Página 34 dos resultados de 4394 itens digitais encontrados em 0.020 segundos

‣ GM1-gangliosidosis (genetic beta-galactosidase deficiency): identification of four mutations in different clinical phenotypes among Japanese patients.

Nishimoto, J; Nanba, E; Inui, K; Okada, S; Suzuki, K
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1991 Português
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GM1-gangliosidosis is a genetic neurological disorder caused by mutations in the lysosomal acid beta-galactosidase gene. While its phenotypic expression is complex, it is usually classified as being of infantile, juvenile, or adult form, on the basis of age at onset, the rate of symptomatic progression, and severity of central nervous system involvement. We have analyzed the acid beta-galactosidase gene in 12 Japanese patients from nine families. The aim was to identify mutations in individual patients and then to examine possible correlation between the mutations and the clinical phenotypes. Northern blotting studies with a full-length human beta-galactosidase cDNA showed that the mRNA ranged from undetectable to substantially decreased in the infantile patients but was normal in quantity and size in all juvenile and adult patients. Four distinct missense mutations have been identified, each limited to the respective clinical forms within our small-size samples. In the infantile patient with decreased but detectable mRNA, a point mutation was found resulting in Arg49----Cys. In the infantile patient with nearly undetectable mRNA, mutation Arg457----Ter was identified. The mutation Arg201----Cys was found in all four of the juvenile patients...

‣ Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses.

Shah, A B; Chernov, I; Zhang, H T; Ross, B M; Das, K; Lutsenko, S; Parano, E; Pavone, L; Evgrafov, O; Ivanova-Smolenskaya, I A; Annerén, G; Westermark, K; Urrutia, F H; Penchaszadeh, G K; Sternlieb, I; Scheinberg, I H; Gilliam, T C; Petrukhin, K
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1997 Português
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Wilson disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver and subsequently in the brain and other organs. On the basis of sequence homology to known genes, the WD gene (ATP7B) appears to be a copper-transporting P-type ATPase. A search for ATP7B mutations in WD patients from five population samples, including 109 North American patients, revealed 27 distinct mutations, 18 of which are novel. A composite of published findings shows missense mutations in all exons-except in exons 1-5, which encode the six copper-binding motifs, and in exon 21, which spans the carboxy-terminus and the poly(A) tail. Over one-half of all WD mutations occur only rarely in any population sample. A splice-site mutation in exon 12 accounts for 3% of the WD mutations in our sample and produces an in-frame, 39-bp insertion in mRNA of patients homozygous, but not heterozygous, for the mutation. The most common WD mutation (His1069Glu) was represented in approximately 38% of all the WD chromosomes from the North American, Russian, and Swedish samples. In several population cohorts, this mutation deviated from Hardy-Weinberg equilibrium, with an overrepresentation of homozygotes. We did not find a significant correlation between His1069Glu homozygosity and several clinical indices...

‣ Spectrum of mutations in the major human skeletal muscle chloride channel gene (CLCN1) leading to myotonia.

Meyer-Kleine, C; Steinmeyer, K; Ricker, K; Jentsch, T J; Koch, M C
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/1995 Português
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Autosomal dominant myotonia congenita and autosomal recessive generalized myotonia (GM) are genetic disorders characterized by the symptom of myotonia, which is based on an electrical instability of the muscle fiber membrane. Recently, these two phenotypes have been associated with mutations in the major muscle chloride channel gene CLCN1 on human chromosome 7q35. We have systematically screened the open reading frame of the CLCN1 gene for mutations by SSC analysis (SSCA) in a panel of 24 families and 17 single unrelated patients with human myotonia. By direct sequencing of aberrant SSCA conformers were revealed 15 different mutations in a total of 18 unrelated families and 13 single patients. Of these, 10 were novel (7 missense mutations, 2 mutations leading to frameshift, and 1 mutation predicted to affect normal splicing). In our overall sample of 94 GM chromosomes we were able to detect 48 (51%) mutant GM alleles. Three mutations (F413C), R894X, and a 14-bp deletion in exon 13) account for 32% of the GM chromosomes in the German population. Our finding that A437T is probably a polymorphism is in contrast to a recent report that the recessive phenotype GM is associated with this amino acid change. We also demonstrate that the R894X mutation may act as a recessive or a dominant mutation in the CLCN1 gene...

