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PubMed1996

A recurrent 1992delCT mutation of the type X collagen gene in a Japanese patient with Schmid metaphyseal chondrodysplasia.

We report here a recurrent frameshift mutation within the carboxyl-terminal noncollagenous domain coding region of the type X collagen gene (COL10A1) in a Japanese patient with Schmid metaphyseal chondrodysplasia. The mutation involves deletion of a CT dinucleotide from position 1992 (1992delCT), and produces a frameshift which creates a premature termination codon close to the site of the deletion. The predicted length of the mutant polypeptide is 664 amino acids, which is shorter than the wild type polypeptide (680 amino acids). A 1992delCT mutation of COL10A1 has been previously reported in one family. The independent occurrence of de novo mutation of this specific dinucleotide repeat suggests that this region is a possible mutational hot spot on COL10A1.

Asian People↗
PubMed2003

Mutations in RAI1 associated with Smith-Magenis syndrome.

Smith-Magenis syndrome (SMS) is a mental retardation syndrome associated with deletions involving chromosome 17p11.2. Persons with SMS have characteristic behavioral abnormalities, including self-injurious behaviors and sleep disturbance, and distinct craniofacial and skeletal anomalies. We identified dominant frameshift mutations leading to protein truncation in RAI1 in three individuals who have phenotypic features consistent with SMS but do not have 17p11.2 deletions detectable by standard fluorescence in situ hybridization techniques.

Abnormalities, Multiple↗
PubMed1994

Antigenic diversity within a family of M proteins from group A streptococci: evidence for the role of frameshift and compensatory mutations.

The genes (emm) encoding M proteins, from isolates of group-A streptococci (GAS) serotyped as M52, M53, M80 and M nontypeable (MNT; serologically related to M53 and M80), were examined. Characterization of emm from these GAS revealed some discrepancies with serotyping, illustrating the difficulty in serotype determination when cross-reactions occur. DNA sequences corresponding to the N-terminal region of M proteins from the isolates showed considerable similarity both in the hypervariable region and the repeat regions. We propose that these serotypes form a family of closely related M types. Frameshift mutations in the hypervariable region followed by a corrective (compensatory) frameshift were observed. This may be an effective mechanism for generating antigenic diversity in the M protein.

Amino Acid Sequence↗
PubMed1998

Pseudohypoparathyroidism type Ia from maternal but not paternal transmission of a Gsalpha gene mutation.

While loss-of-function mutations in Gsalpha are invariably associated with the short stature and brachydactyly of Albright hereditary osteodystrophy (AHO), the association with hormone resistance (to parathyroid hormone and thyrotropin) typical of pseudohypoparathyroidism type Ia (PHP-Ia) is much more variable. Observational studies and DNA polymorphism analysis suggest that maternal transmission of the Gsalpha mutation may be required for full expression of clinical hormone resistance. To test this hypothesis, we studied transmission of a frameshift mutation in Gsalpha through three generations of a pedigree affected by AHO and PHP-Ia. While all family members carrying this loss-of-function mutation in one Gsalpha allele had AHO, neither the presence of the mutation nor the degree of reduction of erythrocyte Gsalpha bioactivity allowed prediction of phenotype (AHO alone versus AHO and PHP-Ia). Paternal transmission of the mutation (from the patriarch of the first generation to three members of the second generation) was not associated with concurrent PHP-Ia, but maternal transmission (from two women in the second generation to four children in the third generation) was invariably associated with PHP-Ia. No expansion of an upstream short CCG nucleotide repeat region was detected, nor was there evidence of uniparental disomy by polymorphism analysis. This report, the first to document the effects across three generations of both paternal and maternal transmission of a specific Gsalpha mutation, strongly supports the hypothesis that a maternal factor determines full expression of Gsalpha dysfunction as PHP-Ia.

DNA Probes↗
PubMed1993

Mutations at U2555, a tRNA-protected base in 23S rRNA, affect translational fidelity.

A plasmid carrying a mutation in the highly conserved base U2555 in Escherichia coli 23S rRNA was isolated by selecting for suppression of the -1 frameshift mutation trpE91. U2555 is normally protected in chemical footprinting experiments by the aminoacyl residue of A-site-bound tRNA. Substitution of U2555 by adenine or guanine (but not by cytosine) increased readthrough of all three stop codons and +1 and -1 frameshifting. These effects on translational fidelity demonstrate the importance of U2555 for selection of the correct tRNA at the ribosomal A site.

