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PubMed1996

Mutations in fliK and flhB affecting flagellar hook and filament assembly in Salmonella typhimurium.

Mutations in the fliK gene of Salmonella typhimurium commonly cause failure to terminate hook assembly and initiate filament assembly (polyhook phenotype). Polyhook mutants give rise to pseudorevertants which are still defective in hook termination but have recovered the ability to assemble filament (polyhook-filament phenotype). The polyhook mutations have been found to be either frameshift or nonsense, resulting in truncation of the C terminus of FliK. Intragenic suppressors of frameshift mutations were found to be ones that restored the original frame (and therefore the C-terminal sequence), but in most cases with substantial loss of natural sequence and sometimes the introduction of artificial sequence; in no cases did intragenic suppression occur when significant disruption remained within the C-terminal region. By use of a novel PCR protocol, in-frame deletions affecting the N-terminal and central regions of FliK were constructed and the resulting phenotypes were examined. Small deletions resulted in almost normal hook length control and almost wild-type swarming. Larger deletions resulted in loss of control of hook length and poor swarming. The largest deletions severely affected filament assembly as well as hook length control. Extragenic suppressors map to an unlinked gene, flhB, which encodes an integral membrane protein (T. Hirano, S. Yamaguchi, K. Oosawa, and S.-I. Aizawa, J. Bacteriol. 176:5439-5449, 1994; K. Kutsukake, T. Minamino, and T. Yokoseki, J. Bacteriol. 176:7625-7629, 1994). They were either point mutations in the C-terminal cytoplasmic region of FlhB or frameshift or nonsense mutations close to the C terminus. The processes of hook and filament assembly and the roles of FliK and FlhB in these processes are discussed in light of these and other available data. We suggest that FliK measures hook length and, at the appropriate point, sends a signal to FlhB to switch the substrate specificity of export from hook protein to late proteins such as flagellin.

Amino Acid Sequence↗
PubMed1994

Adaptive mutation by deletions in small mononucleotide repeats.

Adaptive reversion of a +1 frameshift mutation in Escherichia coli, which requires homologous recombination functions, is shown here to occur by -1 deletions in regions of small mononucleotide repeats. This pattern makes improbable recombinational mechanisms for adaptive mutation in which blocks of sequences are transferred into the mutating gene, and it supports mechanisms that use DNA polymerase errors. The pattern appears similar to that of mutations found in yeast cells and in hereditary colon cancer cells that are deficient in mismatch repair. These results suggest a recombinational mechanism for adaptive mutation that functions through polymerase errors that persist as a result of a deficiency in post-synthesis mismatch repair.

Base Sequence↗
PubMed2007

Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia.

OBJECTIVE: Familial glucocorticoid deficiency type I (FGD1) is a rare form of primary adrenal insufficiency resulting from recessive mutations in the ACTH receptor (MC2R, MC2R). Individuals with this condition typically present in infancy or childhood with signs and symptoms of cortisol insufficiency, but disturbances in the renin-angiotensin system, aldosterone synthesis or sodium homeostasis are not a well-documented association of FGD1. As ACTH stimulation has been shown to stimulate aldosterone release in normal controls, and other causes of hyponatraemia can occur in children with cortisol deficiency, we investigated whether MC2R changes might be identified in children with primary adrenal failure who were being treated for mineralocorticoid insufficiency. DESIGN: Mutational analysis of MC2R by direct sequencing. PATIENTS: Children (n = 22) who had been diagnosed with salt-losing forms of adrenal hypoplasia (19 isolated cases, 3 familial), and who were negative for mutations in DAX1 (NR0B1) and SF1 (NR5A1). RESULTS: MC2R mutations were found in three individuals or kindred (I: homozygous S74I; II: novel compound heterozygous R146H/560delT; III: novel homozygous 579-581delTGT). These changes represent severely disruptive loss-of-function mutations in this G-protein coupled receptor, including the first reported homozygous frameshift mutation. The apparent disturbances in sodium homeostasis were mild, manifest at times of stress (e.g. infection, salt-restriction, heat), and likely resolved with time. CONCLUSIONS: MC2R mutations should be considered in children who have primary adrenal failure with apparent mild disturbances in renin-sodium homeostasis. These children may have been misdiagnosed as having salt-losing adrenal hypoplasia. Making this diagnosis has important implications for treatment, counselling and long-term prognosis.

