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‣ Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome

LIMA, Renata. L. L. Ferreira de; HOPER, Sarah A.; GHASSIBE, Michella; COOPER, Margaret E.; RORICK, Nicholas K.; KONDO, Shinji; KATZ, Lori; MARAZITA, Mary L.; COMPTON, John; BALE, Sherri; HEHR, Ute; DIXON, Michael J.; DAACK-HIRSCH, Sandra; BOUTE, Odile; BA
Fonte: LIPPINCOTT WILLIAMS & WILKINS Publicador: LIPPINCOTT WILLIAMS & WILKINS
Tipo: Artigo de Revista Científica
Português
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Purpose: Interferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and popliteal pterygium syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic Mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with popliteal pterygium syndrome. Methods: We performed direct sequence analysis of interferon regulatory factor 6 exons oil samples from three collections, two with Van der Woude and one with popliteal pterygium syndrome. Results: We identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with popliteal pterygium syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the popliteal pterygium syndrome collection were missense. Further...

‣ Identificação e caracterização de mutações germinativas no gene VHL em famílias com a doença de von Hippel-Lindau; Identification and characterization of germline mutations in the VHL gene in families with von Hippel-Lindau disease

Gomy, Israel
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 02/07/2008 Português
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A doença de von Hippel-Lindau (VHL) é uma síndrome de câncer familial herdada de forma autossômica dominante que predispõe ao desenvolvimento de diversos tipos de neoplasias benignas e malignas. É causada por mutações germinativas e somáticas no gene VHL e tem uma incidência aproximada de um a cada 36.000 nascimentos. O gene VHL é um supressor tumoral e codifica a proteína VHL, a qual possui, entre outras funções, uma atividade ubiquitina-ligase, responsável pela poliubiquitinização e degradação proteassômica da subunidade alfa do fator induzido por hipóxia (HIF) na presença de oxigênio. As principais características da doença de VHL são: hemangioblastomas de sistema nervoso central (SNC), principalmente do cerebelo e medula espinhal; angiomas de retina e carcinoma renal de células claras. A probabilidade de desenvolver cada um desses tumores ao longo da vida é estimada em maior que 70%, podendo manifestar-se desde a infância até a fase adulta, principalmente entre a 2ª e 3ª décadas de vida. Classifica-se a doença de VHL conforme a ausência (tipo 1) ou presença de feocromocitoma (tipo 2). A doença do tipo 2 é causada, essencialmente, por mutações missense no gene VHL. As mutações podem ser grandes deleções (20%) ou pontuais (80%) do tipo missense...

‣ Mutações inativadoras dos genes PROK2 e PROKR2 em pacientes com hipogonadismo hipogonadotrófico isolado; PROK2 and PROKR2 inactivating mutations in patients with idiopathic hypogonadotropic hypogonadism

Silva, Ana Paula de Abreu e
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 14/01/2011 Português
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O sistema da procineticina desempenha um papel importante na migração dos neurônios secretores de GnRH e na neurogênese do bulbo olfatório. Camundongos com ablação dos genes que codificam a procineticina 2 (PROK2) e seu receptor (PROKR2) apresentaram fenótipos semelhantes ao da síndrome de Kallmann descrita em humanos. Mutações inativadoras nos genes PROK2 e PROKR2 foram identificadas em pacientes com hipogonadismo hipogonadotrófico isolado. Com base nestes achados, investigamos a presença de alterações estruturais nos genes PROK2 e PROKR2 em 107 pacientes brasileiros (63 com síndrome de Kallmann e 47 com hipogonadismo hipogonadotrófico isolado normósmico). Cem indivíduos brasileiros que relataram desenvolvimento puberal normal foram utilizados como grupo controle. As regiões codificadoras dos genes PROK2 e PROKR2 foram amplificadas utilizando-se oligonucleotídeos intrônicos específicos, seguida de purificação enzimática e sequenciamento automático. Duas mutações no gene PROK2 foram identificadas: a mutação p.G100fsX121 em homozigose presente em dois irmãos com síndrome de Kallmann; e a mutação p.I55fsX56 em heterozigose identiificada em um paciente com HHIn. Quatro mutações foram identificadas no gene PROKR2 (p.R80C...