‣ p53 Mutations in Nasal Natural Killer/T-Cell Lymphoma from Mexico : Association with Large Cell Morphology and Advanced Disease

Quintanilla-Martinez, Leticia; Kremer, Marcus; Keller, Gisela; Nathrath, Michaela; Gamboa-Dominguez, Armando; Meneses, Abelardo; Luna-Contreras, Lourdes; Cabras, Antonello; Hoefler, Heinz; Mohar, Alejandro; Fend, Falko
Fonte: American Society for Investigative Pathology Publicador: American Society for Investigative Pathology
Tipo: Artigo de Revista Científica
Publicado em /12/2001 Português
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Nasal NK/T-cell lymphoma is a unique form of lymphoma highly associated with Epstein-Barr virus, and with a characteristic geographic distribution. Recently, we showed that p53 is overexpressed in a high percentage of nasal NK/T-cell lymphomas. The aim of this study was to analyze the status of the p53 gene, and correlate it with the expression of p53 protein and its downstream target, the cyclin-dependent kinase inhibitor p21, in a series of 25 cases of well-characterized nasal NK/T-cell lymphoma from Mexico. The highly conserved exons 5 to 8 of the p53 gene were amplified by polymerase chain reaction and screened for mutations by denaturing high-pressure liquid chromatography. Abnormal polymerase chain reaction products detected by denaturing high-pressure liquid chromatography and additional selected cases were sequenced. In addition, the incidence of loss of heterozygosity at the p53 locus was analyzed in 12 cases. Of the 25 patients, 17 were male and 8 female (M:F ratio, 2.1:1), with a median age of 43 years (range, 21 to 93 years). Morphologically, most of the cases were composed of a mixture of medium-sized cells and large transformed cells (21 cases), and four cases were composed exclusively of large transformed cells. Three different groups determined by p53 gene status and expression of p53 protein were identified: group 1 was p53 +/p53 mutated (five cases...

‣ Effects of mutations causing hypokalaemic periodic paralysis on the skeletal muscle L-type Ca2+ channel expressed in Xenopus laevis oocytes

Morrill, James A; Cannon, Stephen C
Fonte: Blackwell Science Inc Publicador: Blackwell Science Inc
Tipo: Artigo de Revista Científica
Publicado em 15/10/1999 Português
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A truncated form of the rabbit α1S Ca2+ channel subunit (α1SΔC) was expressed with the β1b, α2δ and γ auxiliary subunits in Xenopus laevis oocytes. After 5–7 days, skeletal muscle L-type currents were measured (469 ± 48 nA in 10 mm Ba2+). All three of the auxiliary subunits were necessary to record significant L-type current. A rapidly inactivating, dihydropyridine-insensitive endogenous Ba2+ current was observed in oocytes expressing the auxiliary subunits without an exogenous α subunit. Expression of full-length α1S gave 10-fold smaller currents than the truncated form.Three missense mutations causing hypokalaemic periodic paralysis (R528H in domain II S4 of the α1S subunit; R1239H and R1239G in domain IV S4) were introduced into α1SΔC and expressed in oocytes. L-type current was separated from the endogenous current by nimodipine subtraction. All three of the mutations reduced L-type current amplitude (∼40% for R528H, ∼60–70% for R1239H and R1239G).The disease mutations altered the activation properties of L-type current. R528H shifted the G(V) curve ∼5 mV to the left and modestly reduced the voltage dependence of the activation time constant, τact. R1239H and R1239G shifted the G(V) curve ∼5–10 mV to the right and dramatically slowed τact at depolarized test potentials.The voltage dependence of steady-state inactivation was not significantly altered by any of the disease mutations.Wild-type and mutant L-type currents were also measured in the presence of (—)-Bay K8644...

