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PubMed1995

Concentration of mutations causing Schmid metaphyseal chondrodysplasia in the C-terminal noncollagenous domain of type X collagen.

Schmid metaphyseal chondrodysplasia (SMCD) has previously been shown to be the result of mutations in the type X collagen gene, COL10A1. A further three mutations have been identified, including two nonsense mutations (Y268X, W651X) and a frameshift mutation (1856delCC). Each of the 10 SMCD mutations identified to date is within the C-terminal noncollagenous domain of type X collagen and three of five deletions initiated around the same nucleotide. This domain is believed to be involved in the initiation of collagen trimerization. The concentration of mutations within this domain is consistent with the hypothesis that the phenotype is the result of a reduction in the level of mature type X collagen due to the mutant polypeptide's inability to participate in trimer formation, although a dominant-negative mechanism cannot be discounted, on the basis of current evidence.

Amino Acid Sequence↗
PubMed2001

Mutation and abnormal expression of the fragile histidine triad gene in nasopharyngeal carcinoma.

OBJECTIVE: To determine alterations of fragile histidine triad (FHIT) gene in nasopharyngeal carcinoma and the correlation of FHIT gene with nasopharyngeal carcinogenesis. STUDY DESIGN: Prospective study. METHODS: A total of 28 nasopharyngeal carcinoma and 16 normal nasopharyngeal epithelium specimens were examined for abnormalities of FHIT gene by nested reverse-transcriptase-polymerase chain reaction and DNA sequencing. RESULTS: The deletion of FHIT gene was not observed in 16 normal nasopharyngeal epithelium specimens. In 28 cases of nasopharyngeal carcinoma tissues, 12 (42.9%) exhibited FHIT aberrant transcripts. Complementary DNA sequencing revealed exonic deletion, small DNA insertion, synonymous mutation in exon 8, or frameshift mutation in exon 5. CONCLUSIONS: The present results suggest that the FHIT gene may play an important role in the pathogenesis of nasopharyngeal carcinoma and may be one of the candidate tumor suppressor genes in nasopharyngeal carcinoma.

Biopsy↗
PubMed1998

Mutational analysis of the Jagged 1 gene in Alagille syndrome families.

Alagille syndrome (AGS) is an autosomal dominant disease characterized by five major abnormalities in the liver, heart, face, vertebrae and eye. The responsible gene has been recently identified as the human Jagged 1 (JAG1) gene, which encodes a ligand for the Notch receptor. We analyzed the JAG1 gene in eight AGS families, including affected and unaffected individuals, at the genomic DNA level, mainly by single-strand conformational polymorphism (SSCP) and DNA sequencing analysis. Four categories of mutations were identified: (i) four frameshift mutations in exons 9, 22, 24 and 26 were exhibited respectively in affected individuals of four AGS families, which resulted in moving the translational frame of JAG1; (ii) one nonsense mutation, a 1 bp substitution in exon 5 of the EGF-like repeat domain, was detected in two unrelated AGS families, which altered codon 235 from arginine to stop; (iii) one acceptor splice site mutation of exon 5 was revealed in a sporadic patient; and (iv) a 1.3 Mb deletion, which included the entire JAG1 gene, was found in another patient. Our results further demonstrate that AGS is a dominant disease and suggest that the JAG1 gene exerts a fundamental role in regulating genes involved in development.

Alagille Syndrome↗
PubMed1980

[Effect of plasmids col I and pKM101, alone or in combination, on spontaneous and induced mutability of salmonellae].

Comparative studies of plasmids col I and pKM101 effect on lethal and mutagenic response to UV-light and chemical agents (4NQ0, EMS, agent N012074) has been carried out in Salmonella strains used for screening of mutagens (potential carcinogens). It has been found that the plasmid pKM101 has more pronounced effect as compared with coll plasmid. Contrary to plasmid pKM101-mediated ability to form UV-induced frameshift mutation, colI factor lacks this ability and very slightly enhances the rate of frameshift mutagenesis induced by chemical agents under study. The colicinogenic factor is found to enhance only the rate of base-pair substitutions, whereas plasmid pKM101 enhances the rate of both base-pair substitutions and frameshift mutations. We were unable to demonstrate combined effect of these two plasmids on the rate of either spontaneous or induced mutations. Possible mechanisms of plasmid-mediated bacterial mutagenesis and repair are discussed.