Amino Acid Sequence↗
PubMed1994

Spectrum of glycidyl methacrylate-induced mutation in plasmid-Escherichia coli system.

In order to characterize the spectrum of mutation induced by glycidyl methacrylate (GMA), the plasmid pBR322 was modified with this mutagen in vitro, transfected into appropriate Escherichia coli host HB101. The mutants were then screened and defined by DNA sequencing. Sequence analysis reveals that GMA induces two classes of mutations: deletion of the mono-, di- or tetra-base or the insertion of mono- or di-base. Both types of mutations, with about 10% frequency, occur predominantly at C-G runs and at 5'-CNCCN-3' sequence, which are hotspots for GMA damage and may cause frameshift mutation.

Amino Acid Sequence↗
PubMed2002

[Relationship between changes in activities of low density lipoprotein receptor and gene mutation in familial hypercholesterolemia].

OBJECTIVE: To analyse the LDL receptor (LDLR) function and gene mutation in a familial hypercholesterolemia (FH) patient and illustrate the effects of gene mutation type on LDL receptor function. METHODS: The pedigree of a FH proband was set up according to the serum lipid analysis and clinical presentations. The LDLR functions of cultured fibroblasts were investigated by radiolabelled ligand method. PCR-SSCP and DNA sequencing were performed on the genomic DNA isolated from whole blood RESULTS: 11 heterozygotes and 1 homozygote of FH were confirmed by pedigree analysis. The binding of LDL by LDLR of the proband was nearly normal while the uptake and degradation of LDL were only 3.6% and 1.7% as compared with controls. A frameshift mutation resulted from a G insert in codon 599 and a null mutation caused by CCA-->CCG base shift in codon 842 were found in exon 17. CONCLUSION: A novel mutation of LDLR gene was reported. This mutation may severely affect the function of LDLR.

Child↗
PubMed2001

The TES gene at 7q31.1 is methylated in tumours and encodes a novel growth-suppressing LIM domain protein.

Many studies suggest that a multi-tissue tumour suppressor gene is located at human chromosome 7q31.1. We have cloned and characterized a novel gene at this locus. The TES gene lies within the minimal region of overlap of several LOH studies and appears to possess the properties of a tumour suppressor. TES is widely expressed and is predicted to encode a protein of 421 amino acids, with three C-terminal LIM domains. Mutation analysis of the coding TES exons in 21 human tumour-derived cell lines revealed the presence of a frameshift mutation in one allele in the breast cancer cell line ZR-75. Methylation of the CpG island at the 5' end of TES appears to be a remarkably frequent finding, occurring in seven out of 10 ovarian carcinomas and in each of the 30 tumour-derived cell lines tested. Moreover, forced expression of TES in HeLa or OVCAR5 cells, resulted in a profound reduction in growth potential, as determined by the colony formation assay. We believe that TES is a tumour suppressor gene that is inactivated primarily by transcriptional silencing resulting from CpG island methylation.

Base Sequence↗
PubMed1999

Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity.

PTEN/MMAC1 (phosphatase, tensin homologue/mutated in multiple advanced cancers) is a tumor suppressor protein that has sequence homology with dual-specificity phosphatases, which are capable of dephosphorylating both tyrosine phosphate and serine/threonine phosphate residues on proteins. The in vivo function of PTEN/MMAC1 appears to be dephosphorylation of phosphotidylinositol 3,4, 5-triphosphate. The PTEN/MMAC1 gene is mutated in the germline of patients with rare autosomal dominant cancer syndromes and in subsets of specific cancers. Here we review the mutational spectra of the PTEN/MMAC1 gene in tumors from various tissues, especially endometrium, brain, prostate, and ovary, in which the gene is inactivated very frequently. Germline and somatic mutations in the PTEN/MMAC1 gene occur mostly in the protein coding region and involve the phosphatase domain and poly(A)(6) stretches. Compared with germline alterations found in the PTEN/MMAC1 gene, there is a substantially increased frequency of frameshift mutations in tumors. Glioblastomas and endometrial carcinomas appear to have distinct mutational spectra, probably reflecting differences in the underlying mechanisms of inactivation of the PTEN/MMAC1 gene in the two tissue types. Also, depending on the tissue type, the gene appears to be involved in the initiation or the progression of cancers. Further understanding of PTEN/MMAC1 gene mutations in different tumors and the physiologic consequences of these mutations is likely to open up new therapeutic opportunities for targeting this critical gene.

