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At least 1,117 records · Page 62Linked to original sources
PubMed2000

Concurrent factor V Leiden and prothrombin G20210A gene mutations in a patient with a history of recurrent thrombosis.

We report a case of a 35-year-old male with a history of recurrent thromboembolic events, who presented to the emergency room with right sided weakness and difficulty with speech. The patient's past medical history included two myocardial infarctions, two deep vein thromboses, and a pulmonary embolism. Subsequent laboratory evaluation indicated that the patient was heterozygous for both the factor V Leiden and prothrombin G20210A mutations. This case report emphasizes the importance of evaluating patients with suspected hereditary thrombophilia for both of these mutations.

Adult↗
PubMed2000

Novel hotspot detector software reveals a non-CpG hotspot of germline mutation in the factor IX gene (F9) in Latin Americans.

Two-base substitutions at each of two nucleotides in the factor IX gene (F9), but not part of CpG dinucleotides, were recently reported in a small population sample collected in Mexico, a significant observation of recurrent sites ("hotspots") of mutation (P=0.00005). When these new data were combined with previously collected mutation data into two progressively larger and inclusive Latin American samples, additional mutations were observed at one recurrent site, nucleotide 17747, and an additional recurrent nucleotide was observed such that the recurrent nucleotides in these larger samples were also significant (P=0.0003 and 0.0003). In contrast, in three non-Latin American control samples, there was at most only one nucleotide that recurred only once, most likely a chance recurrence (P>/=0.5). When the significance of substitutions was analyzed at each recurrent nucleotide individually, nucleotide 17747 was shown to be a significant recurrent nucleotide by itself in all the Latin American population samples (P</=0.02). Furthermore, a standard statistical comparison of mutation frequencies in the previously collected data alone confirmed that the frequency of mutation at nucleotide 17747 is significantly higher in Latin Americans than in all other populations combined (P=0.01). Thus, nucleotide 17747 is a germline mutation hotspot in F9 specific to Latin American populations. This may be the first evidence for population-specific effects on germline mutation that causes human genetic disease. The significance of the observed recurrent sites was analyzed using new software called Hotspot Detector which is capable of detecting significant recurrent sites in small samples, extending the sensitivity of F9 as a human germline mutagen test. Hotspot Detector uses a Monte-Carlo simulation method that was validated by comparing its results with those from an exact probability formula derived from statistical theory.

CpG Islands↗
PubMed2005

Genetic studies of 20 Japanese families of dystrophic epidermolysis bullosa.

Dystrophic EB (DEB) is clinically characterized by mucocutaneous blistering in response to minor trauma, followed by scarring and nail dystrophy, and is caused by mutations in the COL7A1 gene encoding type VII collagen. DEB is inherited in either an autosomal dominant (DDEB) or recessive (RDEB) fashion. DDEB basically results from a glycine substitution mutation within the collagenous domain on one COL7A1 allele, while a combination of mutations such as premature stop codon, missense, and splice-site mutations on both alleles causes RDEB. In this study, mutation analysis was performed in 20 distinct Japanese DEB families (16 RDEB and four DDEB). The result demonstrated 30 pathogenic COL7A1 mutations with 16 novel mutations, which included four missense, five nonsense, one deletion, two insertion, one indel, and three splice-site mutations. We confirmed that Japanese COL7A1 mutations were basically family specific, although three mutations, 5818delC, 6573 + 1G > C, and E2857X, were recurrent based on previous reports. Furthermore, the Q2827X mutation found in two unrelated families would be regarded as a candidate recurrent Japanese COL7A1 mutation. The study furthers our understanding of both the clinical and allelic heterogeneity displayed in Japanese DEB patients.

Adult↗
PubMed1993

Osteogenesis imperfecta and type-I collagen mutations. A lethal variant caused by a Gly910-->Ala substitution in the alpha 1 (I) chain.

In this study we describe a new dominant point mutation in COL1A1 causing a lethal form of Osteogenesis imperfecta (type II B). Dermal cultured fibroblasts from the proband were shown to produce both normal and heavily overmodified type-I collagen. The mutation introduced a local conformational perturbation, which causes abnormal exposure of arginine residues; the triple helical domain was susceptible to trypsin digestion even at 30 degrees C. The chains bearing the point mutation were poorly secreted and short-term pulse experiments showed that the extensive intracellular retention of mutant trimers also impaired the secretion of normal chains. The molecular defect was localized in a COL1A1 allele by cloning and sequencing a cDNA region corresponding to the CB6 peptide. A G to C transversion which causes the substitution in the triple helical region of Gly910 with alanine was found. The mutation also causes the disappearance of a MspI-recognition site at nucleotide 3263 of the pro alpha 1 (I) coding sequence. Restriction analysis, along with the biochemical screening of collagens, allowed us to perform prenatal diagnosis on cells from chorionic-villus sampling and to exclude the recurrence of the mutation in the sibling.