Adrenal Insufficiency↗
PubMed2005

Mutational and structural analysis of Japanese patients with mucopolysaccharidosis type II.

We investigated mutations of the iduronate-2-sulfatase (I2S) gene and structural characteristics of I2S to clarify genotype/phenotype relationships in 18 Japanese patients with mucopolysaccharidosis type II. The I2S gene was analyzed in five patients with a severe phenotype and in 13 patients with an attenuated phenotype. The tertiary structural model of the human I2S was constructed by homology modeling using the arylsulfatase structure as a template. We identified four missense mutations and a nonsense mutation in the severe phenotype; four missense, two nonsense, three frame shifts, and one each of splice and amino acid deletion in the attenuated phenotype. Seven of them (L73del, Q75X, G140R, C171R, V401 fs, C422 fs, and H441 fs) were novel mutations. Structural analysis indicated that the residues of the mutations found in the severe phenotype would have direct interactions with the active site residues or should break the hydrophobic core domain of I2S, whereas residues of the missense mutations found in the attenuated phenotype were located in the peripheral region. In addition, effects by deletion or frameshift mutations could also be interpreted by the structure. Structural analysis of mutant proteins would help in understanding the genotype/phenotype relationships of Hunter disease.

Adolescent↗
PubMed2004

A novel mutation in KCNQ2 gene causes benign familial neonatal convulsions in a Chinese family.

Benign familial neonatal convulsions (BFNC) are a rare autosomal dominant inherited epilepsy syndrome. Two voltage-gated potassium channel genes, KCNQ2 on chromosome 20q13.3 and KCNQ3 on chromosome 8q24, have been identified as the genes responsible for benign familial neonatal convulsions. By linkage analysis and mutation analysis of KCNQ2 gene, we found a novel frameshift mutation of KCNQ2 gene, 1931delG, in a large Chinese family with benign familial neonatal convulsions. This mutation is located in the C-terminus of KCNQ2, in codon 644 predicting the replacement of the last 201 amino acids with a stretch of 257 amino acids showing a completely different sequence. An unusual clinical feature of this family is that the seizures of every patient did not remit until 12 to 18 months. This is the first report of KCNQ2 gene mutation in China.

Base Sequence↗
PubMed1992

Compound heterozygosity in a complete erythrocyte bisphosphoglycerate mutase deficiency.

Erythrocyte bisphosphoglycerate mutase (BPGM) deficiency is a rare disease associated with a decrease in 2,3-diphosphoglycerate concentration. A complete BPGM deficiency was described in 1978 by Rosa et al (J Clin Invest 62:907, 1978) and was shown to be associated with 30% to 50% of an inactive enzyme detectable by specific antibodies and resulting from an 89 Arg-->Cys substitution. The propositus' three sisters exhibited the same phenotype, while his two children had an intermediate phenotype. Samples from the family were examined using polymerase chain reaction and allele-specific oligonucleotide hybridization and sequencing techniques. Amplification of erythrocyte total RNA from the propositus' sister around the 89 mutation indicated the presence of two forms of messenger RNAs, a major form with the 89 Arg-->Cys mutation and a minor form with a normal sequence. Sequence studies of the propositus' DNA samples indicated heterozygosity at locus 89 and another heterozygosity with the deletion of nucleotide C 205 or C 206. Therefore, the total BPGM deficiency results from a genetic compound with one allele coding for an inactive enzyme (mutation BPGM Créteil I) and the other bearing a frameshift mutation (mutation BPGM Créteil II). Examination of the propositus' two children indicated that they both inherited the BPGM Créteil I mutation.

Arginine↗
PubMed2003

Mutagenicity test system based on a reporter gene assay for short-term detection of mutagens (MutaGen assay).