Brain Neoplasms↗
PubMed2005

Absence of specific cell killing of the BRCA2-deficient human cancer cell line CAPAN1 by poly(ADP-ribose) polymerase inhibition.

The specific killing of cells impaired in BRCA2 function upon treatment with poly (ADP-ribose) polymerase (PARP) inhibitors has recently been reported by two groups. CAPAN1, which was not characterized in these reports, represents the only human cancer cell line harboring the frequent, naturally occurring BRCA2 6174delT frameshift mutation accompanied by loss of the second allele. The severe impact of this mutation on BRCA2 function has been extensively characterized. However, PARP inhibition by 3-aminobenzamide or NU1025 did not result in significant cell death in CAPAN1 cells. Our data raise concern about the uniformity of the specific cell killing of BRCA2-deficient cells upon PARP inhibition and therefore urge caution as to whether prior findings are fully generalizable for the specific treatment of human cancers harboring naturally occurring, inactivating forms of BRCA2 mutations.

Adenocarcinoma↗
PubMed1996

A base substitution in the amino acid acceptor stem of tRNA(Lys) causes both misacylation and altered decoding.

In 1984, our laboratory reported the characterization of the first misacylated tRNA missense suppressor, a mutant Escherichia coli lysine tRNA with a C70 to U base change in the amino acid acceptor stem. We suggested then that the suppressor tRNA, though still acylated to a large extent with lysine, is partially misacylated with alanine. The results reported in this article demonstrate that is the case both in vitro and in vivo. For the in vitro studies, the mutant tRNA species was isolated from the appropriate RPC-5 column fractions and shown to be acylatable with both lysine and alanine. For the in vivo demonstration, use was made of a temperature-sensitive alaS mutation, which results in decreasing acylation with Ala as the temperature is increased, resulting ultimately in lethality at 42 degrees C. The alaSts mutation was also used to demonstrate that the ability of the same missense suppressor, lysT(U70), to suppress a trpA frameshift mutation is not affected by the Ala-acylation deficiency. We conclude that the misacylation and altered decoding are two independent effects of the C70 to U mutation in tRNA(Lys). The influence of an alteration in the acceptor stem, which is in contact with the large (50S) ribosomal subunit, on decoding, which involves contact between the anticodon region of tRNA and the small (30S) ribosomal subunit, may occur intramolecularly, through the tRNA molecule. Alternatively, the U70 effect may be accomplished intermolecularly; for example, it may alter the interaction of tRNA with ribosomal RNA in the 50S subunit, which may then influence further interactions between the two subunits and between the 30S subunit and the anticodon region of the tRNA. Preliminary evidence suggesting some form of the latter explanation is presented. The influence of a single nucleotide on both tRNA identity and decoding may be related to the coevolution of tRNAs, aminoacyl-tRNA synthetases, and ribosomes.

Acylation↗
PubMed2005

Arteriovenous malformations in Cowden syndrome.

Cowden syndrome (OMIM No 158350) is a pleomorphic, autosomal dominant syndrome characterised by hamartomas in tissues derived from the endoderm, mesoderm, and ectoderm. It is caused by germline mutations in the PTEN gene and is allelic to the Bannayan-Riley-Ruvalcaba and Lhermitte-Duclos syndromes. The three syndromes are defined on clinical grounds but there is overlap in their definitions. The clinical features include trichilemmomas, verrucose lesions of the skin, macrocephaly, intellectual disability, cerebellar gangliocytoma, thyroid adenomas, fibroadenomas of the breast, and hamartomatous colonic polyps. Cutaneous haemangiomas are occasionally noted. Malignancies often arise in the affected tissues. Visceral arteriovenous malformations are a recognised component of the Bannayan-Riley-Ruvalcaba syndrome but have been reported rarely in Cowden syndrome. A family is described with a clinical diagnosis of Cowden syndrome, a familial frameshift mutation in the PTEN gene, and large visceral arteriovenous malformations. The association of these pleomorphic syndromes with arteriovenous malformations can be explained by the putative role of the PTEN gene in suppressing angiogenesis. Recognition of arteriovenous malformations as a clinical feature of Cowden syndrome has implications for the clinical management of patients with this disorder.