‣ Human TBX1 Missense Mutations Cause Gain of Function Resulting in the Same Phenotype as 22q11.2 Deletions

Zweier, Christiane; Sticht, Heinrich; Aydin-Yaylagül, Inci; Campbell, Christine E.; Rauch, Anita
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
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Deletion 22q11.2 syndrome is the most frequent known microdeletion syndrome and is associated with a highly variable phenotype, including DiGeorge and Shprintzen (velocardiofacial) syndromes. Although haploinsufficiency of the T-box transcription factor gene TBX1 is thought to cause the phenotype, to date, only four different point mutations in TBX1 have been reported in association with six of the major features of 22q11.2 deletion syndrome. Although, for the two truncating mutations, loss of function was previously shown, the pathomechanism of the missense mutations remains unknown. We report a novel heterozygous missense mutation, H194Q, in a familial case of Shprintzen syndrome and show that this and the two previously reported missense mutations result in gain of function, possibly through stabilization of the protein dimer DNA complex. We therefore conclude that TBX1 gain-of-function mutations can result in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions.

‣ Functional analysis of dicer-2 missense mutations in the siRNA pathway of Drosophila

Lim, Do Hwan; Kim, Jung; Kim, Sanguk; Carthew, Richard W.; Lee, Young Sik
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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The Drosophila RNase III enzyme Dicer-2 processes double-stranded RNA (dsRNA) precursors into small interfering RNAs (siRNAs). It also interacts with the siRNA product and R2D2 protein to facilitate the assembly of an RNA-induced silencing complex (RISC) that mediates RNA interference. Here, we characterized six independent missense mutations in the dicer-2 gene. Four mutations (P8S, L188F, R269W, and P365L) in the DExH helicase domain reduced dsRNA processing activity. Two mutations were located within an RNase III domain. P1496L caused a loss of dsRNA processing activity comparable to a null dicer-2 mutation. A1453T strongly reduced both dsRNA processing and RISC activity, and decreased the levels of Dicer-2 and R2D2 proteins, suggesting that this mutation destabilizes Dicer-2. We also found that the carboxyl-terminal region of R2D2 is essential for Dicer-2 binding. These results provide further insight into the structure–function relationship of Dicer, which plays a critical role in the siRNA pathway.

‣ Only Missense Mutations Affecting the DNA Binding Domain of P53 Influence Outcomes in Patients with Breast Carcinoma

Végran, Frédérique; Rebucci, Magali; Chevrier, Sandy; Cadouot, Muriel; Boidot, Romain; Lizard-Nacol, Sarab
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 24/01/2013 Português
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The presence of a TP53 gene mutation can influence tumour response to some treatments, especially in breast cancer. In this study, we analysed p53 mRNA expression, LOH at 17p13 and TP53 mutations from exons 2 to 11 in 206 patients with breast carcinoma and correlated the results with disease-free and overall survival. The observed mutations were classified according to their type and location in the three protein domains (transactivation domain, DNA binding domain, oligomerization domain) and correlated with disease-free and overall survival. In our population, neither p53 mRNA expression nor LOH correlated with outcome. Concerning TP53 mutations, 27% of tumours were mutated (53/197) and the presence of a mutation in the TP53 gene was associated with worse overall survival (p = 0.0026) but not with disease-free survival (p = 0.0697), with median survival of 80 months and 78 months, respectively. When alterations were segregated into mutation categories and locations, and related to survival, tumours harbouring mutations other than missense mutations in the DNA binding domain of P53 had the same survival profiles as wild-type tumours. Concerning missense mutations in the DNA binding domain, median disease-free and overall survival was 23 months and 35 months...