The construction of a bacterial mutation assay system detecting reversions of base substitutions and frameshifts in tetracycline (tet) and ampicillin resistance genes located on low copy plasmids is described. Frameshift mutations were introduced into repetitive GC-sequences and G-repeats known to be mutagenic hot-spots. Base pair substitutions were inserted in or around the active site of the ampicillinase gene thus generating reversibility of the ampicilline sensitivity. The plasmids carry genes to enable sensitive, fast and specific detection of mutagens in bacteria. MucAB was cloned into the test plasmid to enhance error-prone DNA-repair. The conventional reversion principle has been combined with the luminometric measurement of an inducible reporter gene. The revertants are detected after induction of the beta-galactosidase-producing lacZ-gene either controlled by its natural lac-promotor or by the more stringently repressed (anhydrotetracyclin inducible) tetA promotor. The tester strains containing the tetA/lacZ reporter gene construct can grow in full medium over the complete assay. This test procedure enables screening for mutations within one working day. Incubation for 16 h reveals high sensitivity.

Amino Acid Sequence↗
PubMed1993

Mutations in the type II 3 beta-hydroxysteroid dehydrogenase gene in a patient with classic salt-wasting 3 beta-hydroxysteroid dehydrogenase deficiency congenital adrenal hyperplasia.

Inherited adrenal and gonadal 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency is most likely caused by a mutation of the type II 3 beta-HSD gene. Cloning and sequencing of exons I-II, III, and IV and portions of the adjacent introns, amplified by polymerase chain reaction using primers specific for the type II gene, in one male pseudohermaphrodite with salt-wasting classic 3 beta-HSD deficiency congenital adrenal hyperplasia revealed the same mutation in all nine clones of exon IV consisting of a missense mutation at codon 248 [GTC(Val)-->AAC(Asn)] followed by a frameshift mutation at codon 249 [CGA (Arg)-->TA], resulting in a stop codon TAG, and normal sequences of exon I-II and III and the adjacent portions of introns. The same codon 248 and 249 mutations were found on one clone of his mother's DNA, but two other clones revealed normal sequences. These data indicate a homozygous combined missense/frameshift mutation in exon IV of the type II 3 beta-HSD gene resulting in severe salt-wasting adrenal and gonadal 3 beta-HSD deficiency in the patient.

3-Hydroxysteroid Dehydrogenases↗
PubMed2003

Clinical and molecular analysis of Grebe acromesomelic dysplasia in an Omani family.

Grebe syndrome is a rare autosomal recessive acromesomelic dysplasia. The syndrome was studied clinically, radiographically, and genetically in an Omani family with four affected children. The affected persons had normal axial skeletons, severely shortened, and deformed limbs with severity increasing in a proximo-distal gradient, and subluxated joints. The humeri and femora were hypoplastic with distal malformations. The radii/ulnae were shortened and deformed whereas carpal bones were invariably rudimentary or absent. The tibiae appeared rudimentary; fibulae were absent in two children, and some tarsal and metatarsal bones were absent. The proximal and middle phalanges were absent while the distal phalanges were present. The father and mother had short first metacarpal and middle phalynx of the fifth finger and hallux valgus respectively. Transition A1137G and deletion delG1144 mutations in the gene encoding the cartilage-derived morphogenetic protein-1 (CDMP-1) were identified in this family. The A1137G is a silent mutation coding for lysine, whereas the delG1144 predicts a frameshift mutation resulting in a presumable loss of the CDMP-1 biologically active carboxy-terminal domain. The affected siblings were homozygous for the delG1144 mutation while parents were heterozygous.

Abnormalities, Multiple↗
PubMed1994

Additional mutations of type X collagen confirm COL10A1 as the Schmid metaphyseal chondrodysplasia locus.

