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PubMed2005

A homozygous nonsense mutation in the EVER2 gene leads to epidermodysplasia verruciformis.

Epidermodysplasia verruciformis (EV) is a genodermatosis with mainly autosomal recessive inheritance. Pathogenic mutations in two adjacent genes, EVER1 and EVER2, have recently been identified. In this study, we performed mutation detection for the EVER1 and EVER2 genes on samples from a Chinese patient with EV, who had consanguineous parents. A homozygous C-->T transition at nucleotide position 568 within exon 6 of the EVER2 gene was detected. The mutation led to a premature translation termination (R190X) and the predicted protein lacked 537 amino acids. This novel nonsense mutation is, to our knowledge, the first mutation reported in Chinese patients with EV.

Adult↗
PubMed2003

Identification of a novel missense mutation that is as damaging to DAX-1 repressor function as a nonsense mutation.

Mutations in the DAX-1 (NROB1) gene result in X-linked congenital adrenal hypoplasia (AHC) and hypogonadotropic hypogonadism. The clinical presentation is usually as adrenal insufficiency in early life, with hypogonadotropic hypogonadism detected at the time of expected puberty. In this study we identified mutations in the DAX-1 gene of two patients with AHC. One mutation, Y399X, resulted in a premature stop codon and was associated with loss of Leydig cell responsiveness to human chorionic gonadotropin. The second, L297P, was a missense mutation, and human chorionic gonadotropin responsiveness was maintained. Kindred analysis established that the mutations had been inherited from the proband's mothers. The L297P has not been described previously and occurs within a highly conserved binding motif (LLXLXL). Transient transfection assays demonstrated that both mutations resulted in a severe loss of DAX-1 repressor activity. Immunohistochemical analysis of testicular tissue obtained from an affected sibling of the subject with the Y399X mutation, who had died with adrenal failure as a neonate, showed normal testicular morphology and expression of DAX-1, steroidogenic factor-1, and anti-Mullerian hormone protein. These data extend the clinical and molecular information on DAX-1 mutations, confirm normal testicular development at the neonatal stage, and illustrate variability in Leydig cell function.

Adrenal Glands↗
PubMed1996

Anticonvulsant effect of reduced NMDA receptor expression in audiogenic DBA/2 mice.

Pretreatment of DBA/2 mice (n = 14-15 per group) with an 18-mer antisense probe to the NMDA-receptor submit NR1 (2 x 1 micrograms, or 2 x 83 pmol, NR1 antisense probe intracerebroventricularly, -29 and -7 h before testing for seizure response) resulted in almost complete suppression of sound-induced clonic seizures. A saline-treated group gave a 100% seizures response, while the group treated with NR1 antisense probe gave a 7% seizure response to the sound stimulus. The group treated with NR1 nonsense-probe showed no anticonvulsant protection (93% seizure response). The anticonvulsant protection observed following NR1 antisense administration was of relatively short duration, with seizure response gradually returning to control levels 12 to 24 h following the termination of antisense administration. When NR1 receptor levels were assessed by receptor autoradiography ([3H]-MK 801 and -CGP 39653 binding) in the same groups of mice, significant (20%) reductions in NR1 levels were observed in the retrosplenial cortex and the overall cortex. The seizure-induced expression of c-fos and NGFI-A in thalamus, hypothalamus, inferior colliculus and medical geniculate seen in vehicle- and NR1 nonsense-treated mice was completely blocked by NR1 antisense pretreatment.

Acoustic Stimulation↗
PubMed2001

Construction of an in vivo nonsense readthrough assay system and functional analysis of ribosomal proteins S12, S4, and S5 in Bacillus subtilis.

To investigate the function of ribosomal proteins and translational factors in Bacillus subtilis, we developed an in vivo assay system to measure the level of nonsense readthrough by utilizing the LacZ-LacI system. Using the in vivo nonsense readthrough assay system which we developed, together with an in vitro poly(U)-directed cell-free translation assay system, we compared the processibility and translational accuracy of mutant ribosomes with those of the wild-type ribosome. Like Escherichia coli mutants, most S12 mutants exhibited lower frequencies of both UGA readthrough and missense error; the only exception was a mutant (in which Lys-56 was changed to Arg) which exhibited a threefold-higher frequency of readthrough than the wild-type strain. We also isolated several ribosomal ambiguity (ram) mutants from an S12 mutant. These ram mutants and the S12 mutant mentioned above (in which Lys-56 was changed to Arg) exhibited higher UGA readthrough levels. Thus, the mutation which altered Lys-56 to Arg resulted in a ram phenotype in B. subtilis. The efficacy of our in vivo nonsense readthrough assay system was demonstrated in our investigation of the function of ribosomal proteins and translational factors.

