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Results for “Codon, Terminator”

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PubMed1998

An SP-B gene mutation responsible for SP-B deficiency in fatal congenital alveolar proteinosis: evidence for a mutation hotspot in exon 4.

Mutations and polymorphisms within the human SP-B locus have been linked to fatal congenital alveolar proteinosis (CAP) and associated with respiratory distress syndrome (RDS), respectively. In the present study we used PCR and direct sequence analysis of the SP-B gene of three individuals from a family with CAP to search for additional SP-B mutations resulting in CAP and/or polymorphisms that could be used as markers in association studies of RDS and/or CAP. We found three novel mutations/polymorphisms in this family. One is a C/A substitution at nt 1013 at the splice junction of intron 2-exon 3. A second one is a single base T deletion at nt 1553 in exon 4. The single base (T) deletion at nucleotide 1553 (1553delT) shifts the reading frame at amino acid 122(122delT) and creates a premature termination codon at amino acid 214 in exon 6. The mutated gene produces no mature SP-B protein. Genotype analysis from the nuclear family carrying this mutation showed that both parents and three of the four living children are heterozygous for the mutation. One of the four living children is homozygous for the normal allele and a child that died in the perinatal period from CAP is homozygous for the mutation. A third change is a C/T substitution at nt 1580 in exon 4 that changes amino acid 131 from threonine to isoleucine (Thr131Ile). The location of a previously reported mutation, 121ins2 (1), is only 4 nt upstream of 122delT, and the missense mutation Thr131Ile (exon 4) is only 27 nt downstream of 122delT. These changes are within or in close proximity to a CCTG sequence and a poly(C) tract, both of which are shown in other systems to be mutation hotspots. The 122delT occurs within the CCTG and the poly(C) tract sequences, the Thr131Ile occurs 26 nt downstream from the CCTG sequence, and the 121ins2 occurs 2 nt upstream from CCTG sequence and within the poly(C) tract. The present observations suggest that the short SP-B sequence containing the CCTG motif and the poly(C) tract is a mutation hotspot.

Base Sequence↗

PubMed1997

Biologic properties of hepatitis B viral genomes with mutations in the precore promoter and precore open reading frame.

It is now well recognized that mutations in the hepatitis B virus (HBV) genome occur during the natural course of chronic viral infection. Regions of the viral genome that are frequently affected by such mutations, rearrangements, and/or deletions generally involve the precore promoter, precore, and core as well as the preS gene regions. However, little is known regarding the biologic consequences of these mutations on the functional properties of the variant viral strains with respect to effects on viral replication. In this study, we investigated the functional significance of precore promoter and precore gene mutations that reduce or abolish the synthesis of hepatitis B e antigen (HBeAg). We found that precore promoter mutations diminished the expression of HBeAg but did not affect the synthesis of pregenomic RNA. However, these precore mutations were associated with a modest increase in HBV replication. In contrast, a naturally occurring mutant that carries a termination codon in position 28 of the precore open reading frame demonstrated increased encapsidation of pregenomic mRNA into nucleocapsid particles. Consequently, this variant viral strain demonstrated a substantial increase in the level of viral replication compared to "wild-type" HBV and other precore promoter mutant viral strains. These studies suggest that substitutions in the precore promoter and precore gene not only alter the synthesis of HBeAg but also affect the level of viral replication.

Codon, Terminator↗

PubMed1995

An AT-deletion causing a frameshift in the arylsulfatase A gene of a late infantile metachromatic leukodystrophy patient.

A metachromatic leukodystrophy (MLD) patient affected with the late infantile form was found to be homozygous for an AT-deletion (2324delAT) in the arylsulfatase A gene. The mutation causes a frameshift at the beginning of exon 8 leading to an early termination codon. The parents and unaffected brother of the patient were heterozygous for the microdeletion. The mutation was not detected in another 31 MLD Italian patients. No aberrant transcript caused by the mutation was revealed by the reverse transcription-polymerase chain reaction method.