Alanine↗
PubMed1993

Identification and characterization of sporadic and inherited mutations in exon 31 of the neurofibromatosis (NF1) gene.

Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders in humans, and presents with a variety of clinical symptoms, which are highly variable in expression. The mutation rate for NF1 is high, with as many as half of all cases resulting from new mutations. Although the NF1 gene has been cloned and its cDNA sequence determined, the specific role of the NF1 gene product in contributing to the NF1 mutations is one of the first steps in correlating genotype with clinical symptoms of the disease. In this paper we describe two independent mutations in exon 31 of the NF1 gene identified following polymerase chain reaction (PCR) amplification, heteroduplexing, and single strand conformational polymorphism (SSCP) analysis. One is a novel insertion that segregates with the disease phenotype in that particular family (5852insTT), while the other is a further example of the sporadic, recurrent C-->T mutation previously described in the literature (C5842T). The relationship between these mutations and clinical features of NF1 presented by the patients will be discussed.

Adolescent↗
PubMed1996

Radioresistance and p53 status of T2 laryngeal carcinoma. Analysis by immunohistochemistry and denaturing gradient gel electrophoresis.

BACKGROUND: Animal experiments and tumor cell line studies have shown that p53 alterations can cause radioresistance. This has not yet been demonstrated in patient groups. METHODS: We report p53 status in 20 patients with T2 laryngeal carcinoma and recurrent disease after curative therapy. The control group consisted of 16 patients with T2 laryngeal carcinoma without recurrent disease. The p53 gene (exons 5 to 9) was analyzed by Denaturing Gradient Gel Electrophoresis (DGGE). Expression of p53 in biopsy material was visualized by immunohistochemistry (monoclonal antibody BP 53-12-1). RESULTS: The group with recurrent disease showed a mutation in 9 cases (45%) and overexpression in 14 cases (70%). In 17 cases (85%) either mutation or overexpression was found. The control group showed a mutation in 7 cases (44%) and overexpression in 14 cases (88%). In 14 cases (88%) either mutation or overexpression was found. Adding up both groups a discordance of 50% was found between both detection techniques. The same mutated exon was found in 6 patients (66%) in both primary and recurrent tumors. CONCLUSIONS: A discordance between immunohistochemistry and DGGE exists in 50% of the cases. Assuming that both p53 mutation and p53 overexpression are indicative of a disturbed p53 checkpoint system, 31 cases (86%) in both groups show an alteration of the p53 system. No significant difference in p53 status in patients with or without recurrent disease exists. Analysis of the p53 status is not of prognostic significance for irradiation as primary treatment.

Adult↗
PubMed2000

A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO).

Hypohidrotic ectodermal dysplasia (HED), a congenital disorder of teeth, hair, and eccrine sweat glands, is usually inherited as an X-linked recessive trait, although rarer autosomal dominant and recessive forms exist. We have studied males from four families with HED and immunodeficiency (HED-ID), in which the disorder segregates as an X-linked recessive trait. Affected males manifest dysgammaglobulinemia and, despite therapy, have significant morbidity and mortality from recurrent infections. Recently, mutations in IKK-gamma (NEMO) have been shown to cause familial incontinentia pigmenti (IP). Unlike HED-ID, IP affects females and, with few exceptions, causes male prenatal lethality. IKK-gamma is required for the activation of the transcription factor known as "nuclear factor kappa B" and plays an important role in T and B cell function. We hypothesize that "milder" mutations at this locus may cause HED-ID. In all four families, sequence analysis reveals exon 10 mutations affecting the carboxy-terminal end of the IKK-gamma protein, a domain believed to connect the IKK signalsome complex to upstream activators. The findings define a new X-linked recessive immunodeficiency syndrome, distinct from other types of HED and immunodeficiency syndromes. The data provide further evidence that the development of ectodermal appendages is mediated through a tumor necrosis factor/tumor necrosis factor receptor-like signaling pathway, with the IKK signalsome complex playing a significant role.

Adolescent↗
PubMed2001

Mild recurrent neuropathy in CMT1B with a novel nonsense mutation in the extracellular domain of the MPZ gene.