Adult↗
PubMed2003

Functional analysis of a mutation in PAX9 associated with familial tooth agenesis in humans.

Pax9 is a paired domain-containing transcription factor that plays an essential role in the patterning of murine dentition. In humans, mutations in PAX9 are associated with unique phenotypes of familial tooth agenesis that mainly involve posterior teeth. Among these, a frameshift mutation (219InsG) within the paired domain of PAX9 produces a protein product associated with a severe form of molar agenesis in a single family. The objectives of this study were to gain new insights into the molecular pathogenesis of the 219InsG mutation and its role in tooth agenesis. Here we describe functional defects in DNA binding and transactivation of mutant 219InsGPax9. Although wild type Pax9 binds to the high affinity paired domain recognition sequences, e5 and CD19-2(A-ins), the 219InsGPax9 mutant protein was unable to bind to these cognate DNA-binding sites. In co-transfection assays, wild type Pax9 activated reporter gene transcription although the mutant was transcriptionally inactive. Immunolocalization data show that Pax9 and 219InsGPax9 proteins are synthesized in mammalian cells but that the nuclear localization of the mutant Pax9 protein is altered. Furthermore, transactivation by the full-length Pax9 protein from paired domain binding sites was not impaired by the 219InsGPax9 mutant. The latter did not alter the DNA binding activities of wild type Pax9 in gel mobility shift assays. The combined defects in DNA binding activities and transactivation function of mutant 219InsGPAX9 likely alter the selective activation and/or repression of PAX9 effector genes during odontogenesis. This loss-of-function of PAX9 most likely results in its haploinsufficiency during the patterning of dentition and the subsequent loss of posterior teeth.

Amino Acid Sequence↗
PubMed2002

Insertions in the anticodon loop of tRNA1Gln(sufG) and tRNA(Lys) promote quadruplet decoding of CAAA.

Base insertion mutations in the anticodons of two different Escherichia coli tRNAs have been isolated that allow suppression of a series of +1 frameshift mutations. Insertion of a U between positions 34 and 35 of tRNAGln1 or addition of a G between positions 36 and 37 of tRNA(Lys) expand the anticodons of both tRNAs similarly to 3'-GUUU(-5') and allow decoding of complementary 5'-CAAA(-3') quadruplets. Analysis of the suppressed mRNA sequences suggests that suppression occurs by pairing of the expanded anticodons to all four bases of the complementary, quadruplet codon. The tRNA Gln mutants are identical to the sufG class of frameshift suppressors isolated both in Salmonella enterica serovar Typhimurium and E. coli by Kohno and Roth and previously thought to affect tRNA(Lys).

Anticodon↗
PubMed2000

Analysis of specific gene mutations in the transforming growth factor-beta signal transduction pathway in human ovarian cancer.

Several proteins, including transforming growth factor beta (TGF-beta) receptor type I (RI), TGF-beta receptor type II (RII), Smad2, Smad3, and Smad4/DPC4, have been identified in the transduction pathway of the tumor suppressor TGF-beta. Mutations in TGF-beta RI, TGF-beta RII, Smad2, and Smad4/DPC4 genes are associated with several human cancers. The present study examines these gene mutations in 32 human ovarian cancers and 14 patient-matched normal tissues. For the first time, mutations in the Smad2 and Smad4 genes were analyzed in relation to human ovarian cancer. Gene mutations of TGF-beta RI, TGF-beta RII, Smad2, and Smad4 were analyzed using specific primers by PCR-single-strand conformational polymorphism (SSCP), and the results revealed a frameshift mutation at codons 276-277 (CTCTGG-->CTGCGTGG) in exon 5 of TGF-beta RI in 10 of 32 tumor samples (31.3%). This mutation was associated with reduced or absent expression of TGF-beta RI protein and p53 protein in tumor tissues. We detected SSCP variants of TGF-beta RII in exon 2 in 20 of 32 tumors. Sequence analysis of these variants revealed an A to G transition at the seventh band of intron 2. In this A to G polymorphism in intron 2, 12 samples (37.5%) had A/A alleles, 12 (37.5%) had A/G alleles, and 8 (25%) had G/G alleles. We detected Smad2 SSCP variants in exon 4 in 12 of 32 tumors (37.5%). Sequence analysis revealed a 2-bp deletion in the polypyrimidine tract of intron 3, which is located at position -39 to -56 in the splice acceptor site of the intron 3-exon 4 junction. No SSCP variants were detected in the Smad4 gene. These findings suggest that mutations in the TGF-beta RI and in its signal transduction pathway are likely responsible for human ovarian carcinogenesis.