Amino Acid Sequence↗

PubMed1994

Pseudogene of dihydrolipoyl succinyltransferase (E2k) found by PCR amplification and direct sequencing of rodent-human cell hybrid DNAs.

Previous studies have indicated that the cDNA for the E2k component of the human alpha-ketoglutarate dehydrogenase complex (KGDHC) hybridized not only to a major locus on chromosome 14q24.3 in a region associated with familial Alzheimer's disease and with Joseph-Machado disease, but also to another locus on chromosome 1p31. We now report that PCR of genomic DNA and direct sequencing indicated that the chromosome 1 locus is an intronless pseudogene. PCR of genomic DNA amplified E2k fragments from mouse-human cell hybrids containing human chromosome 1 DNA but not from hybrids containing human chromosome 14 DNA. The resulting amplicons were of comparable sizes to those when the cDNA was used as template. The direct sequencing of these amplicons confirmed the lack of introns and indicated a frame shift, which led to the presence of four termination codons early in the coding region. PCR followed by direct sequencing of the amplicons appears to be a convenient method for identifying intronless pseudogenes.

Acyltransferases↗

PubMed1997

Multiple identification of a particular type of hereditary C1q deficiency in the Turkish population: review of the cases and additional genetic and functional analysis.

Complete selective deficiencies of the complement component C1q are rare genetic disorders that are associated with recurrent infections and a high prevalence of lupus erythematosus-like symptoms. All C1q deficiencies studied at the genetic level revealed single-base mutations leading to termination codons, frameshifts or amino acid exchanges and these were thought to be responsible for the defects as no other aberrations were found. One particular mutation, leading to a stop codon in the C1qA gene, was first identified in members of a Gypsy family from the Slovak Republic. The same mutation has been found in all cases of C1q deficiency from Turkey that have been investigated. Here we present the results of genetic analysis of the C1q genes from three families and give information on further C1q-deficient members of two families that have not been reported elsewhere. Reviewing all cases of C1q deficiency from Turkey prompted us to hypothesize that one particular defective allele is present in the population of southeast Europe and Turkey. With a novel polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and allele-specific PCR we are able to detect even asymptomatic, heterozygous carriers of the mutation, which will enable genetic counseling of the affected individuals.

Amino Acid Sequence↗

PubMed1995

RNA editing in wheat mitochondria.

C to U transitions in plant mitochondrial mRNA (RNA editing) lead to amino acid changes as well as to the creation of new initiation or termination codons. We established an in vitro system to assay and to dissect the process of wheat mitochondrial mRNA editing. A deamination mechanism explains most easily the observed C to U transitions. Several fractions of organellar protein participate in the editing machinery. Some of these proteins presumably carry the catalytic activity while others are typical RNA binding proteins and may confer specificity to the 'editosome' complex. To investigate the functional properties of protein products synthesized from unedited mRNAs, we constructed transgenic tobacco plants carrying an unedited gene coding for subunit 9 (ATP9) of the ATP synthase complex. The nuclear encoded 'unedited' protein product is targeted to the mitochondria with a heterologous presequence. A significant number of male sterile tobacco plants were obtained suggesting that at least the functional ATP9 protein requires RNA editing. This result suggests a novel approach to obtain artificial male sterile plants by using a physiological effect resulting in CMS which mimics the situation found in many natural populations.

Codon, Initiator↗

PubMed1996

Sequencing and expression of the human ALDH8 encoding a new member of the aldehyde dehydrogenase family.