4-Nitroquinoline-1-oxide↗
PubMed2001

Familial hypomagnesemia-hypercalciuria in 2 siblings.

Familial hypomagnesemia-hypercalciuria with nephrocalcinosis and renal insufficiency in childhood is a rarely described disease. Two siblings of consanguineous Tunesian parents (first cousins), a 2-year-old boy and a 4-year-old girl presented with renal insufficiency and severe bilateral nephrocalcinosis. Both were found to have decreased serum and intracellular magnesium concentrations, increased urinary excretion of magnesium and calcium, mild glomerular and severe tubular proteinuria and low citrate excretion in urine. Pathological biochemical findings and the severity of nephrocalcinosis of the boy compared to findings of the sister were strongly marked, Histology of the boy's kidney showed severe medullary nephrocalcinosis, tubular atrophy, focal lymphoplasmacellulary infiltration, focal cortical fibrosis, immature glomerula, segmental and global glomerulosclerosis. Subsequent mutation analysis revealed a homozygous frameshift mutation in the gene paracellin-1 in both affected individuals. Therapy consisted of sodium bicarbonate, cholecalciferol, calcitriol, hydrochlorothiazide, citrate salts and oral magnesium administration. Hypercalciuria decreased in both children by therapy with thiazide diuretics, but hypomagnesemia was unresponsive to magnesium administration. After a 32-month follow-up the boy commenced hemodialysis at the age of 5 years, whereas his sister showed no decline in renal function.

Calcium↗
PubMed2006

Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma.

PR domain containing 1 with zinc finger domain (PRDM1)/B lymphocyte-induced maturation protein 1 (BLIMP1) is a transcriptional repressor expressed in a subset of germinal center (GC) B cells and in all plasma cells, and required for terminal B cell differentiation. The BLIMP1 locus lies on chromosome 6q21-q22.1, a region frequently deleted in B cell lymphomas, suggesting that it may harbor a tumor suppressor gene. We report here that the BLIMP1 gene is inactivated by structural alterations in 24% (8 out of 34) activated B cell-like diffuse large cell lymphoma (ABC-DLBCL), but not in GC B cell-like (n = 0/37) or unclassified (n = 0/21) DLBCL. BLIMP1 alterations included gene truncations, nonsense mutations, frameshift deletions, and splice site mutations that generate aberrant transcripts encoding truncated BLIMP1 proteins. In all cases studied, both BLIMP1 alleles were inactivated by deletions or mutations. Furthermore, most non-GC type DLBCL cases (n = 20/26, 77%) lack BLIMP1 protein expression, despite the presence of BLIMP1 mRNA. These results indicate that a sizable fraction of ABC-DLBCL carry an inactive BLIMP1 gene, and suggest that the same gene is inactivated by epigenetic mechanisms in an additional large number of cases. These findings point to a role for BLIMP1 as a tumor suppressor gene, whose inactivation may contribute to lymphomagenesis by blocking post-GC differentiation of B cells toward plasma cells.

B-Lymphocytes↗
PubMed2004

Genetic and serological markers to identify phenotypic subgroups in a Dutch Crohn' s disease population.