‣ Mexiletine block of disease-associated mutations in S6 segments of the human skeletal muscle Na+ channel

Takahashi, Masanori P; Cannon, Stephen C
Fonte: Blackwell Science Inc Publicador: Blackwell Science Inc
Tipo: Artigo de Revista Científica
Publicado em 15/12/2001 Português
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Over twenty different missense mutations in the α-subunit of the adult skeletal muscle Na+ channel (hSkM1) have been identified as a cause of myotonia or periodic paralysis. We examined state-dependent mexiletine block for mutations involving the putative binding site in S6 segments (V445M, S804F, V1293I, V1589M and M1592V). Whole-cell Na+ currents were measured from wild-type (WT) and mutant channels transiently expressed in HEK cells.Use-dependent block (10 ms pulses to −10 mV, at 20 Hz) in 100 μm mexiletine was reduced modestly by mutations in IVS6 (V1589M, M1592V) and enhanced by the mutation in IS6 (V445M). For mutations in IIS6 (S804F) and IIIS6 (V1293I) use-dependent block was not statistically different from that of wild-type channels.Resting-state block (10 ms pulses to −10 mV from −150 mV, at 0.1 Hz) of S6 mutants was comparable to that of WT (dissociation constant for resting channels, KR = 650 ± 40 μm, n = 9). The S6 mutant with the greatest change in KR was V445M (KR = 794 ± 45 μm, n = 5), but this difference was only marginally significant (P = 0.047).A modified technique for estimating local anaesthetic affinity of inactivated channels was developed to reduce errors due to slow inactivation and to failure of drug binding to reach equilibrium. Mexiletine affinity for inactivated channels was reduced by mutations in IVS6 (V1589M: dissociation constant for the inactivated state (KI) = 44.7 μm; M1592V: KI = 40.0 μm) and increased by the mutation in IS6 (V445M: KI = 15.0 μm)...

‣ MSH6 germline mutations in early-onset colorectal cancer patients without family history of the disease

Pinto, C; Veiga, I; Pinheiro, M; Mesquita, B; Jeronimo, C; Sousa, O; Fragoso, M; Santos, L; Moreira-Dias, L; Baptista, M; Lopes, C; Castedo, S; Teixeira, M R
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Germline MLH1 and MSH2 mutations are scarce in young colorectal cancer patients with negative family history of the disease. To evaluate the contribution of germline MSH6 mutations to early-onset colorectal cancer, we have analysed peripheral blood of 38 patients diagnosed with this disease before 45 years of age and who presented no family history of hereditary nonpolyposis colorectal cancer-related cancers. Blood samples from 108 healthy volunteers were analysed for those genetic alterations suspected to affect the function of MSH6. Of the seven (18.4%) MSH6 alterations found, we have identified three novel germline mutations, one 8 bp deletion leading to a truncated protein and two missense mutations resulting in the substitution of amino acids belonging to different polarity groups. High-frequency microsatellite instability was found in the patient with the MSH6 deletion, but not in the other 27 carcinomas analysed. No MLH1 promoter methylation was detected in tumour tissue. Our findings suggest that germline MSH6 mutations contribute to a subset of early-onset colorectal cancer. Further studies are warranted to understand the genetic and environmental factors responsible for the variable penetration of MSH6 germline mutations...

‣ Mutations at embB Codon 306 Are an Important Molecular Indicator of Ethambutol Resistance in Mycobacterium tuberculosis▿

Starks, Angela M.; Gumusboga, Aysel; Plikaytis, Bonnie B.; Shinnick, Thomas M.; Posey, James E.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
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Ethambutol resistance in clinical Mycobacterium tuberculosis isolates is associated primarily with missense mutations in the embB gene. However, recent reports have described the presence of embB mutations, especially those at embB codon 306, in isolates susceptible to ethambutol. To clarify the role of embB mutations in ethambutol resistance, we sequenced the ethambutol resistance-determining region in spontaneous ethambutol-resistant mutants. In our study, 66% of spontaneous mutants contained a single point mutation in embB, with 55% of these occurring at embB 306. The MIC of ethambutol for spontaneous mutants was increased two- to eightfold relative to the pansusceptible M. tuberculosis strains from which the mutants were generated. To further characterize the role of embB 306 mutations, we directly introduced mutant alleles, embB(M306V) or embB(M306I), into pansusceptible M. tuberculosis strains and conversely reverted mutant alleles in spontaneous ethambutol-resistant mutants back to those of the wild type via allelic exchange using specialized linkage transduction. We determined that the MIC of ethambutol was reduced fourfold for three of the four spontaneous ethambutol-resistant embB 306 mutants when the mutant allele was replaced with the wild-type embB allele. The MIC for one of the spontaneous mutants genetically reverted to wild-type embB was reduced by only twofold. When the wild-type embB allele was converted to the mutant allele embB(M306V)...