The human aldehyde dehydrogenase gene (ALDH) family is characterized by two major conserved DNA sequences encoding residues which are possibly involved in the catalytic function and the maintenance of the functional conformation of the ALDH enzyme. This property is the basis for synthesizing the degenerate primers to clone several cDNAs of the ALDH isozymes. In this report, we describe the cDNA sequence and the expression of a new member of this family, ALDH8. The human ALDH8 gene was identified during the process of the screening for the human ALDH7 genomic clones. Overlapping ALDH8 cDNA clones were isolated by polymerase chain reaction (PCR) amplification of human salivary gland total RNA or lambda gt11 cDNA library. When the ALDH8 cDNA sequence was aligned with that of the ALDH7 which encodes a polypeptide chain of 468 amino acid (aa) residues, it was found that a termination codon (TGA) is placed in frame at the ALDH8 sequence corresponding to the codon GCG for the seventeenth aa position of the ALDH7. Therefore, the human ALDH8 gene is a potential nonprocessed pseudogene in the ALDH multigene family which has no other pseudogenes reported so far. Alternatively, the ALDH8 gene is a functional gene if the premature stop codon is suppressed, or if the first downstream in-frame ATG serves as the initiator codon. This longest putative open reading frame (ORF) encodes a polypeptide chain of 385 aa residues, includes the two ALDH conserved regions, and demonstrates 86% identity with the corresponding ORF region of the human ALDH7. The expression of the ALDH8 transcripts is restricted to the salivary gland among the human tissues examined.

Aldehyde Dehydrogenase↗

PubMed1997

Human metallothionein gene MT1L mRNA is present in several human tissues but is unlikely to produce a metallothionein protein.

A human MT gene from the functional locus on chromosome 16, MT1L, is characterised and shown to produce mRNA in at least four human tissues. This gene is unlikely to produce a metallothionein protein because it contains a termination codon at position 26, by analogy to other human MT1 genes. MT1L cDNA is almost identical to another metallothionein cDNA clone reported recently, MT1R, suggesting that either there are unmapped human metallothionein genes, or that MT1L is polymorphic.

Amino Acid Sequence↗

PubMed1997

Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility syndrome.

Members of the armadillo protein gene family, which includes plakoglobin and beta-catenin, have important functions in cytoskeleton/cell membrane interactions. These proteins may act as linker molecules at adherens junctions and desmosomes at the plasma membrane; in addition, they may have pivotal roles in signal transduction pathways and significant effects on cell behaviour during development. Here, we describe the first human mutations in one of these dual function proteins, plakophilin 1 (band-6 protein; refs 8-10). The affected individual has a complete absence of immunostaining for plakophilin 1 in the skin and is a compound heterozygote for autosomal-recessively inherited premature termination codons of translation on both alleles of the plakophilin 1 gene (PKP1). Clinically, there are features of both cutaneous fragility and congenital ectodermal dysplasia affecting skin, hair and nails. There is no evidence of significant abnormalities in other epithelia or tissues. Desmosomes in the skin are small and poorly formed with widening of keratinocyte intercellular spaces and perturbed desmosome/keratin intermediate filament interactions. The molecular findings and clinical observations in this patient attest to the dual importance of plakophilin 1 in both cutaneous cell-call adhesion and epidermal morphogenesis.

Base Sequence↗

PubMed1985

Sequences of the S1 genes of the three serotypes of reovirus.

The S1 genes of the three serotypes of reovirus have been cloned and sequenced. The S1 genes encode protein sigma 1, the protein against which serotype-specific neutralizing antibodies are directed; it is also the reovirus hemagglutinin and cell-attachment protein and is a major determinant of host range/tissue specificity and of the nature of the interaction of reovirus with cells of the immune system. The S1 genes of serotypes 1, 2, and 3 are 1458, 1442, and 1416 nucleotides long, respectively. They possess untranslated regions 13, 13, and 12 nucleotides long at their 5' termini and 188, 229, and 36 nucleotides long at their 3' termini. They possess two open reading frames. The first starts with a "weak" initiation codon and extends for 418, 399, and 455 codons, respectively; this is the size expected for the sigma 1 proteins. The other reading frame starts at a "strong" initiation codon about 70 residues downstream from the 5' terminus but extends for only about 120 codons, being terminated by 3 in-phase termination codons in all three genes. The proteins encoded by these short open reading frames are quite basic. The serotype 1 and 2 S1 genes are much more closely related to each other (28% homology) than to the serotype 3 S1 gene (5% and 9% homology, respectively). These figures are based on direct homology calculations, adjusted for 25% random coincidence. Serologic evidence and hydrophobicity profiles agree that the sigma 1 proteins of serotypes 1 and 2 are much more closely related to each other (about 40% homology) than to that of serotype 3 (only about 20% homology). The fact that the serotype 1 and 2 S1 genes are much more closely related to each other than to the serotype 3 S1 gene is remarkable since for all other nine reovirus genes the serotype 1 and 3 genes are much more closely related to each other than to the serotype 2 gene. Mechanisms that may effect this remarkable evolutionary pattern are discussed.