BACKGROUND AND AIMS: Both genetic and microbial factors seem to play a pivotal role in the aetiopathogenesis of Crohn's disease. The CARD15 frameshift mutation might link host genetic factors and the indigenous microbial flora, since CARD15 expression is stimulated by peptidoglycan, thereby activating NF-kappaB. It is hypothesised that CARD15 mutation carriers have defective anti-microbial reactions, resulting in more penetrating lesions and antibody responses, which are now being used as highly specific markers for Crohn's disease. The serological marker anti-Saccharomyces cerevisiae antibody directed against cell wall oligomannosidic epitopes has high specificity for Crohn's disease. Perinuclear anti-neutrophil cytoplasmic antibodies have been found in a subgroup of Crohn's disease patients, mostly with colonic involvement. METHODS: We investigated the incidence of two CARD15 mutations (3020insC and 2722G>C), anti-S. cerevisiae antibody, and perinuclear anti-neutrophil cytoplasmic antibody in 108 (73F/35M) patients with Crohn's disease with a mean duration of disease since diagnosis of 16 (1-41) years in relation to their phenotype, according to the Vienna classification. RESULTS: The prevalence of CARD15 frameshift mutation was 21%. Of all patients, 62% were anti-S. cerevisiae antibody positive, and 9% had perinuclear anti-neutrophil cytoplasmic antibodies. The prevalence of both anti-S. cerevisiae antibodies and perinuclear anti-neutrophil cytoplasmic antibodies was higher in the mutation carriers compared to non-carriers. Remarkably, all patients with a CARD15 mutation and positive anti-S. cerevisiae antibody had ileal disease. Carriership of the mutation was significantly associated with penetrating behaviour of the disease and weakly associated with stricturing behaviour. Furthermore, anti-S. cerevisiae antibody was associated with ileal disease involvement. Finally, most perinuclear anti-neutrophil cytoplasmic antibody positive patients showed ulcerative-like behaviour of disease (by means of colonic localisation). CONCLUSIONS: Genetic and serologic markers might be useful in defining patient subgroups. This may result in a more accurate prediction of disease behaviour, prognosis and therapeutic approach.

Adult↗
PubMed2002

Mutation analysis of EP300 in colon, breast and ovarian carcinomas.

The putative tumour suppressor gene EP300 is located on chromosome 22q13 which is a region showing frequent loss of heterozygosity (LOH) in colon, breast and ovarian cancers. We analysed 203 human breast, colon and ovarian primary tumours and cell lines for somatic mutations in EP300. LOH across the EP300 locus was detected in 38% of colon, 36% of breast, and 49% of ovarian primary tumours but no somatic mutations in EP300 were identified in any primary tumour. Analysis of 17 colon, 11 breast, and 11 ovarian cancer cell lines identified truncating mutations in 4 colon cancer cell lines (HCT116, HT29, LIM2405 and LIM2412). We confirmed the presence of a previously reported frameshift mutation in HCT116 at codon 1699 and identified a second frameshift mutation at codon 1468. Bi-allelic inactivation of EP300 was also detected in LIM2405 that harbours an insC mutation at codon 927 as well an insA mutation at codon 1468. An insA mutation at codon 1468 was identified in HT29 and a CGA>TGA mutation at codon 86 was identified in LIM2412. Both these lines were heterozygous across the EP300 locus and western blot analysis confirmed the presence of an apparently wild-type protein. Our study has established that genetic inactivation of EP300 is rare in primary colorectal, breast and ovarian cancers. In contrast, mutations are common among colorectal cancer cell lines with 4/17 harbouring homozygous or heterozygous mutations. The rarity of EP300 mutations among these tumour types that show a high frequency of LOH across 22q13 may indicate that another gene is the target of the loss. It is possible that bi-allelic inactivation of EP300 is not necessary and that haploinsufficiency is sufficient to promote tumorigenesis. Alternatively, silencing of EP300 may be achieved by epigenetic mechanisms such as promoter methylation.

Acetyltransferases↗
PubMed2006

A novel mutation and large size polymorphism affecting the V2 domain of keratin 1 in an African-American family with severe, diffuse palmoplantar keratoderma of the ichthyosis hystrix Curth-Macklin type.

Keratin gene mutations affecting nonhelical head and tail domains are not usually associated with prominent skin blistering and keratin filament clumping. Instead, they have been associated with several distinct clinical phenotypes, such as epidermolysis bullosa simplex with mottled pigmentation (mutation P25L in the V1 domain of keratin 5), epidermolysis bullosa simplex with migratory circinate erythema (frameshift mutation c1649delG in the V2 domain of keratin 5), striate palmoplantar keratoderma (PPK), and ichthyosis hystrix Curth-Macklin (different frameshift mutations in the V2 domain of keratin 1 (K1)). We have studied a family with severe, diffuse, nonepidermolytic PPK and verrucous hyperkeratotic plaques over the joints and in flexures and identified a new KRT1 gene mutation that is predicted to completely alter the K1 tail domain. In addition, a new K1 size polymorphism has been detected, which is especially prevalent among the African-American population. These results further emphasize the functional importance of the nonhelical tail domain in keratin molecules despite the obvious variability in the number of glycine loop motifs and underscore the broad phenotypic spectrum of disorders due to dominant keratin tail mutations.