Amino Acid Substitution↗
PubMed2003

New connections in the prokaryotic toxin-antitoxin network: relationship with the eukaryotic nonsense-mediated RNA decay system.

BACKGROUND: Several prokaryotic plasmids maintain themselves in their hosts by means of diverse post-segregational cell killing systems. Recent findings suggest that chromosomally encoded copies of toxins and antitoxins of post-segregational cell killing systems - such as the RelE system - might function as regulatory switches under stress conditions. The RelE toxin cleaves ribosome-associated transcripts, whereas another post-segregational cell killing toxin, ParE, functions as a gyrase inhibitor. RESULTS: Using sequence profile analysis we were able unify the RelE- and ParE-type toxins with several families of small, uncharacterized proteins from diverse bacteria and archaea into a single superfamily. Gene neighborhood analysis showed that the majority of these proteins were encoded by genes in characteristic neighborhoods, in which genes encoding toxins always co-occurred with genes encoding transcription factors that are also antitoxins. The transcription factors accompanying the RelE/ParE superfamily may belong to unrelated or distantly related superfamilies, however. We used this conserved neighborhood template to transitively search genomes and identify novel post-segregational cell killing-related systems. One of these novel systems, observed in several prokaryotes, contained a predicted toxin with a PilT-N terminal (PIN) domain, which is also found in proteins of the eukaryotic nonsense-mediated RNA decay system. These searches also identified novel transcription factors (antitoxins) in post-segregational cell killing systems. Furthermore, the toxin Doc defines a potential metalloenzyme superfamily, with novel representatives in bacteria, archaea and eukaryotes, that probably acts on nucleic acids. CONCLUSIONS: The tightly maintained gene neighborhoods of post-segregational cell killing-related systems appear to have evolved by in situ displacement of genes for toxins or antitoxins by functionally equivalent but evolutionarily unrelated genes. We predict that the novel post-segregational cell killing-related systems containing a PilT-N terminal domain toxin and the eukaryotic nonsense-mediated RNA decay system are likely to function via a common mechanism, in which the PilT-N terminal domain cleaves ribosome-associated transcripts. The core of the eukaryotic nonsense-mediated RNA decay system has probably evolved from a post-segregational cell killing-related system.

Adenosine Triphosphatases↗
PubMed2002

A new mutation of the ATP-binding cassette, sub-family C, member 2 (ABCC2) gene in a Japanese patient with Dubin-Johnson syndrome.

Dubin-Johnson syndrome (DJS) is an inherited disorder characterized by conjugated hyperbilirubinemia and is caused by mutations of the canalicular multispecific organic anion transporter (cMOAT)/ multidrug resistance protein 2 (MRP2)/ ATP-binding cassette, sub-family C, member 2 (ABCC2) gene. The ABCC2 protein is located in the apical membrane of hepatocytes, and known mutations of this gene cause impaired maturation and trafficking of the mutated protein from the endoplasmic reticulum (ER) to the Golgi complex. We have characterized the ABCC2 gene in a Japanese DJS patient by polymerase chain reaction and DNA sequencing, resulting in the identification of two mutations. One mutation, 1815+2 (T>A) in the splice donor site of intron 13, has already been reported. However, we have identified a novel nonsense mutation consisting of a (C>T) transition at nucleotide 3928 in exon 28.

ATP-Binding Cassette Transporters↗
PubMed1998

ATP is a cofactor of the Upf1 protein that modulates its translation termination and RNA binding activities.

The nonsense-mediated mRNA decay pathway decreases the abundance of mRNAs that contain premature termination codons and prevents suppression of nonsense alleles. The UPF1 gene in the yeast Saccharomyces cerevisiae was shown to be a trans-acting factor in this decay pathway. The Upf1p demonstrates RNA-dependent ATPase, RNA helicase, and RNA binding activities. The results presented here investigate the binding affinity of the Upf1p for ATP and the consequences of ATP binding on its affinity for RNA. The results demonstrate that the Upf1p binds ATP in the absence of RNA. Consistent with this result, the TR800AA mutant form of the Upf1p still bound ATP, although it does not bind RNA. ATP binding also modulates the affinity of Upf1p for RNA. The RNA binding activity of the DE572AA mutant form of the Upf1p, which lacks ATPase activity, still bound ATP as efficiently as the wild-type Upf1p and destabilized the Upf1p-RNA complex. Similarly, ATPgammaS, a nonhydrolyzable analogue of ATP, interacted with Upf1p and promoted disassociation of the Upf1p-RNA complex. The conserved lysine residue (K436) in the helicase motif Ia in the Upf1p was shown to be critical for ATP binding. Taken together, these findings formally prove that ATP can bind Upf1p in the absence of RNA and that this interaction has consequences on the formation of the Upf1p-RNA complex. Further, the results support the genetic evidence indicating that ATP binding is important for the Upf1p to increase the translation termination efficiency at a nonsense codon. Based on these findings, a model describing how the Upf1p functions in modulating translation and turnover and the potential insights into the mechanism of the Upf1p helicase will be discussed.