Amino Acid Sequence↗

PubMed1990

Mutation eliminating mitochondrial leader sequence of methylmalonyl-CoA mutase causes muto methylmalonic acidemia.

Methylmalonyl-CoA mutase (EC 5.4.99.2) is a mitochondrial matrix enzyme whose activity is deficient in the inherited disorder methylmalonic acidemia. Previous studies on primary fibroblast cell lines from patients with methylmalonic acidemia have delineated a variety of biochemical phenotypes underlying this disorder. One cell line with primary mutase apoenzyme deficiency exhibited a particularly unusual phenotype; it expressed an abnormally small and unstable immunoreactive protein, which was not imported by mitochondria. We now report cloning and sequencing of the cDNA encoding this mutant protein. The mutation is a single base change, a cytosine----thymine transition, which introduces an amber termination codon at position 17 within the mitochondrial leader sequence. The immunoreactive protein produced by these cells reflects translation from AUG codons downstream from this termination codon and, hence, lacks a mitochondrial leader peptide. This mutation represents a complex prototype for a class of mutations in which absence of the mitochondrial targeting sequence leads to absence of a functioning gene product.

Amino Acid Metabolism, Inborn Errors↗

PubMed1991

Multiple human D5 dopamine receptor genes: a functional receptor and two pseudogenes.

Three genes closely related to the D1 dopamine receptor were identified in the human genome. One of the genes lacks introns and encodes a functional human dopamine receptor, D5, whose deduced amino acid sequence is 49% identical to that of the human D1 receptor. Compared with the human D1 dopamine receptor, the D5 receptor displayed a higher affinity for dopamine and was able to stimulate a biphasic rather than a monophasic intracellular accumulation of cAMP. Neither of the other two genes was able to direct the synthesis of a receptor. Nucleotide sequence analysis revealed that these two genes are 98% identical to each other and 95% identical to the D5 sequence. Relative to the D5 sequence, both contain insertions and deletions that result in several in-frame termination codons. Premature termination of translation is the most likely explanation for the failure of these genes to produce receptors in COS-7 and 293 cells even though their messages are transcribed. We conclude that the two are pseudogenes. Blot hybridization experiments performed on rat genomic DNA suggest that there is one D5 gene in this species and that the pseudogenes may be the result of a relatively recent evolutionary event.

Amino Acid Sequence↗

PubMed1993

Sequence analysis of the beta-N-acetylhexosaminidase gene of Vibrio vulnificus: evidence for a common evolutionary origin of hexosaminidases.

DNA cloned from the marine bacterium Vibrio vulnificus into Escherichia coli HB101 can hydrolyze chitin oligomer analogs in the recipient. The nucleotide sequence of the cloned DNA was determined and a single long open reading frame of 2541 base pairs (initiation codon through termination codon) was found. The nucleotide sequence predicts a gene product of 847 amino acids and a molecular mass of 94.3 kDa. In vitro transcription and translation analyses indicated a single protein of 94 kDa encoded by the cloned DNA. The gene product hydrolyzes methylumbelliferyl beta-D conjugates of chitotriose, chitobiose, N-acetylglucosamine, and N-acetylgalactosamine and has, therefore, been termed a beta-N-acetylhexosaminidase. The predicted protein shares a high degree of sequence similarity with the chitobiase of Vibrio harveyi and limited similarity with the alpha chain of human beta-hexosaminidase. Cluster analyses suggest a common evolutionary ancestor for all known hexosaminidase enzymes, with no detectable relationship to known chitinases.

