Home About us Contact
|
Home About us Contact | ||
|
|
||
Unique Mutations (unique + mutation)
Selected AbstractsEvaluation of mutant frequencies of chemically induced tumors and normal tissues in ,/cII transgenic miceENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 1 2005Jon C. Mirsalis Abstract Genomic instability has been implicated as an important component in tumor progression. Evaluation of mutant frequencies (MFs) in tumors of transgenic mice containing nontranscribed marker genes should be useful for quantitating mutation rates in tumors as the physiologically inactive transgene provides neither a positive nor a negative selective pressure on the tumor. We have conducted long-term carcinogenicity studies in ,/cII transgenic B6C3F1 mice using a variety of genotoxic and nongenotoxic test agents and have evaluated the mutant frequencies in both tumors and normal tissues from these animals. Mice were administered diethylnitrosamine (DEN) as three intraperitoneal injections of 15 mg/kg; phenobarbital (PB) or oxazepam (OXP) provided ad libitum at 0.1% or 0.25% in the diet, respectively; DEN initiation plus PB in the diet; or urethane (UTH) provided ad libitum at 0.2% in the drinking water. Normal tissues and tumors were isolated at various times over a 2-year period and half of each tissue/tumor was evaluated histopathologically and the other half was evaluated for MF in the cII transgene. Approximately 20 mutants from each of 166 individual tissues (tumor and nontumor) were sequenced to determine whether increases in MF represented unique mutations or were due to clonal expansion. UTH produced significant increases in MF in normal liver and lung. DEN either with or without PB promotion produced significant increases in MF in liver and correction of MF for clonality produced little change in the overall MF in these groups. PB produced a twofold increase in liver MF over controls after 27 weeks of treatment, but a similar increase was not observed with longer dosing times; at later time points, the MF in the PB groups was lower than that of the control group, suggesting that PB is not producing direct DNA damage in the liver. OXP failed to produce an increase in MF over controls, even after 78 weeks of treatment. Selected cases of genomic instability were observed in tumors from all treatments except OXP, with individual liver tumors showing very high MF values even after clonal correction. One rare and interesting finding was noted in a single mouse treated with UTH, where a mammary metastasis had an MF approximately 10-fold greater than the parent tumor, with 75% of the mutations independent, providing strong evidence of genomic instability. There was no clear correlation between tumor phenotype and MF except that pulmonary adenomas generally had higher MFs than normal lung in both genotoxic and nongenotoxic treatment groups. Likewise, there was no correlation between tumor size and MF after correction for clonality. The results presented here demonstrate that individual tumors can show significant genomic instability, with very significant increases in MF that are not attributed to clonal expansion of a single mutant cell. Environ. Mol. Mutagen., 2005. © 2004 Wiley-Liss, Inc. [source] Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA),,HUMAN MUTATION, Issue 5 2008Kathleen S. Hruska Abstract Gaucher disease (GD) is an autosomal recessive disorder caused by the deficiency of glucocerebrosidase, a lysosomal enzyme that catalyses the hydrolysis of the glycolipid glucocerebroside to ceramide and glucose. Lysosomal storage of the substrate in cells of the reticuloendothelial system leads to multisystemic manifestations, including involvement of the liver, spleen, bone marrow, lungs, and nervous system. Patients with GD have highly variable presentations and symptoms that, in many cases, do not correlate well with specific genotypes. Almost 300 unique mutations have been reported in the glucocerebrosidase gene (GBA), with a distribution that spans the gene. These include 203 missense mutations, 18 nonsense mutations, 36 small insertions or deletions that lead to either frameshifts or in-frame alterations, 14 splice junction mutations, and 13 complex alleles carrying two or more mutations in cis. Recombination events with a highly homologous pseudogene downstream of the GBA locus also have been identified, resulting from gene conversion, fusion, or duplication. In this review we discuss the spectrum of GBA mutations and their distribution in the patient population, evolutionary conservation, clinical presentations, and how