Clinical, electrophysiological, and neuropathological features are reported associated with a novel heterozygote point mutation in the extracellular domain of the MPZ gene, where a transversion at codon 71 in exon 3 leads to a codon stop: Glu71stop (ie GAA-->TAA). A 36 year old woman developed a mild recurrent neuropathy after intensive manual work. The motor nerve conduction velocities were slow without conduction blocks and the nerve biopsy showed signs of demyelination-remyelination, axonal loss, and regular uncompacted myelin lamellae. She inherited the mutation from her father who displayed the same mutation with a normal phenotype. This nonsense mutation may cause a dosage difference of normal P0, and is probably underrepresented in the current mutation data bases. This report further extends the phenotype of MPZ mutations and also emphasises that mild phenotype of CMT1B may be more frequent than has been appreciated.

Adult↗
PubMed2005

Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence.

PURPOSE: To evaluate the relationship between mutations of the epidermal growth factor receptor (EGFR) gene and the effectiveness of gefitinib treatment in patients with recurrent lung cancer after pulmonary resection. PATIENTS AND METHODS: We sequenced exons 18-21 of the EGFR gene using total RNA extracted from 59 patients with lung cancer who were treated with gefitinib for recurrent lung cancer. Gefitinib effectiveness was evaluated by both imaging studies and change in serum carcinoembryonic antigen (CEA) levels. RESULTS: EGFR mutations were found in 33 patients (56%). Of these mutations, 17 were deletions around codons 746-750 and 15 were point mutations (12 at codon 858, three at other codons), and one was an insertion. EGFR mutations were significantly more prevalent in females, adenocarcinoma, and never-smokers. Gefitinib treatment resulted in tumor shrinkage and/or CEA decrease to less than half of the baseline level in 26 patients, tumor growth and/or CEA elevation in 24 patients, and gefitinib effect was not assessable in nine patients. Female, never-smoking patients with adenocarcinoma tended to respond better to gefitinib treatment. Gefitinib was effective in 24 of 29 patients with EGFR mutations, compared with two of 21 patients without mutations (P < .0001). Of note, del746-750 might be superior to L858R mutations for prediction of gefitinib response. Patients with EGFR mutations survived for a longer period than those without the mutations after initiation of gefitinib treatment (P = .0053). CONCLUSION: EGFR mutations were a good predictor of clinical benefit of gefitinib in this setting.

Adult↗
PubMed2005

Detection of point mutations at codon 12 of KI-ras in ophthalmic pterygia.

AIMS: Ophthalmic pterygium is a potentially vision-threatening lesion of unknown etiology, related to an exposure to solar light. Mutations to the ras genes are frequently observed in lesions related to an exposure to solar light. The present study aims at screening pterygia for mutations at codons 12 and 13 of the ras genes. METHODS: In all, 50 pterygia were examined, together with respective blood samples and specimens of normal conjunctiva. A PCR reaction was performed to amplify sequences containing codons 12 and 13 of Ki-ras, H-ras, and N-ras. An RFLP analysis was then performed to detect point mutations at codon 12. The mutational status at codons 12 and 13 was further explored with sequencing of PCR products. RESULTS: RFLP analysis revealed Ki-ras mutations at codon 12 in five (10%) of pterygia, whereas H-ras or N-ras mutations were not observed. Sequencing confirmed Ki-ras mutations at codon 12 and revealed absence of mutations at codon 13. The presence of Ki-ras mutations was significantly correlated with postoperative recurrence (P=0.02) and young age (P=0.04). Mutations were not observed in specimens of blood or normal conjunctiva for any of the genes examined. CONCLUSIONS: The absence of N-ras mutations is in agreement with previous reports concerning mucosal lesions. The detection of Ki-ras mutations and the association with postoperative recurrence implies a possible role of Ki-ras in the clinical profile of pterygium. The mechanism of Ki-ras mutations is unclear and could be independent of the action of UV light.

Adult↗
PubMed2003

UVA induces C-->T transitions at methyl-CpG-associated dipyrimidine sites in mouse skin epidermis more frequently than UVB.

We studied the kinetics of mutation induction in skin epidermis and dermis of UVA-irradiated transgenic Muta mice and analyzed the sequence changes in 80 lacZ transgene mutants from the irradiated epidermis. The mutant frequency increased linearly in both the epidermis and dermis up to 240 kJ/m2 UVA, twice as efficiently in the epidermis as in the dermis, without provoking any inflammatory reactions in the exposed skin. The 83 mutations detected in the UVA-exposed epidermis were dominated by C-->T transitions (88%), found almost exclusively at dipyrimidine sites, and specified by four occurrences of CC-->TT tandem substitutions, suggesting that UV-specific photoproducts induced in DNA have a major role in the genotoxicity. No T-->G transversions, which have been considered as a UVA signature mutation, and few mutations suggesting the relevance of oxidative damage were recovered in the present study. An analysis of the bases adjacent to the mutated cytosines revealed that the 3'-cytosine of dipyrimidine sites is the preferred target of UVA-induced C-->T transition. Moreover, C-->T transitions were induced at dipyrimidine sites associated with CpG much more frequently by UVA than by UVB, forming hotspots at several of these sites. These results suggest that UVA contributes more to the formation of recurrent or hotspot mutations at methylated CpG sites in the mammalian genome than UVB, since methylation of the CpG motif is observed entirely in the lacZ transgenes and is known to enhance the formation of cyclobutane pyrimidine dimers by longer wavelength UV.