Adenosine Triphosphate↗
PubMed1997

Maximal gamma-globin expression in the compound heterozygous state for -175G gamma HPFH and beta degree 39 nonsense thalassaemia: a case study.

The -175 (T-->C) G gamma hereditary persistence of fetal haemoglobin is a very rare promoter mutation occurring in Caucasians as well as in African-Americans. Heterozygotes for this non-deletional HPFH show 20% HbF, mostly of G gamma type. We describe here a healthy Sardinian man who coinherited -175 (T-->C) G gamma HPFH with the beta-thalassaemia codon 39 nonsense mutation in trans; he showed 64% HbF, 100% of G gamma type. Although the beta-globin haplotype pattern (II/II) was indicative of the presence of the A gamma T allele on both chromosomes, the A gamma T expression was undetectable by HPLC even in red cell populations separated by age. The proband was, moreover, homozygous for the -4 bp deletion at position -225 to -222 of A gamma promoter which has recently been associated with decreased A gamma T globin expression. These findings suggest that this maximal overexpression of G gamma-globin probably reflects intensified stimulation of the mutated G gamma promoter in this hitherto undescribed genetic condition.

Adult↗
PubMed2001

A compound heterozygous one amino-acid insertion/nonsense mutation in the plectin gene causes epidermolysis bullosa simplex with plectin deficiency.

Plectin is a cytoskeleton linker protein expressed in a variety of tissues including skin, muscle, and nerves. Mutations in its gene are associated with epidermolysis bullosa simplex with late-onset muscular dystrophy. Whereas in most of these patients the pathogenic events are mediated by nonsense-mediated mRNA decay, the consequences of an in-frame mutation are less clear. We analyzed a patient with compound heterozygosity for a 3-bp insertion at position 1287 leading to the insertion of leucine as well as the missense mutation Q1518X leading to a stop codon. The presence of plectin mRNA was demonstrated by a RNase protection assay. However, a marked reduction of plectin protein was found using immunofluorescence microscopy of the patient's skin and Western blot analysis of the patient's cultured keratinocytes. The loss of plectin protein was associated with morphological alterations in plectin-containing structures of the dermo-epidermal junction, in skeletal muscle, and in nerves as detected by electron microscopy. In an in vitro overlay assay using recombinant plectin peptides spanning exons 2 to 15 the insertion of leucine resulted in markedly increased self-aggregation of plectin peptides. These results describe for the first time the functional consequences of an in-frame insertion mutation in humans.

Base Sequence↗
PubMed2000

Identification of four novel mutations in five unrelated Korean families with Fabry disease.

Fabry disease is a X-linked recessively inherited metabolic disorder, which results from the deficient activity of the lysosomal hydrolase alpha-galactosidase A leading to the systemic deposition of glycosphingolipids with terminal alpha-galactosyl moieties. Single-strand conformation polymorphism (SSCP) analysis was performed, followed by DNA sequencing of PCR amplified exons of the human alpha-galactosidase A gene in 5 unrelated Korean patients with classic Fabry disease. Five different mutations were identified; two nonsense mutations (Y86X and R342X), one missense mutation (D266N), and two small deletions (296del2 and 802del4). Except for R342X mutation, four were novel mutations (Y86X, D266N, 296del2, 802del4). A T to G transversion at nucleotide position 5157 in exon 2 caused a tyrosine-to-stop substitution at codon 86. A G to A transition at position 10287 in exon 5 substituted an asparagine for an aspartate at codon 266. Mutation 296del2 in exon 2 resulted in a frame shift with a stop signal at the 22th codon downstream from the mutation, whereas mutation 802del4 resulted in a stop codon at the site of 4 bp deletion. In addition, the 802del4 was found to be a de novo mutation. This is the first report on mutation analysis of the human alpha-galactosidase A gene in Korean patients with Fabry disease.

Adolescent↗
PubMed2001

Intramedullary and spinal canal tumors in patients with neurofibromatosis 2: MR imaging findings and correlation with genotype.