Type X collagen is a short chain collagen expressed in hypertrophic chondrocytes during bone growth. A 13bp deletion has been shown to segregate with Schmid metaphyseal chondrodysplasia, an autosomal dominant disorder of the osseous skeleton, in a large Mormon kindred. To increase our understanding of the role type X collagen plays in development we have used SSCP analysis to identify three additional mutations in patients with Schmid metaphyseal chondrodysplasia. Two are frameshift mutations (1856delC and 1992delCT) and one is a missense mutation (C591R). Of interest, the apparently unaffected mother of the patient with the missense mutation is a somatic mosaic for the mutant allele. All three mutations are in the carboxy-terminal non-collagenous domain suggesting that the effect of these mutations is to impair the mutant polypeptide's ability to participate in chain association and trimer formation.

Alleles↗
PubMed1998

Close correlation between mutations of E2F4 and hMSH3 genes in colorectal cancers with microsatellite instability.

Defects in mismatch repair function can lead to the microsatellite instability (MI+; replication error) phenotype in certain human cancers. We previously reported that MI+ tumor-specific repeat number alteration at 13 consecutive trinucleotide (CAG) repeats within a coding exon of the E2F4 gene is a possible target of the defective repair pathway. Additional investigations revealed that E2F4 mutations are common (11 of 17 cases, 65%, mostly deletions) in a subset of human colorectal cancers with extensive MI+ phenotype, with respect to the proportion of loci affected and that most of these E2F4-mutated tumors (9 of 11, 82%) were accompanied by frameshift mutations in a polyadenine stretch within the seventh exon of the hMSH3 gene, a known mismatch repair gene that is responsible for repair of mismatch loops of two to four nucleotides. However, neither of these mutations was detected in 15 tumors with a lower incidence of MI+ loci. Similar repeat number alterations were less frequent in CAG repeats from other genes in all of the MI+ tumors we examined. These results indicate the presence of a novel cascade of mutational events that may be involved in acquisition of the malignant phenotype of human colorectal cancers with genetic instability.

Colorectal Neoplasms↗
PubMed2004

A novel mutation in the PITX2 gene in a family with Axenfeld-Rieger syndrome.

PURPOSE: To determine the underlying genetic cause of Axenfeld-Rieger syndrome (ARS) in a three-generation family. INTRODUCTION: ARS is a multisystem, autosomal dominant disorder characterized by specific ocular and non-ocular anomalies sometimes caused by mutations in the transcription factor gene, PITX2. METHODS: The three coding exons of the PITX2 gene, i.e., exons 2, 3, and 4, in affected and unaffected subjects were amplified by polymerase chain reaction (PCR) and sequenced. The PCR products of exon 4 were subcloned and sequenced to confirm the nature of the mutation. RESULTS: A deletion of thymine (T) 1261 was identified, creating a frameshift mutation in codon 227. This change is predicted to create 11 novel amino acids downstream, followed by premature truncation of the protein. CONCLUSIONS: This mutation highlights the functional importance of a conserved 14-amino acid sequence at the C-terminus of the protein thought to be important in repressing DNA binding and in protein-protein interactions.

Abnormalities, Multiple↗
PubMedDate not supplied

Mutational specificities of 1'-acetoxysafrole, N-benzoyloxy-N-methyl-4-aminoazobenzene, and ethyl methanesulfonate in human cells.

We have used an oriP-tk shuttle vector to determine the types of mutations induced in human cells by ethyl methanesulfonate (EMS), 1'-acetoxysafrole (AcOS), and N-benzoyloxy-N-methyl-4-aminoazobenzene (BzOMAB). Plasmid DNA was treated in vitro with mutagen and electroporated into human lymphoblastoid cells. After replication of the vector in human cells, plasmids were analyzed for mutations in the herpes simplex virus type 1 thymidine kinase gene. Ethyl methanesulfonate induced predominantly GC----AT transition mutations. Treatment of the shuttle vector with AcOS induced 5 of the 6 possible base substitution mutations, including GC----AT (32%) and AT----GC (14%) transition mutations, GC----TA (9%), GC----CG (18%), and AT----TA (14%) transversion mutations, as well as a low frequency (9%) of -1 frameshift mutations at GC base pairs. Replication in human cells of DNA modified with BzOMAB yielded a significant increase (17-fold) in the frequency of deletion mutations relative to solvent-treated DNA. A majority (94%) of the point mutations induced by BzOMAB occurred at GC base pairs and were predominantly GC----AT transitions (33%) and -1 frameshift (22%) mutations, with the remainder consisting mainly of transversions at GC base pairs (28%). The broad spectrum of base substitution mutations observed for AcOS and BzOMAB may indicate the frequent insertion of a variety of bases during replicative bypass of aralkylated bases in human cells.