they may affect the structure and function of glucocerebrosidase. Hum Mutat 29(5), 567,583, 2008. Published 2008 Wiley-Liss, Inc. [source] Molecular pathology of NEU1 gene in sialidosis,HUMAN MUTATION, Issue 5 2003Volkan Seyrantepe Abstract Lysosomal sialidase (EC 3.2.1.18) has a dual physiological function; it participates in intralysosomal catabolism of sialylated glycoconjugates and is involved in cellular immune response. Mutations in the sialidase gene NEU1, located on chromosome 6p21.3, result in autosomal recessive disorder, sialidosis, which is characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides. Sialidosis type I is a milder, late-onset, normosomatic form of the disorder. Type I patients develop visual defects, myoclonus syndrome, cherry-red macular spots, ataxia, hyperreflexia, and seizures. The severe early-onset form, sialidosis type II, is also associated with dysostosis multiplex, Hurler-like phenotype, mental retardation, and hepatosplenomegaly. We summarize information on the 34 unique mutations determined so far in the sialidase gene, including four novel missense and one novel nonsense mutations found in two Czech and two French sialidosis patients. The analysis of sialidase mutations in sialidosis revealed considerable molecular heterogeneity, reflecting the diversity of clinical phenotypes that make molecular diagnosis difficult. The majority of sialidosis patients have had missense mutations, many of which have been expressed; their effects on activity, stability, intracellular localization, and supramolecular organization of sialidase were studied. A structural model of sialidase allowed us to localize mutations in the sialidase molecule and to predict their impact on the tertiary structure and biochemical properties of the enzyme. Hum Mutat 22:343,352, 2003. © 2003 Wiley-Liss, Inc. [source] Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiencyHUMAN MUTATION, Issue 4 2001Luigi D. Notarangelo Abstract During the last 10 years, an increasing number of genes have been identified whose abnormalities account for primary immunodeficiencies, with defects in development and/or function of the immune system. Among them is the JAK3 -gene, encoding for a tyrosine kinase that is functionally coupled to cytokine receptors which share the common gamma chain. Defects of this gene cause an autosomal recessive form of severe combined immunodeficiency with almost absent T-cells and functionally defective B-cells (T,B+ SCID). Herewith, we present molecular information on the first 27 unique mutations identified in the JAK3 gene, including clinical data on all of the 23 affected patients reported so far. A variety of mutations scattered throughout all seven functional domains of the protein, and with different functional effects, have been identified. Availability of a molecular screening test, based on amplification of genomic DNA, facilitates the diagnostic approach, and has permitted recognition that JAK3 deficiency may also be associated with atypical clinical and immunological features. Development of a structural model of the JAK3 kinase domain has allowed characterization of the functional effects of the various mutations. Most importantly, molecular analysis at the JAK3 locus results in improved genetic counseling, allows early prenatal diagnosis, and prompts appropriate treatment (currently based on hematopoietic stem cell transplantation) in affected families. Hum Mutat 18:255,263, 2001. © 2001 Wiley-Liss, Inc. [source] Molecular epidemiology of hepatitis A virus in Korea,JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 5 2001Kwan Soo Byun Abstract Background: The prevalence of antibodies for hepatitis A virus (anti-HAV) in adolescents and young adults has decreased remarkably following the economic growth in Korea. As a result, this age group has a high risk for HAV infection paradoxically, and over 1500 cases of clinically overt hepatitis A occurred in 1998. Human isolates of hepatitis A virus (HAV) are categorized within four genotypes (I, II, III, and VII). In some geographic regions, closely related isolates cluster, suggesting endemic spread of the virus, while in other regions multiple genotypes circulate. Virtually no data are available with regard to the genetic relatedness of Korean strains of HAV. Methods and Results: A 168 base pair segment encompassing the putative VP1/2A junction of the HAV genome was amplified by RT-PCR and sequenced in sera of 18 Korean patients with a sporadic form of acute hepatitis A. Pairwise comparisons of the nucleic acid and amino acid sequences of 18 Korean