‣ UNIQUE PHENOTYPE OF HEPATOCELLULAR CANCERS WITH EXON-3 MUTATIONS IN BETA-CATENIN GENE

Cieply, Benjamin; Zeng, Gang; Proverbs-Singh, Tracy; Geller, David A.; Monga, Satdarshan P. S.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /03/2009 Português
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Wnt/β-catenin signaling plays an important role in liver development and regeneration. Its aberrant activation, however, is observed in a subset of primary hepatocellular cancers (HCCs). In the present study we compare and contrast the tumor characteristics of HCC in the presence or absence of mutations in the β-catenin gene (CTNNB1). Frozen HCC (n=32) including five fibrolamellar (FL) variants, and control livers (n=3) from Health Sciences Tissue Bank and Department of Surgery at the University of Pittsburgh Medical Center, were examined for mutations in CTNNB1, protein levels of β-catenin, tyrosine-654-phosphorylated-β-catenin (Y654-β-catenin) and glutamine synthetase (GS). Missense mutations in the exon-3 of CTNNB1 were identified in 9/32 HCCs. Total β-catenin levels were higher than controls in most tumors, however GS was exclusively increased in HCC with mutations. Phenotypically, greater percentages of mutated HCCs showed macro- and micro-vascular invasion. Also the tumor size was greater than double in mutated HCCs. High levels of total β-catenin protein were observed in multinodular tumors independent of β-catenin mutations. In addition, significant cases with mutations showed absence of cirrhosis. Finally, highest levels of Y654-β-catenin were exclusively observed in FL-HCC cases.

‣ PTHR1 mutations associated with Ollier disease result in receptor loss of function

Couvineau, Alain; Wouters, Vinciane; Bertrand, Guylène; Rouyer, Christiane; Gérard, Bénédicte; Boon, Laurence M.; Grandchamp, Bernard; Vikkula, Miikka; Silve, Caroline
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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PTHR1-signaling pathway is critical for the regulation of endochondral ossification. Thus, abnormalities in genes belonging to this pathway could potentially participate in the pathogenesis of Ollier disease/Maffucci syndrome, two developmental disorders defined by the presence of multiple enchondromas. In agreement, a functionally deleterious mutation in PTHR1 (p.R150C) was identified in enchondromas from two of six unrelated patients with enchondromatosis. However, neither the p.R150C mutation (26 tumors) nor any other mutation in the PTHR1 gene (11 patients) could be identified in another study. To further define the role of PTHR1-signaling pathway in Ollier disease and Maffucci syndrome, we analyzed the coding sequences of four genes (PTHR1, IHH, PTHrP and GNAS1) in leucocyte and/or tumor DNA from 61 and 23 patients affected with Ollier disease or Maffucci syndrome, respectively. We identified three previously undescribed missense mutations in PTHR1 in patients with Ollier disease at the heterozygous state. Two mutations (p.G121E, p.A122T) were present only in enchondromas, and one (p.R255H) in both enchondroma and leukocyte DNA. Assessment of receptor function demonstrated that these three mutations impair PTHR1 function by reducing either the affinity of the receptor for PTH or the receptor expression at the cell surface. These mutations were not found in DNA from 222 controls. Including our data...