PURPOSE: To determine the appearance of spinal tumors on magnetic resonance (MR) images of patients with neurofibromatosis 2 (NF2), to assess the biologic behavior of these tumors, and to determine the correlation between NF2 germline mutations and these tumors. MATERIALS AND METHODS: Spinal MR images in 49 patients with NF2 were reviewed retrospectively. Intramedullary and intradural extramedullary tumors were counted, and imaging features and growth patterns of intramedullary tumors were determined. Medical records were reviewed for spinal tumor surgery. Data on spinal tumors and NF2 germline mutations in 37 patients from 19 families were analyzed for genotype-phenotype correlation. RESULTS: Thirty-one patients (63%) had spinal tumors: Twenty-six (53%) had intramedullary tumors, 27 (55%) had intradural extramedullary tumors, and 22 (45%) had at least one tumor of each type. Three (12%) patients with intramedullary tumors versus 16 (59%) with extramedullary tumors had undergone surgery for the respective types of tumors. Compared with patients with all other types of mutations, a higher percentage of patients with nonsense and frameshift mutations had intramedullary tumors (P <.025); these patients also had higher mean numbers of all tumors (P <.001), intramedullary tumors (P <.001), and nerve sheath tumors (NSTs) (P <.001). CONCLUSION: In patients with NF2 and spinal tumors, extramedullary tumors (predominantly NSTs) were present in higher numbers and were associated with more surgery than were intramedullary tumors. Our data suggest that the association between nonsense and frameshift mutations and severe NF2 may extend to specific categories of spinal tumors.

Adult↗
PubMed2002

A novel nonsense mutation (Q352X) in the mitochondrial cytochrome b gene associated with a combined deficiency of complexes I and III.

We identified a novel mitochondrial cytochrome b mutation in a patient with progressive exercise intolerance, muscle cramps and lactic acidosis. A marked reduction of the enzymatic activities of respiratory chain complexes I and III was found in muscle biopsy. The mutation was a heteroplasmic C15800T transition, determining a stop-codon at amino acid position 352 (Q352X). Mutant mtDNA was approximately 45% of total genomes in muscle, while it was absent in all of the other examined tissues of the patient and in lymphocytes of the patient's mother. Clinical presentation and laboratory findings strongly support the hypothesis that this mutation is the primary cause of the disease in our patient.

Adult↗
PubMed1999

Mutant transcripts of the LDL receptor gene: mRNA structure and quantity.

mRNA of the low-density lipoprotein receptor (LDLR) gene from 22 heterozygous familial hypercholesterolemic subjects possessing different mutations in this gene was analyzed by Northern blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) in order to detect abnormally spliced transcripts. These analyses revealed abnormally spliced transcripts for the two splice-site mutations 1359-1G-->A and 1705 + 1G-->T. The abnormally spliced transcript for mutation 1359-1G-->A was caused by activation of a cryptic acceptor splice site in exon 10. As a result, seven nucleotides of exon 10 were deleted. For mutation 1705 + 1G-->T, two mutant transcripts were observed. In the first transcript, exon 10 was spliced to exon 13, and in the second transcript intron 11 was retained. The relative amount of mutant transcripts from 14 of the 22 subjects was determined by use of an RT-PCR-based method. Quantitation of the relative amounts of mutant transcripts for five missense mutations resulted in a mean value (+/-SD) of 52.8% (+/-4.55). In comparison, quantitation of the relative amounts of mutant transcripts for five nonsense mutations resulted in a mean value of 31.8% (+/-6.91). This value was significantly lower than the value of 54.2% (+/-2.38) obtained for nine healthy subjects (P < 0.0001). The relative amount of mutant transcripts for the 1705 + 1G-->T mutation was 36%. Thus, transcripts from alleles containing premature stop codons are present in reduced amounts, whereas transcripts from alleles containing missense mutations are present in normal amounts. These findings underscore the importance of determining how mutations affect mRNA structure and quantity in order to understand how mutations cause disease.

Alleles↗
PubMed2001

Molecular characterization of the PK-LR gene in sixteen pyruvate kinase-deficient patients.

We studied the PK-LR gene in 16 unrelated patients with congenital haemolytic anaemia associated with erythrocyte pyruvate kinase deficiency. Fifteen different mutations were detected among the 28 mutated alleles identified: two deletions (del 1010G, del 1042--1044); one four nucleotide duplication (nt 1515--1518, GGTC); one splice site [IVS6(-2)t]; nine missense (991A, 1003A, 1151T, 1160G, 1181T, 1181A, 1456T, 1483A, 1529A); and two nonsense (721T, 1675T) mutations. Eight of them [del 1010G, del 1042--1044, dupl 1515--1518, IVS6(-2)t, 1003A, 1160G, 1181T, 1181A] were novel. The deletion 1042-1044 causes the loss of Lys 348. Deletion 1010G and duplication 1515-1518 determine a frameshift and the creation of a stop codon at nucleotides 1019 and 1554 respectively. Mutation IVS6(-2)t leads to an alteration of the 5' and 3' splice site consensus sequence; the cDNA analysis shows a 67-bp deletion in the first part of exon 11 (del 1437--1503). All the four new missense mutations involve highly conserved amino acids. The most frequent mutation in Italy would appear to be 1456T. Correlation was made between mutations, biochemical characteristics of the enzyme and clinical course of the disease.

Adult↗