Adolescent↗
PubMed2001

Analysis of p53 and BAX mutations, loss of heterozygosity, p53 and BCL2 expression and apoptosis in basal cell carcinoma in Korean patients.

BACKGROUND: Apart from some Japanese studies, there are few data on the gene mutations involved in the development of basal cell carcinomas (BCC) in Koreans or other Asians. Objective To gain insight into the molecular pathogenesis of BCC in Koreans. METHODS: A collection of 33 cases of BCC were screened for mutations of p53 and BAX genes, p53 and BCL2 expression, loss of heterozygosity (LOH) and apoptosis. RESULTS: Mutations of p53, found in 9% (three of 33) of the cases, were all mis-sense mutations (G-->C transversions) at codon 246 on exon 7. In 6% (two of 33), BAX gene showed frameshift mutations resulting from deletions in the poly(G) tract. LOH on chromosome 9q was seen in 58% (14 of 24), and p53 mutations developed only among the 9q LOH+ cases; LOH on chromosome 18q, where BCL2 gene is located, was found in 13% (four of 30). Immunohistochemical expression of p53 was seen in 27% (nine of 33), and its expression did not coincide with p53 mutations. BCL2 expression was seen in 39% (13 of 33). Apoptosis was revealed in 21%. In BCC, 9q LOH and p53 mutations seem to be closely related; the immunoreactivity of p53 and its mutations were not directly related; and p53 and BCL2 expression were negatively correlated. Frameshift mutations of the BAX gene in BCC are documented for the first time. CONCLUSIONS: Various molecular mechanisms operate with redundant complexity in the pathogenesis of BCC. The LOH on chromosome 9q is the most frequent genetic alteration, as in other races; however, p53 mutations are much less frequent in Koreans than in Caucasians and suggest aetiologies other than ultraviolet radiation.

Adult↗
PubMed1994

Endonuclease VII of phage T4 nicks N-2-acetylaminofluorene-induced DNA structures in vitro.

We have tested in vitro the activity of T4 endonuclease VII on three different double-stranded oligonucleotides bearing a single N-2-acetylaminofluorene (AAF) adduct covalently bound to each of the three guanine residues located within the NarI site (G1G2CG3CC), a strong frameshift mutation hot spot in E. coli. With the oligonucleotides modified at G2 and G3 a specific cleavage pattern with T4 endonuclease VII was observed in the complementary strand while no cleavage was found in the adduct-bearing strand. On the other hand, when G1 was modified, only a very faint cleavage band was observed (< 1%). These differences in nicking among the three AAF-modified DNA substrates are discussed in terms of the polymorphic nature in adduct-induced DNA structures as previously shown. This "non-physiological" activity of a DNA resolvase is discussed in terms of a potential role for such enzymes in the induction of frameshift mutations.

2-Acetylaminofluorene↗
PubMed2001

[A study of mutation(s) of the epithelial sodium channel gene in a Liddle's syndrome family].

OBJECTIVE: To study the genetic mechanism of Liddle's syndrome in a family and help the diagnosis (specially ante-natal) and treatment of Liddle's syndrome clinically. METHODS: (1) Physical examination and measurement of serum potassium, plasma aldosterone and renin activity respectively by biochemical and radioimmunological assays were made for the member of the family. (2) Venous blood samples were collected from the members of the family and total genomic DNA was prepared. One set of specific primers was used for direct polymerase chain reaction, for amplifying C terminus of beta-subunit of epithelial sodium channel (hbetaENaC). Polymerase chain reaction products were subjected to single-strand conformation polymorphism and direct DNA sequence analysis. RESULTS: A new frameshift mutation (1bp, INS, 600G) of the gene of C terminus of beta-subunit of hbetaENaC was found in the Liddle's syndrome family. This mutation introduced a new stop codon at position 605 and deleted the last 34 normal amino acids from the C teminus of hbeta ENaC. Eight genetically affected subjects had severe hypertension and suppressed levels of plasma aldosterone and plasma renin activity; half of them had hypokalemia. CONCLUSION: The frameshift mutation (1bp, INS, 600G) of hbetaENaC gene is the likely cause of Liddle's syndrome in this Chinese family.