‣ RAD21 Mutations Cause a Human Cohesinopathy

Deardorff, Matthew A.; Wilde, Jonathan J.; Albrecht, Melanie; Dickinson, Emma; Tennstedt, Stephanie; Braunholz, Diana; Mönnich, Maren; Yan, Yuqian; Xu, Weizhen; Gil-Rodríguez, María Concepcion; Clark, Dinah; Hakonarson, Hakon; Halbach, Sara; Micheli
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em 08/06/2012 Português
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The evolutionarily conserved cohesin complex was originally described for its role in regulating sister-chromatid cohesion during mitosis and meiosis. Cohesin and its regulatory proteins have been implicated in several human developmental disorders, including Cornelia de Lange (CdLS) and Roberts syndromes. Here we show that human mutations in the integral cohesin structural protein RAD21 result in a congenital phenotype consistent with a “cohesinopathy.” Children with RAD21 mutations display growth retardation, minor skeletal anomalies, and facial features that overlap findings in individuals with CdLS. Notably, unlike children with mutations in NIPBL, SMC1A, or SMC3, these individuals have much milder cognitive impairment than those with classical CdLS. Mechanistically, these mutations act at the RAD21 interface with the other cohesin proteins STAG2 and SMC1A, impair cellular DNA damage response, and disrupt transcription in a zebrafish model. Our data suggest that, compared to loss-of-function mutations, dominant missense mutations result in more severe functional defects and cause worse structural and cognitive clinical findings. These results underscore the essential role of RAD21 in eukaryotes and emphasize the need for further understanding of the role of cohesin in human development.

‣ Exome Sequencing Identifies INPPL1 Mutations as a Cause of Opsismodysplasia

Huber, Céline; Faqeih, Eissa Ali; Bartholdi, Deborah; Bole-Feysot, Christine; Borochowitz, Zvi; Cavalcanti, Denise P.; Frigo, Amandine; Nitschke, Patrick; Roume, Joelle; Santos, Heloísa G.; Shalev, Stavit A.; Superti-Furga, Andrea; Delezoide, Anne-Li
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em 10/01/2013 Português
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Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet. The main radiological features are severe platyspondyly, squared metacarpals, delayed skeletal ossification, and metaphyseal cupping. In order to identify mutations causing OPS, a total of 16 cases (7 terminated pregnancies and 9 postnatal cases) from 10 unrelated families were included in this study. We performed exome sequencing in three cases from three unrelated families and only one gene was found to harbor mutations in all three cases: inositol polyphosphate phosphatase-like 1 (INPPL1). Screening INPPL1 in the remaining cases identified a total of 12 distinct INPPL1 mutations in the 10 families, present at the homozygote state in 7 consanguinous families and at the compound heterozygote state in the 3 remaining families. Most mutations (6/12) resulted in premature stop codons, 2/12 were splice site, and 4/12 were missense mutations located in the catalytic domain, 5-phosphatase. INPPL1 belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family, a family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. Our finding of INPPL1 mutations in OPS...

‣ Dominant-negative STAT1 SH2 domain mutations in unrelated patients with Mendelian susceptibility to mycobacterial disease

Tsumura, Miyuki; Okada, Satoshi; Sakai, Hidemasa; Yasunaga, Shin’ichiro; Ohtsubo, Motoaki; Murata, Takuji; Obata, Hideto; Yasumi, Takahiro; Kong, Xiao-Fei; Abhyankar, Avinash; Heike, Toshio; Nakahata, Tatsutoshi; Nishikomori, Ryuta; Al-Muhsen, Saleh; Bo
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Patients carrying two loss-of-function (or hypomorphic) alleles of STAT1 are vulnerable to intracellular bacterial and viral diseases. Heterozygosity for loss-of-function dominant-negative mutations in STAT1 is responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD), whereas heterozygosity for gain-of-function loss-of-dephosphorylation mutations causes AD chronic mucocutaneous candidiasis (CMC). The two previously reported types of AD MSMD-causing STAT1 mutations are located in the tail domain (p.L706S) or in the DNA-binding domain (p.E320Q and p.Q463H), whereas the AD CMC-causing mutations are located in the coiled-coil domain. We identified two cases with AD-STAT1 deficiency in two unrelated patients from Japan and Saudi Arabia carrying heterozygous missense mutations affecting the SH2 domain (p.K637E and p.K673R). p.K673R is a hypomorphic mutation that impairs STAT1 tyrosine phosphorylation, whereas the p.K637E mutation is null and affects both STAT1 phosphorylation and DNA-binding activity. Both alleles are dominant-negative and result in impaired STAT1-mediated cellular responses to IFN-γ and IL-27. By contrast, STAT1-mediated cellular responses against IFN-α and IFN-λ1 were preserved at normal levels in patients’ cells. We describe here the first dominant mutations in the SH2 domain of STAT1...