isolates with one another revealed that the Korean isolates showed > 94.6% and > 96.4% identity, respectively. All of the 18 Korean isolates clustered within genotype IA, irrespective of the geographic locations and the time that hepatitis occurred. Unique amino acid sequence changes that had never been reported in genotype IA were found in nine of the 18 isolates. These changes were Gln,Ser and Lys,Arg in 2A-19 and 2A-10 amino acid positions. Conclusion: The presence of single genotype and unique mutations may be related with the circulation of endemic HAV over a long period of time in Korea. [source] Genetic characterization of G3 rotaviruses detected in Italian children in the years 1993,2005JOURNAL OF MEDICAL VIROLOGY, Issue 12 2009Simona De Grazia Abstract In recent years an apparent increase in the frequency of detection of G3P[8] rotaviruses has been observed worldwide. Similarly, in Italy G3P[8] strains have been detected sporadically and in a scattered fashion over 20 years, whereas in 2003 and 2005 G3P[8] rotavirus activity increased markedly. By analysis of the VP7, VP4, VP6, and NSP4 genes of a selection of G3P[8] rotaviruses detected between 1993 and 2005, a remarkable sequence conservation was observed in the VP7, VP4, and VP6 genes. By converse, after 2002 the Italian G3P[8] strains were found to possess unique mutations in significant regions of the NSP4 protein. J. Med. Virol. 81:2089,2095, 2009. © 2009 Wiley-Liss, Inc. [source] Analysis of clinical and molecular characteristics of Wiskott,Aldrich syndrome in 24 patients from 23 unrelated Chinese familiesPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 3 2010Zhi-Yong Zhang Zhang Z-Y, Xiao H-Q, Jiang L-P, Zhou Y, Zhao Q, Yu J, Liu W, Yang X-Q, Zhao X-D. Analysis of clinical and molecular characteristics of Wiskott,Aldrich syndrome in 24 patients from 23 unrelated Chinese families. Pediatr Allergy Immunol 2010: 21: 522,532. © 2010 John Wiley & Sons A/S The clinical data of 24 children with Wiskott,Aldrich syndrome (WAS) from 23 unrelated Chinese families were reviewed in the present study. WAS protein (WASP) expression in peripheral blood mononuclear cells was examined by flow cytometry (FCM); WASP gene was amplified by PCR and directly sequenced to analyze mutations in the WASP gene in patients and their female relatives. FCM analysis of 21 patients showed that 18 cases were WASP-negative, and three had partially WASP expression. WASP gene analysis revealed mutations in 23 patients, including five missense mutations, four nonsense mutations, four deletion mutations, three insertion mutations, six splice site mutations, and one complex mutation, among which, 20 unique mutations were detected, including seven novel mutations (168 C>A, 747,748del T, 793,797del C, 1185 ins C, Dup 1251,1267, 1277 insA and 1266 C>G; 1267,1269del C). Five WAS children underwent stem cell transplantation. After 2 months of transplantation, WASP expression was restored to normal in all five patients whereas one patient died of cytomegalovirus-induced interstitial lung disease. WASP gene analysis can make a definite diagnosis of WAS and identify mutation carriers, beneficial for timely treatment and genetic counseling for children with WAS. [source] Transcriptional regulatory defects in the first intron of Bruton's tyrosine kinasePEDIATRICS INTERNATIONAL, Issue 6 2008Dong-Min Shin Abstract Background: X-linked agammaglobulinemia (XLA), characterized by the early onset of recurrent bacterial infections, profound hypogammaglobulinemia, and a markedly diminished number of peripheral B lymphocytes, is caused by mutations in the Bruton's tyrosine kinase (BTK) gene. The >600 unique mutations identified to date include single base pair substitutions, small insertions or deletions, and gross deletions. A few cases, however, have been found to have no mutations in the coding region even with reduced BTK mRNA or protein expression. Mutations in intron 1 positions +5 (G,A) and +6 (T,G) of the BTK gene have been identified, and these changes were associated with reduced transcriptional activity. Methods: In the present study a novel mutation in intron 1 position +5 (G,T) was identified in a Japanese patient with XLA. The reporter constructs containing these mutations were made, and the reporter activities were measured using a luciferase assay. Results: All the mutant constructs were demonstrated to have reduced transcriptional activity. Conclusions: Positions +5 and +6 in intron 1 of the BTK gene are critical for transcriptional activity, and defects in these regions cause XLA. [source] | |||||||||||||