Adolescent↗
PubMed2005

Identification of a new class of recombinant prolamin genes in wheat.

A novel storage protein gene with obvious [corrected] chimeric structure was isolated from an immature kernel-specific cDNA library prepared from the old Hungarian wheat [corrected] variety, Bánkúti 1201. This clone contains gamma-gliadin sequences in the 5' region and LMW-glutenin sequences on the 3' end. A frameshift mutation was also introduced by the putative recombination event. Hence, the amino acid sequence of the C-terminal region was transformed to a completely new polypeptide. Based on this finding, 7 additional recombinant prolamin genes of similar structure were isolated with specific PCR primers. The 8 chimeric clones seem to be derived from 4 individual gamma-gliadin and 3 LMW-glutenin sequences. These genes show remarkable diversity in size, gliadin:glutenin ratio, frameshift mutations, and sulphur content. The putative functional characteristics of the chimeric polypeptides and problems related to the origin of the encoding genes are discussed.

Amino Acid Sequence↗
PubMed1992

Impaired secretion of the elongated mutant of protein C (protein C-Nagoya). Molecular and cellular basis for hereditary protein C deficiency.

Genetic analysis of a heterozygous protein C-deficient patient revealed a novel deletion of a single guanine residue (8857G) among four consecutive guanine nucleotides [380Trp(TGG)-381Gly(GGT)] in exon IX, which encodes the carboxyl-terminal region of protein C. This deletion results in a frameshift mutation and substitution of the last 39 amino acids (381Gly-419Pro) with 81 abnormal amino acid residues, and we have designated this elongated variant as Protein C-Nagoya. A mutagenic primer was designed which replaced the third guanine residue upstream from the deletion with cytosine, thereby creating a new AvaI site in an otherwise normal allele. Analysis of the polymerase chain reaction products derived from this mutagenic primer showed that the abnormal allele has been inherited in this family. To elucidate how this molecular abnormality leads to protein C deficiency, an expression plasmid containing this mutation was transfected into COS 7, BHK, and psi-2 cells, and the secretory process of the expressed Protein C-Nagoya was analyzed. ELISA and immunoprecipitation analysis with [35S]methionine labeling indicated that the mutant protein C, which was larger in size than normal, was mostly retained within the cells, and only a small portion of it was secreted into the medium. These results suggest that most of Protein C-Nagoya undergoes degradation within the producing cells, and this frameshift mutation apparently leads to protein C deficiency by impairment of secretion of the elongated protein C into plasma.

Amino Acid Sequence↗
PubMed1993

A single-base-pair deletion in the beta-glucuronidase gene accounts for the phenotype of murine mucopolysaccharidosis type VII.

Murine mucopolysaccharidosis type VII is a heritable disease caused by a spontaneous mutation, gus(mps), closely linked to the beta-glucuronidase structural gene on chromosome 5. Mice homozygous for the mutation have a > 200-fold decrease in beta-glucuronidase mRNA levels and virtually no enzyme activity detectable by a sensitive fluorometric assay. Approximately 20 kb of genomic DNA containing the beta-glucuronidase gene Gus and > 2 kb of 5' and 3' flanking sequences were cloned from both a gus(mps)/gus(mps) mouse and a +/+ mouse of the progenitor strain. Restriction enzyme digests containing DNA fragments 20-400 bp in length were generated from each of the two Gus alleles and then compared by using nondenaturing polyacrylamide DNA-sequencing gels. This method rapidly identified a large number of restriction sites and was sensitive enough to detect a restriction fragment length variation resulting from a 1-bp deletion in the gus(mps) allele. DNA-sequence analysis of the mutant genomic fragment showed that the 1-bp deletion created a frameshift mutation within exon 10. Insertion of the deleted nucleotide by oligonucleotide site-directed mutagenesis restored function to the corrected mutant gene when transfected into gus(mps)/gus(mps) fibroblasts. We concluded that the frameshift mutation, which introduces a premature stop codon at codon 497 in exon 10, accounts for the molecular, biochemical, and pathological abnormalities associated with the gus(mps) phenotype.