‣ Novel Oncogenic PDGFRA Mutations in Pediatric High-Grade Gliomas

Paugh, Barbara S.; Zhu, Xiaoyan; Qu, Chunxu; Endersby, Raelene; Diaz, Alexander K.; Zhang, Junyuan; Bax, Dorine A.; Carvalho, Diana; Reis, Rui M.; Onar-Thomas, Arzu; Broniscer, Alberto; Wetmore, Cynthia; Zhang, Jinghui; Jones, Chris; Ellison, David W.; Ba
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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The outcome for children with high-grade gliomas (HGG) remains dismal, with a two-year survival rate of only 10–30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet derived growth factor receptor alpha (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs. To determine whether PDGFRA is also targeted by more subtle mutations missed by copy number analysis, we sequenced all PDGFRA coding exons from a cohort of pediatric HGGs. Somatic activating mutations were identified in 14.4% (13/90) of non-brainstem pediatric HGGs and 4.7% (2/43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. 40% of tumors with mutation showed concurrent amplification, while 60% carried heterozygous mutations. Six different mutations impacting different domains all resulted in ligand-independent receptor activation that was blocked by small molecule inhibitors of PDGFR. Expression of mutants in p53-null primary mouse astrocytes conferred a proliferative advantage in vitro, and generated HGGs in vivo with complete penetrance when implanted into brain. The gene expression signatures of these murine HGGs reflected the spectrum of human diffuse HGGs. PDGFRA intragenic deletion of exons 8 and 9 were previously shown in adult HGG...

‣ Evidence That GRIN2A Mutations in Melanoma Correlate with Decreased Survival

D’mello, Stacey Ann N.; Flanagan, Jack U.; Green, Taryn N.; Leung, Euphemia Y.; Askarian-Amiri, Marjan E.; Joseph, Wayne R.; McCrystal, Michael R.; Isaacs, Richard J.; Shaw, James H. F.; Furneaux, Christopher E.; During, Matthew J.; Finlay, Graeme J.; B
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 13/01/2014 Português
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Previous whole-exome sequencing has demonstrated that melanoma tumors harbor mutations in the GRIN2A gene. GRIN2A encodes the regulatory GluN2A subunit of the glutamate-gated N-methyl-d-aspartate receptor (NMDAR), involvement of which in melanoma remains undefined. Here, we sequenced coding exons of GRIN2A in 19 low-passage melanoma cell lines derived from patients with metastatic melanoma. Potential mutation impact was evaluated in silico, including within the GluN2A crystal structure, and clinical correlations were sought. We found that of 19 metastatic melanoma tumors, four (21%) carried five missense mutations in the evolutionarily conserved domains of GRIN2A; two were previously reported. Melanoma cells that carried these mutations were treatment-naïve. Sorting intolerant from tolerant analysis predicted that S349F, G762E, and P1132L would disrupt protein function. When modeled into the crystal structure of GluN2A, G762E was seen to potentially alter GluN1–GluN2A interactions and ligand binding, implying disruption to NMDAR functionality. Patients whose tumors carried non-synonymous GRIN2A mutations had faster disease progression and shorter overall survival (P < 0.05). This was in contrast to the BRAF V600E mutation, found in 58% of tumors but showing no correlation with clinical outcome (P = 0.963). Although numbers of patients in this study are small...