Amino Acid Sequence↗

PubMed1998

Extent of laminin-5 assembly and secretion effect junctional epidermolysis bullosa phenotype.

Junctional epidermolysis bullosa (JEB) is an autosomal recessive skin blistering disease with both lethal and nonlethal forms, with most patients shown to have defects in laminin-5. We analyzed the location of mutations, gene expression levels, and protein chain assembly of the laminin-5 heterotrimer in six JEB patients to determine how the type of genetic lesion influences the pathophysiology of JEB. Mutations within laminin-5 genes were diversely located, with the most severe forms of JEB correlating best with premature termination codons, rather than mapping to any particular protein domain. In all six JEB patients, the laminin-5 assembly intermediates we observed were as predicted by our previous work indicating that the alpha3beta3gamma2 heterotrimer assembles intracellularly via a beta3gamma2 heterodimer intermediate. Since assembly precedes secretion, mutations that disrupt protein-protein interactions needed for assembly are predicted to limit the secretion of laminin-5, and likely to interfere with function. However, our data indicate that typically the most severe mutations diminish mRNA stability, and serve as functional null alleles that block chain assembly by resulting in either a deficiency (in the nonlethal mitis variety) or a complete absence (in lethal Herlitz-JEB) of one of the chains needed for laminin-5 heterotrimer assembly.

Adult↗

PubMed1997

Characterization of 18 new mutations in COL7A1 in recessive dystrophic epidermolysis bullosa provides evidence for distinct molecular mechanisms underlying defective anchoring fibril formation.

We have characterized 21 mutations in the type VII collagen gene (COL7A1) encoding the anchoring fibrils, 18 of which were not previously reported, in patients from 15 unrelated families with recessive dystrophic epidermolysis bullosa (RDEB). COL7A1 mutations in both alleles were identified by screening the 118 exons of COL7A1 and flanking intron regions. Fourteen mutations created premature termination codons (PTCs) and consisted of nonsense mutations, small insertions, deletions, and splice-site mutations. A further seven mutations predicted glycine or arginine substitutions in the collagenous domain of the molecule. Two mutations were found in more than one family reported in this study, and six of the seven missense mutations showed clustering within exons 72-74 next to the hinge region of the protein. Patients who were homozygous or compound heterozygotes for mutations leading to PTCs displayed both absence or drastic reduction of COL7A1 transcripts and undetectable type VII collagen protein in skin. In contrast, missense mutations were associated with clearly detectable COL7A1 transcripts and with normal or reduced expression of type VII collagen protein at the dermo/epidermal junction. Our results provide evidence for at least two distinct molecular mechanisms underlying defective anchoring fibril formation in RDEB: one involving PTCs leading to mRNA instability and absence of protein synthesis, the other implicating missense mutations resulting in the synthesis of type VII collagen polypeptide with decreased stability and/or altered function. Genotype-phenotype correlations suggested that the nature and location of these mutations are important determinants of the disease phenotype and showed evidence for interfamilial phenotypic variability.

Alleles↗

PubMed1994

Identification of a novel family of human endogenous retroviruses and characterization of one family member, HERV-K(C4), located in the complement C4 gene cluster.