Animals↗
PubMed2006

Clonal persistence and evolution during a decade of recurrent melanoma.

A patient with metastatic cutaneous melanoma responsive to immunotherapy experienced several recurrences over a decade of observation. With each recurrence, biopsies were obtained and cell lines generated. A rare mutation of the beta-catenin gene and an unbalanced methylation of the androgen receptor were documented in all cell lines. Karyotyping and comparative genomic hybridization identified consistent genetic traits in spite of divergent phenotypes, suggesting that all the metastases were derived from the same primary tumor, although they were each probably not derived from the most recent previous metastasis in a sequential manner. Thus, metastatic melanoma recurs from a common progenitor cell and phenotypic changes occur around a central core of genetic stability. This observation may bear significance for the development of targeted anticancer therapies.

Cell Line, Tumor↗
PubMed2000

Well-differentiated villoglandular adenocarcinoma of the uterine cervix: oncogene/tumor suppressor gene alterations and human papillomavirus genotyping.

Twelve well-differentiated villoglandular adenocarcinomas (WDVAs) of the uterine cervix were retrospectively analyzed for the presence and specific genotype of human papillomavirus (HPV), tumor suppressor loss (p53, MCC, APC, BRCA1), cancer gene mutation (K-ras-2, exons 1 and 2, p53 exons 5 to 8), and oncogene amplification (c-erbB-2/HER-2/neu, int-2). Tissue for genetic evaluation was obtained by microdissection, using 4-micron-thick histology sections of archival, formalin-fixed, paraffin-embedded specimens. Genotyping involved nucleic acid amplification and DNA sequencing with gene-specific oligonucleotides and L1 region consensus primers for common strains of HPV. Point mutation and HPV strain determination were accomplished by DNA sequence analysis. Tumor suppressor gene loss and oncogene amplification were performed by allelic imbalance analysis in informative subjects based on DNA sequence and microsatellite-length polymorphisms. HPV was present in all tumors and consisted of type 16 (n = 5, 42%) and type 18 (n = 7, 58%) strains, which have been closely associated with cervical neoplasia. K-ras-2 and p53 genes did not manifest point mutational damage. There was no evidence of oncogene amplification or tumor suppressor gene loss. The presence of HPV in all 12 tumors supports the role of HPV infection in the molecular pathogenesis of this uncommon neoplasm. The absence of associated oncogene or tumor suppressor gene damage is consistent with indolent biological behavior and the favorable prognosis of this unusual tumor.

Adenocarcinoma↗
PubMed2003

Analysis of mutation spectra in UVB-exposed mouse skin epidermis and dermis: frequent occurrence of C-->T transition at methylated CpG-associated dipyrimidine sites.

We recently reported the kinetics of mutation induction by UVB in the skin epidermis and dermis of transgenic Muta trade mark mice [Ikehata and Ono, Mutat Res 508:41-47, 2002]. In the present study we determined the complete DNA sequence of the lacZ transgene in 208 mutants isolated from the dermis and epidermis of UVB-irradiated and control mice. The resulting mutation patterns for the dermis and epidermis were similar, although two CC-->TT tandem substitutions, one of the signature mutations for UV insult, were detected only among the UVB-induced epidermal mutants. The spectra of the UVB-induced and control mutations were both dominated by C-->T transitions (83% and 62%); however, the C-->T transitions from irradiated mice occurred almost exclusively in dipyrimidine sites, while those from control mice preferred CpG sites. Thus, the mutation spectrum detected for the irradiated skin tissues was different from the background spectrum and UV-specific, confirming the utility of the transgenic system for UVB-induced mutation studies in vivo. An analysis of the bases adjacent to the mutated cytosines from irradiated mice revealed that the dipyrimidine sites preferred for UVB-induced mutation were 5'-TC-3' > 5'-CC-3' > 5'-CT-3'. Among mutants from irradiated mice, C-->T transitions were recovered frequently at dipyrimidine sites associated with CpG. We showed that CpG sites in the lacZ transgene of Muta trade mark mice were heavily methylated in both the epidermis and dermis. Thus, CpG methylation could contribute to the UVB-induced recurrent or hotspot mutations in the mammalian genome.

Animals↗