

alpha-Thalassemia trait is common in Black Americans; the (-alpha) haplotype occurs in 30% of that population. However, hemoglobin H disease (genotype:- -/-alpha) is very uncommon due to the rarity of the (- -) haplotype. A subject with HbH-HbG Philadelphia (alpha 2(68)Asn----Lys) synthesized only alpha G and no alpha A. Digestion of DNA with BamHI produced a single 10-kilobase (kb) alpha-specific fragment. Her son had alpha-thalassemia trait, did not make HbG Philadelphia, and demonstrated 14- and 10-kb alpha fragments upon BamHI digestion. Since the 14-kb fragment could not have been inherited from the mother, the son apparently received from her a chromosome bearing a single nonfunctional (alpha T) gene. Therefore, the two genotypes are: mother (-alpha G/-alpha T), son (-alpha T/alpha alpha). A 16-kb BglII fragment, containing the gene of interest from the son, was cloned into the BamHI site of phage EMBL 3 followed by subcloning of a 1.5-kb PstI alpha-specific fragment into plasmid pBR322. The mutant alpha gene demonstrated a deletion of an AG dinucleotide from the tandem repeat normally occurring in the Glu-Arg codons 30 and 31 at the junction of the first exon with intervening sequence 1. The loss of two nucleotides leads to a reading frameshift and a totally novel amino acid coding sequence in the second exon from codons 31-54 followed by the appearance of a chain termination codon (TAA) at position 55. No complete globin chain can be produced from this gene. HbH disease in this Black family is thus due to the combination of gene deletion and a nonfunctional alpha gene.

Base Sequence↗

PubMed1988

A novel beta-thalassemia frameshift mutation (codon 14/15), detectable by direct visualization of abnormal restriction fragment in amplified genomic DNA.

A new frameshift mutation due to an insertion of G between codon 14/15 of the beta-globin gene was found in two unrelated Chinese patients with Cooley's anemia. The first patient (W.S.) was homozygous for haplotype 5 (Chinese) and carried a codon 41/42 (four base pair deletion) mutant, while the second patient (C.K.) was homozygous for haplotype 2 (Chinese), and also had a codon 17 (A----T) nonsense mutation. Molecular cloning and M13 sequencing of the beta gene in patient W.S. revealed that the new mutant was found in a beta-globin gene framework type 3 (Asian). Direct sequencing was performed on polymerase chain reaction-amplified genomic DNA from patient C.K. With the new mutation, an additional BstNI or EcoRII recognition site is generated and the abnormal restriction fragment (134 basepair) can be directly visualized on polyacrylamide gel electrophoresis of the amplified genomic DNA.

Base Sequence↗

PubMed1987

alpha 1-Antitrypsin nullGranite Falls, a nonexpressing alpha 1-antitrypsin gene associated with a frameshift to stop mutation in a coding exon.

alpha 1-Antitrypsin (alpha 1-AT) deficiency is a hereditary disorder associated with serum alpha 1-AT levels less than 35% of normal. There are two categories of alpha 1-AT genes that cause this state: the deficient alleles, in which alpha 1-AT is present in serum but in low levels, and the null alleles, in which no alpha 1-AT in serum can be attributed to the gene. The present study defines the molecular basis for the alpha 1-AT gene nullGranite Falls, identified and cloned from genomic DNA of an individual with severe alpha 1-AT deficiency and emphysema resulting from the heterozygous inheritance of the nullGranite Falls and Z alpha 1-AT genes. Sequencing of the 5'-flanking region, all five coding exons, and all exon-intron junctions of nullGranite Falls demonstrated it was identical with the common normal M1(Ala213) alpha 1-AT gene, except for two bases: a single deletion in the codon for amino acid Tyr160 of the mature protein and a single base substitution 168 base pairs 5' to exon I. Although no role for the promoter region mutation could be assigned, the coding exon deletion [Tyr(TAC)----(TA-)] resulted in a frameshift causing a stop coding to be formed approximately 44% from the N terminus of the precursor protein. Using oligonucleotide probes to evaluate the family of the index case demonstrated the deletion----frameshift/stop mutation was inherited in an autosomal co-dominant fashion. Thus, although the molecular basis for alpha 1-AT deficiency of the alpha 1-AT null haplotype such as nullGranite Falls is very different from the molecular basis of the more common deficient haplotypes such as Z, the phenotypic consequences of the two genes are similar; i.e. severe alpha 1-AT deficiency and an association of a high risk for the development of emphysema.

Adult↗