We have identified a novel family of about 10-50 human endogenous retrovirus elements (HERVs) and have characterized one family member (HERV-KC4). This retrovirus element is integrated within intron 9 of and complement C4A genes and also in some C4B genes, and is a principal contribution to interlocus and interallelic length heterogeneity of C4 genes. The HERV-K(C4) sequence has a typical retrovirus structure with elements of gag, pol and env domains, flanked by two long terminal repeats (LTRs) and is similar to type A, B and D retroviruses. Multiple termination codons preclude the existence of long open reading frames, suggesting that the HERV-K(C4) sequence is no longer functional. Zoo blot hybridization reveals that New World monkeys appear to lack sequences similar to HERV-K(C4), suggesting that integration has occurred after the divergence of Old and New World monkeys. Retrotransposition of prototype viruses is presumed to have led to the amplification and integration of the members of the family in different loci, which in humans, appear to be dispersed over several chromosomes. The absence of the HERV-K(C4) element in some C4B genes in both humans and orangutangs indicate that the retrovirus inserted into the C4A gene after the duplication of the cluster. Subsequent spread of the HERV-K(C4) sequence to C4B genes presumably occurred by interlocus sequence exchange mechanisms, such as unequal crossover and gene conversion-like mechanisms.

Animals↗

PubMed1998

Wheat cytoplasmic arginine tRNA isoacceptor with a U*CG anticodon is an efficient UGA suppressor in vitro.

Many RNA viruses express part of their genomic information by read-through over internal termination codons. We have recently characterized tobacco cytoplasmic (cyt) and chloroplast (chl) tRNACmCATrp and tRNAGCACys as natural suppressor tRNAs that are able to read the leaky UGA codon in RNA-1 of tobacco rattle virus, albeit with different efficiencies. Here we have identified a third natural UGA suppressor in plants. We have purified and sequenced four cyt tRNAArg isoacceptors with ICG, CCG, U*CG and CCU anticodons from wheat germ. With the exception of tRNAICGArg, these are the first sequences of plant tRNAsArg. In order to study the potential suppressor activity of wheat tRNAsArg we have used in vitro synthesized mRNA transcripts in which different viral read-through regions had been placed. In vitro translation was carried out in a homologous wheat germ extract. We found that tRNAU*CGArg is an efficient UGA suppressor in vitro, whereas the other three tRNAArg isoacceptors exhibit no or very low suppressor activity. Interaction of tRNAU*CGArg with the UGA codon requires a G:U base pair at the third anticodon position. This is the first time that an arginine-accepting tRNA has been characterized as a natural UGA suppressor. A remarkable feature of cyt tRNAU*CGArg is its ability to misread the UGA at the end of the coat protein cistron in RNA-1 of pea enation mosaic virus, which is not accomplished by cyt tRNACmCATrp or cyt tRNAGCACys, due to an unfavourable codon context.

Anticodon↗

PubMed1981

Skeletal muscle actin mRNA. Characterization of the 3' untranslated region.

Plasmids p749, p106, and p150 contain cDNA inserts complementary to rat skeletal muscle actin mRNA. Nucleotide sequence analysis indicates the following sequence relationships: p749 specifies codons 171 to 360; p150 specifies codons 357 to 374 together with 120 nucleotides of the 3'-non-translated region; p106 specifies the last actin amino acid codon, the termination codon and the entire 3' non-translated region. Plasmid p749 hybridized with RNA extracted from rat skeletal muscle, cardiac muscle, smooth (stomach) muscle, and from brain. It also hybridizes well with RNA extracted from skeletal muscle and brain of dog and chick. Plasmid p106 hybridized specifically with rat striated muscles (skeletal and cardiac muscle) mRNA but not with mRNA from rat stomach and from rat brain. It also hybridized to RNA extracted from skeletal muscle of rabbit and dog but not from chick. Thermal stability of the hybrids and sensitivity to S1 digestion also indicated substantial divergence between the 3' untranslated end of rat and dog skeletal muscle actins. The investigation shows that the coding regions of actin genes are highly conserved, whereas the 3' non-coding regions diverged considerably during evolution. Probes constructed from the 3' non-coding regions of actin mRNAs can be used to identify the various actin mRNA and actin genes.

Actins↗