Activin Receptors, Type I↗
PubMed1999

DNA sequence analysis of spontaneous tonB deletion mutations in a polA1 strain of Escherichia coli K12.

By DNA sequence analysis, we have determined a spectrum of 61 spontaneous mutations occurring in the endogenous tonB gene in the polA1 strain of Escherichia coli. The overall mutation frequency was approximately 2.4-fold higher in the polA1 strain and this was attributable to enhanced rates of deletion and frameshift mutations. Among 39 deletions, a hot spot (17 mutations) was detected: a 13-bp deletion presumably directed by a 3-bp repeated sequence at its end points. The remaining 22 were distributed among 19 different mutations either flanked (16/19) or not flanked (3/19) by repeated sequences. Single-base frameshifts accounted for 8 mutations of either repeated (3/8) or nonrepeated (5/8) bases among which 6 were minus one frameshift. In contrast to previous reports, we did not frequently observe a 5'-GTGG-3' sequence in the vicinity of the deletions and frameshifts. The results presented here indicated an anti-deletion and anti-frameshift role for DNA polymerase I.

Bacterial Proteins↗
PubMed2001

Severe factor XI deficiency caused by compound heterozygosity for the type III mutation and a novel insertion in exon 9 (codons 324/325 +G).

We investigated a 42-year-old Caucasian woman with severe factor XI deficiency and her family members. Restriction enzyme analysis and DNA sequencing revealed compound heterozygosity in the patient for the known type III mutation, which is a Phe283Leu amino acid substitution in the fourth apple domain causing impaired dimerization and secretion, and for a novel frameshift mutation in exon 9 (codons 324/325 +G), leading to premature termination with lack of parts of the fourth apple domain and the downstream serine protease domain.

Adult↗
PubMed2004

TPIT mutations are associated with early-onset, but not late-onset isolated ACTH deficiency.

OBJECTIVE: Congenital isolated ACTH deficiency (IAD) is a rare inherited disorder that is clinically and genetically heterogeneous. Patients are characterised by low or absent cortisol production secondary to low plasma ACTH despite normal secretion of other pituitary hormones and the absence of structural pituitary defects. Onset may occur in the neonatal period, but may first be observed in later childhood. Recently, mutations in the TPIT gene, a T-box factor selectively expressed in developing corticotroph cells, have been found in cases of early-onset IAD. DESIGN: Here we report the screening of the TPIT gene in seven patients with IAD, four of whom had neonatal onset. METHODS: Genomic DNA was extracted and the sequences of the 8 TPIT exons and their intron/exon junctions were determined by automated sequencing. RESULTS: Two siblings with early-onset IAD were both compound heterozygotes for mutations in exons 2 and 6. The missense mutation (Met86Arg) in exon 2 within the T-box (or DNA binding domain) is predicted to disrupt DNA binding. A frameshift mutation in exon 6 (782delA) introduces a premature stop codon and is likely to lead to a non-functional truncated protein. No nucleotide changes were observed in exonic sequences in the other two early- or the three later-onset cases. Fifteen single nucleotide polymorphisms that were not predicted to change the TPIT transcript were also detected. CONCLUSIONS: These findings provide a further illustration of the genetic heterogeneity of IAD and are highly suggestive of one or more other genes being implicated in this disorder.

Adrenocorticotropic Hormone↗