‣ Biochemical Activities of Streptococcus pneumoniae Serotype 2 Capsular Glycosyltransferases and Significance of Suppressor Mutations Affecting the Initiating Glycosyltransferase Cps2E

James, David B. A.; Gupta, Kanupriya; Hauser, Jocelyn R.; Yother, Janet
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /12/2013 Português
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The capsular polysaccharide (CPS) is essential for Streptococcus pneumoniae virulence. Its synthesis requires multiple enzymes, and defects that block completion of the pathway can be lethal in the absence of secondary suppressor mutations. In this study, we examined the functions of three capsular glycosyltransferases (Cps2F, Cps2G, and Cps2I) involved in serotype 2 CPS synthesis, whose deletions select for secondary mutations. We demonstrate that Cps2F is a rhamnosyltransferase that catalyzes addition of the third and fourth sugars in the capsule repeat unit, while Cps2G adds the fifth sugar (glucose). Addition of the terminal residue (glucuronic acid) could not be detected; however, activities of the other glycosyltransferases together with bioinformatic analyses suggest that this step is mediated by Cps2I. Most of the secondary suppressor mutations resulting from loss of these enzymes occur in cps2E, the gene encoding the initiating glycosyltransferase. Examination of the 69 S. pneumoniae serotypes containing Cps2E homologues yielded a consensus amino acid sequence for this protein and demonstrated that there is a highly significant association between the residues that are 100% conserved and those altered by suppressor mutations. Cps2E contains an extracytoplasmic loop whose function is unknown. Among our collection of mutants...

‣ Prevalence of PIK3CA mutations and the SNP rs17849079 in Arab breast cancer patients

Karakas, Bedri; Colak, Dilek; Kaya, Namik; Ghebeh, Hazem; Al-Qasem, Abeer; Hendrayani, Fawziah; Toulimat, Mohamed; Al-Tweigeri, Taher; Park, Ben Ho; Aboussekhra, Abdelilah
Fonte: Landes Bioscience Publicador: Landes Bioscience
Tipo: Artigo de Revista Científica
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Carcinomas initiate and progress due to genetic and epigenetic alterations in epithelial cells. However, recently, these alterations have also been reported in stromal fibroblasts. The gain-of-function mutations in the PI3K p110 catalytic subunit (PIK3CA) have been identified in many cancers with a current global incidence of 26% (18–40%) in breast carcinomas. We analyzed the mutational frequency of PIK3CA of three hotspots (exons 1, 9, and 20) in 81 primary invasive breast cancers (BC) and 25 cultured breast cancer-associated fibroblast (CAF) samples by Sanger sequencing in Arab breast cancer patients. Associations between the incidence of any PIK3CA mutation and several clinicopathologic characteristics were assessed using chi-square tests for categorical or t test for continuous variables. Furthermore, survival curves were estimated using the Kaplan–Meier method with the log rank test to evaluate the significance of their differences. We identified a total of 21 PIK3CA missense mutations with a frequency of 25.9%. The majority of the mutations, 17 out of 21 (81%), were in exon 20 (p.His1047Arg, p.His1047Lys, p.Thr1025Ala, p.Gly1049Arg, p.Asp1056Asn) while the remainder, 4 out of 21 (19%) were in exon 9 (p.Glu545Lys). PIK3CA mutations were significantly associated with lower grade and hormone receptor positivity. Although there was a favorable trend in overall survival for patients whose tumor harbored PIK3CA mutations...

‣ Mutations in Intron 1 and Intron 22 Inversion Negative Haemophilia A Patients from Western India

Nair, Preethi S.; Shetty, Shrimati D.; Chandrakala, S.; Ghosh, Kanjaksha
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 20/05/2014 Português
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Despite increased awareness and diagnostic facilities, 70–80% of the haemophilia A (HA) patients still remain undiagnosed in India. Very little data is available on prevalent mutations in HA from this country. We report fifty mutations in seventy one Indian HA patients, of which twenty were novel. Ten novel missense mutations [p.Leu11Pro (p.Leu-8Pro), p.Tyr155Ser (p.Tyr136Ser), p.Ile405Thr (p.Ile386Thr), p.Gly582Val (p.Gly563Val) p.Thr696Ile (p.Thr677Ile), p.Tyr737Cys (p.Tyr718Cys), p.Pro1999Arg (p.Pro1980Arg), p.Ser2082Thr (p.Ser2063Thr), p.Leu2197Trp (p.Leu2178Trp), p.Asp2317Glu (p.Asp2298Glu)] two nonsense [p.Lys396* (p.Lys377*), p.Ser2205* (p.Ser2186*)], one insertion [p.Glu1268_Asp1269ins (p.Glu1249_Asp1250)] and seven deletions [p.Leu882del (p.Leu863del), p.Met701del (p.Met682del), p.Leu1223del (p.Leu1204del), p.Trp1961_Tyr1962del (p.Trp1942_Tyr1943del) p.Glu1988del (p.Glu1969del), p.His1841del (p.His1822del), p.Ser2205del (p.Ser2186del)] were identified. Double mutations (p.Asp2317Glu; p.Thr696Ile) were observed in a moderate HA case. Mutations [p. Arg612Cys (p.Arg593Cys), p.Arg2326Gln (p.Arg2307Gln)] known to be predisposing to inhibitors to factor VIII (FVIII) were identified in two patients. 4.6% of the cases were found to be cross reacting material positive (CRM+ve). A wide heterogeneity in the nature of mutations was seen in the present study which has been successfully used for carrier detection and antenatal diagnosis in 10 families affected with severe to moderate HA.