Azo Compounds↗
PubMed2003

Extracellular matrix protein 1 gene (ECM1) mutations in lipoid proteinosis and genotype-phenotype correlation.

The autosomal recessive disorder lipoid proteinosis results from mutations in extracellular matrix protein 1 (ECM1), a glycoprotein expressed in several tissues (including skin) and composed of two alternatively spliced isoforms, ECM1a and ECM1b, the latter lacking exon 7 of this 10-exon gene (ECM1). To date, mutations that either affect ECM1a alone or perturb both ECM1 transcripts have been demonstrated in six cases. However, lipoid proteinosis is clinically heterogeneous with affected individuals displaying differing degrees of skin scarring and infiltration, variable signs of hoarseness and respiratory distress, and in some cases neurological abnormalities such as temporal lobe epilepsy. In this study, we sequenced ECM1 in 10 further unrelated patients with lipoid proteinosis to extend genotype-phenotype correlation and to add to the mutation database. We identified seven new homozygous nonsense or frameshift mutations: R53X (exon 3); 243delG (exon 4); 507delT (exon 6); 735delTG (exon 7); 785delA (exon 7); 892delC (exon 7) and 1190insC (exon 8), as well as two new compound heterozygous mutations: W160X/F167I (exon 6) and 542insAA/R243X (exons 6/7), none of which were found in controls. The mutation 507delT occurred in two unrelated subjects on different ECM1 haplotypes and may therefore represent a recurrent mutation in lipoid proteinosis. Taken with the previously documented mutations in ECM1, this study supports the view that exons 6 and 7 are the most common sites for ECM1 mutations in lipoid proteinosis. Clinically, it appears that mutations outside exon 7 are usually associated with a slightly more severe mucocutaneous lipoid proteinosis phenotype, but neurological features do not show any specific genotype-phenotype correlation.

Adolescent↗
PubMed1998

Effect of cellular level of FliK on flagellar hook and filament assembly in Salmonella typhimurium.

Frameshift mutations in the fliK gene of Salmonella result in abnormal elongation of the hook and the failure to assemble filament (polyhook phenotype). Second-site suppressor mutations restore filament assembly, but the cells often remain defective in hook-length control (polyhook-filament phenotype). Where the suppressor mutations are intragenic, the second mutation restores the original frame, generating a region of frameshifted sequence, but restoring the natural C terminus. Some of these frameshifted sequences contain a UGA (opal) termination codon. These cells have few flagella and swarm poorly. We suspected that readthrough of UGA by tRNATrp might be the reason for the partial function. When the UGA codon was changed to the Trp codon UGG, flagellar assembly and function were restored to wild-type levels. Conversely, underexpression of the wild-type fliK gene, achieved by changing the sole Trp codon in the sequence (Trp271) to UGA, decreased both the number of flagella and the ability to swarm. These results validate the readthrough hypothesis and indicate that low levels of FliK sustain some degree of flagellation and motility. At low levels of FliK, most flagella had polyhooks. With increasing amounts, the morphology progressively changed to polyhook-filament, and eventually to wild-type hook-filament. When FliK was overproduced, the hook length was slightly shorter (46(+/-7) nm) than that of the wild-type strain (55(+/-9) nm). FliK levels were measured by immunoblotting. Wild-type levels were about 40 to 80 molecules/cell. FliK synthesized by UGA readthrough could be detected when overproduced from plasmid fliK-W271opal, and the levels indicated a probability of readthrough of 0.002 to 0.01. This value was used to estimate the cellular level of underexpressed FliK, which could partly restore function to a fliK mutant, at about 0.07 to 0.8 molecule/cell. These results suggest that FliK does not form a large structure in the cytoplasm and may function as a regulatory protein for protein export. A model for hook-length control is presented that involves feedback from the assembly point to the export apparatus.