Alleles↗
PubMed2005

Mass-spectrometry DNA sequencing.

Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been explored widely for DNA sequencing. Compared to gel electrophoresis based sequencing systems, mass spectrometry produces very high resolution of sequencing fragments, rapid separation on microsecond time scales, and completely eliminates compressions associated with gel-based systems. While most of the research efforts have focused on using mass spectrometers to analyze the DNA products from Sanger sequencing or enzymatic digestion reactions, the read lengths attainable are currently insufficient for large-scale de novo sequencing. The advantage of mass-spectrometry sequencing is that one can unambiguously identify frameshift mutations and heterozygous mutations making it an ideal choice for resequencing projects. In these applications, DNA sequencing fragments that are the same length but with different base compositions are generated, which are challenging to consistently distinguish in gel-based sequencing systems. In contrast, MALDI-TOF MS produces mass spectra of these DNA sequencing fragments with nearly digital resolution, allowing accurate determination of the mixed bases. For these reasons mass spectrometry based sequencing has mainly been focused on the detection of frameshift mutations and single nucleotide polymorphisms (SNPs). More recently, assays have been developed to indirectly sequence DNA by first converting it into RNA. These assays take advantage of the increased resolution and detection ability of MALDI-TOF MS for RNA.

Base Sequence↗
PubMed1986

Construction of a single-copy integration vector and its use in analysis of regulation of the trp operon of Bacillus subtilis.

A single-copy integration vector was used for the in vitro construction of translational fusions to the lacZ gene of Escherichia coli. Insertion of a single copy of the lacZ fusion into the B. subtilis chromosome leads to an easily detected Amy- phenotype. A trpE-lacZ fusion was constructed in which the trp promoter directs hybrid beta-galactosidase (beta Gal) synthesis. The level of beta Gal in a wild-type strain carrying the trpE-lacZ fusion in the chromosome is regulated by exogenous tryptophan, while a 5-methyltryptophan-resistant mutant constitutively synthesizes betaGal. A trpF-lacZ fusion was constructed and used to determine the effect of a frameshift mutation in the trpE gene on expression of the trpF-lacZ fusion. The frameshift mutation in trpE led to a three-fold reduction in the levels of the trpF-lacZ fusion. The levels of the betaGal activity of these integrated lacZ fusions appear to provide a quantitative measure of the expression of B. subtilis genes under single-copy conditions.

Amino Acid Sequence↗
PubMed2003

A WW domain binding region in methyl-CpG-binding protein MeCP2: impact on Rett syndrome.

Rett syndrome is a dominant neurological disorder caused by loss-of-function mutations of methyl-CpG-binding protein 2 (MeCP2). MeCP2 is an abundant chromatin-associated protein that contains two well characterized domains. Through an N-terminal domain it recognizes methyl-CpGs and binds to nonmethylated DNA. A domain in the middle of the protein can act as a transcriptional repressor in transient transfection studies. The C-terminal region of the protein is equally essential for the function of MeCP2, as documented by recurrently found frameshift mutations. However, little is known about its functional role. Here we mapped a domain within MeCP2 capable of binding specifically to Group II WW domains of splicing factors formin-binding protein (FBP) 11 and HYPC. Binding was assessed by glutathione S-transferase pull-down assays and coimmunoprecipitation assays. The Group II WW domain binding region was localized from residue 325 to the C-terminus, with the interacting proline-rich sequence at its center. We then used comparison with genotype-phenotype studies in Rett syndrome patients to evaluate the relevance of Group II WW domain interactions of MeCP2 for pathogenesis. Truncation of the WW domain binding region by 48 C-terminal amino acids (to residue 438), causing Rett syndrome, resulted in reduced or loss of WW domain binding activity. Truncation to residue 400, representing a large group of frameshift mutations accounting for approx. 10% of Rett syndrome cases, abolished WW domain binding activity completely. On the other hand, two benign missense mutations did not affect binding. Furthermore, a short C-terminal truncation and an internal deletion, both causing mild to moderate mental retardation in males, were associated with weak or loss of WW domain binding activity.

Animals↗