‣ PIK3CA and TP53 Gene Mutations in Human Breast Cancer Tumors Frequently Detected by Ion Torrent DNA Sequencing

Bai, Xusheng; Zhang, Enke; Ye, Hua; Nandakumar, Vijayalakshmi; Wang, Zhuo; Chen, Lihong; Tang, Chuanning; Li, Jianhui; Li, Huijin; Zhang, Wei; Han, Wei; Lou, Feng; Zhang, Dandan; Sun, Hong; Dong, Haichao; Zhang, Guangchun; Liu, Zhiyuan; Dong, Zhishou; Guo
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 11/06/2014 Português
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Breast cancer is the most common malignancy and the leading cause of cancer deaths in women worldwide. While specific genetic mutations have been linked to 5–10% of breast cancer cases, other environmental and epigenetic factors influence the development and progression of the cancer. Since unique mutations patterns have been observed in individual cancer samples, identification and characterization of the distinctive breast cancer molecular profile is needed to develop more effective target therapies. Until recently, identifying genetic cancer mutations via personalized DNA sequencing was impractical and expensive. The recent technological advancements in next-generation DNA sequencing, such as the semiconductor-based Ion Torrent sequencing platform, has made DNA sequencing cost and time effective with more reliable results. Using the Ion Torrent Ampliseq Cancer Panel, we sequenced 737 loci from 45 cancer-related genes to identify genetic mutations in 105 human breast cancer samples. The sequencing analysis revealed missense mutations in PIK3CA, and TP53 genes in the breast cancer samples of various histologic types. Thus, this study demonstrates the necessity of sequencing individual human cancers in order to develop personalized drugs or combination therapies to effectively target individual...

‣ Mutations Affecting the SAND Domain of DEAF1 Cause Intellectual Disability with Severe Speech Impairment and Behavioral Problems

Vulto-van Silfhout, Anneke T.; Rajamanickam, Shivakumar; Jensik, Philip J.; Vergult, Sarah; de Rocker, Nina; Newhall, Kathryn J.; Raghavan, Ramya; Reardon, Sara N.; Jarrett, Kelsey; McIntyre, Tara; Bulinski, Joseph; Ownby, Stacy L.; Huggenvik, Jodi
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em 01/05/2014 Português
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Recently, we identified in two individuals with intellectual disability (ID) different de novo mutations in DEAF1, which encodes a transcription factor with an important role in embryonic development. To ascertain whether these mutations in DEAF1 are causative for the ID phenotype, we performed targeted resequencing of DEAF1 in an additional cohort of over 2,300 individuals with unexplained ID and identified two additional individuals with de novo mutations in this gene. All four individuals had severe ID with severely affected speech development, and three showed severe behavioral problems. DEAF1 is highly expressed in the CNS, especially during early embryonic development. All four mutations were missense mutations affecting the SAND domain of DEAF1. Altered DEAF1 harboring any of the four amino acid changes showed impaired transcriptional regulation of the DEAF1 promoter. Moreover, behavioral studies in mice with a conditional knockout of Deaf1 in the brain showed memory deficits and increased anxiety-like behavior. Our results demonstrate that mutations in DEAF1 cause ID and behavioral problems, most likely as a result of impaired transcriptional regulation by DEAF1.