Bacterial Proteins↗
PubMed1991

Mutagenicity of coolwhite fluorescent light for Salmonella.

The most common fluorescent lamps in use today in homes and businesses in the United States, 'coolwhite' fluorescent lamps, emit light that is mutagenic for Salmonella. Strains that carry both a uvrB mutation and plasmid pKM101 are extremely susceptible to this light-induced mutation. Both base substitution and frameshift mutations can be induced without substantial lethal effects on the bacteria. Induced mutations accumulate essentially as a linear function of the time bacteria are exposed to illumination. Of Salmonella histidine-requiring strains with known nucleotide target sequences (Hartman et al., 1986; Cebula and Koch, 1989, 1990), strains either carrying one of the base substitution mutations, hisG428 and hisG46, or one of the frameshifts, hisC3076 and hisD6610, are most highly mutagenized whereas frameshift strains with hisD6580 and hisD3052 exhibit lower rates of mutagenesis. Mutagenicity does not appear to require the presence of oxygen. A filter blocking wavelengths below 370 nm eliminates mutagenesis. Polystyrene, cellulose acetate and, especially, mylar and glass filters reduce mutagenesis, indicating that at least some of the mutagenic effects can be attributed to leakage of radiations below 290 nm (far-ultraviolet light) from 'coolwhite' lamps. The more recently introduced fluorescent 'softwhite' lamps are roughly 10-fold less mutagenic at approximately equal light intensity. Incandescent light bulbs are much less mutagenic than are these fluorescent lamps. Our mutational data correlate closely with previous results in eukaryotic cells (Jacobson and Krell, 1982). A uvrB recA Salmonella double mutant is hypersensitive to the lethal effects of coolwhite fluorescent light, even when illuminated through the lids of glass Petri dishes. Thus, appropriate Salmonella strains would appear to be simple and useful screens for both the mutagenic and the lethal activities of fluorescent lamps. These systems are amenable to classroom laboratory use as relatively safe and effective means of demonstrating environmental mutagenesis.

Catalase↗
PubMed2004

Missense mutations of MADH4: characterization of the mutational hot spot and functional consequences in human tumors.

PURPOSE AND EXPERIMENTAL DESIGN: The mutational spectrum of MADH4 (DPC4/SMAD4) opens valuable insights into the functions of this protein that confer its tumor-suppressive nature in human tumors. We present the MADH4 genetic status determined on a new set of pancreatic, biliary, and duodenal cancers with comparison to the mutational data reported for various tumor types. RESULTS: Homozygous deletion, followed by inactivating nonsense or frameshift mutations, is the predominant form of MADH4 inactivation in pancreatic cancers. Among the naturally occurring MADH4 missense mutations, the MH2 domain is the most frequent target (77%) of missense mutations in human tumors. A mutational hot spot resides within the MH2 domain corresponding to codons 330 to 370, termed the mutation cluster region (MCR). A relationship was found between the locations of the missense mutations (the MH1 domain, the MH2-MCR, and the MH2 outside of the MCR) and the tumor types, suggesting environmental or selective influences in the development of MADH4 mutations. Immunohistochemical studies for Madh4 protein in nine archival cancers (six pancreatic cancers, two duodenal cancers, and one biliary cancer) with known missense mutations indicated that all mutations within the MH1 or MH2 domain COOH-terminal to the MCR (seven of nine cases) had negative or weak labeling, whereas two cancers with mutations within the MCR had strong positive nuclear labeling for Madh4 protein. CONCLUSIONS: These findings have important implications for in vitro functional studies, suggesting that the majority of missense mutations inactivate Madh4 by protein degradation in contrast to those that occur within the MCR.

Animals↗