‣ Evolution- and Structure-Based Computational Strategy Reveals the Impact of Deleterious Missense Mutations on MODY 2 (Maturity-Onset Diabetes of the Young, Type 2)

George, Doss C. Priya; Chakraborty, Chiranjib; Haneef, SA Syed; NagaSundaram, Nagarajan; Chen, Luonan; Zhu, Hailong
Fonte: Ivyspring International Publisher Publicador: Ivyspring International Publisher
Tipo: Artigo de Revista Científica
Publicado em 29/01/2014 Português
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Heterozygous mutations in the central glycolytic enzyme glucokinase (GCK) can result in an autosomal dominant inherited disease, namely maturity-onset diabetes of the young, type 2 (MODY 2). MODY 2 is characterised by early onset: it usually appears before 25 years of age and presents as a mild form of hyperglycaemia. In recent years, the number of known GCK mutations has markedly increased. As a result, interpreting which mutations cause a disease or confer susceptibility to a disease and characterising these deleterious mutations can be a difficult task in large-scale analyses and may be impossible when using a structural perspective. The laborious and time-consuming nature of the experimental analysis led us to attempt to develop a cost-effective computational pipeline for diabetic research that is based on the fundamentals of protein biophysics and that facilitates our understanding of the relationship between phenotypic effects and evolutionary processes. In this study, we investigate missense mutations in the GCK gene by using a wide array of evolution- and structure-based computational methods, such as SIFT, PolyPhen2, PhD-SNP, SNAP, SNPs&GO, fathmm, and Align GVGD. Based on the computational prediction scores obtained using these methods...

‣ Three Epilepsy-Associated GABRG2 Missense Mutations at the γ+/β− interface Disrupt GABAA Receptor Assembly and trafficking by Similar MeChanisms but to Different Extents

Huang, Xuan; Hernandez, Ciria C.; Hu, Ningning; Macdonald, Robert L.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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We compared the effects of three missense mutations in the GABAA receptor γ2 subunit on GABAA receptor assembly, trafficking and function in HEK293T cells cotransfected with α1, β2, and wildtype or mutant γ2 subunits. The mutations R82Q and P83S were identified in families with genetic epilepsy with febrile seizures plus (GEFS+), and N79S was found in a single patient with generalized tonic-clonic seizures (GTCS). Although all three mutations were located in an N terminal loop that contributes to the γ+/β− subunit-subunit interface, we found that each mutation impaired GABAA receptor assembly to a different extent. The γ2(R82Q) and γ2(P83S) subunits had reduced α1β2γ2 receptor surface expression due to impaired assembly into pentamers, endoplasmic reticulum (ER) retention and degradation. In contrast, γ2(N79S) subunits were efficiently assembled into GABAA receptors with only minimally altered receptor trafficking, suggesting that N79S was a rare or susceptibility variant rather than an epilepsy mutation. Increased structural variability at assembly motifs was predicted by R82Q and P83S, but not N79S, substitution, suggesting that R82Q and P83S substitutions were less tolerated. Membrane proteins with missense mutations that impair folding and assembly often can be “rescued” by decreased temperatures. We coexpressed wildtype or mutant γ2 subunits with α1 and β2 subunits and found increased surface and total levels of both wildtype and mutant γ2 subunits after decreasing the incubation temperature to 30 °C for 24 hours...

‣ An integrated computational approach can classify VHL missense mutations according to risk of clear cell renal carcinoma

Gossage, Lucy; Pires, Douglas E. V.; Olivera-Nappa, Álvaro; Asenjo, Juan; Bycroft, Mark; Blundell, Tom L.; Eisen, Tim
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
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Mutations in the von Hippel–Lindau (VHL) gene are pathogenic in VHL disease, congenital polycythaemia and clear cell renal carcinoma (ccRCC). pVHL forms a ternary complex with elongin C and elongin B, critical for pVHL stability and function, which interacts with Cullin-2 and RING-box protein 1 to target hypoxia-inducible factor for polyubiquitination and proteasomal degradation. We describe a comprehensive database of missense VHL mutations linked to experimental and clinical data. We use predictions from in silico tools to link the functional effects of missense VHL mutations to phenotype. The risk of ccRCC in VHL disease is linked to the degree of destabilization resulting from missense mutations. An optimized binary classification system (symphony), which integrates predictions from five in silico methods, can predict the risk of ccRCC associated with VHL missense mutations with high sensitivity and specificity. We use symphony to generate predictions for risk of ccRCC for all possible VHL missense mutations and present these predictions, in association with clinical and experimental data, in a publically available, searchable web server.

‣ Functional Characterization and Categorization of Missense Mutations that Cause Methylmalonyl-CoA Mutase (MUT) Deficiency

Forny, Patrick; Froese, D. Sean; Suormala, Terttu; Yue, Wyatt W.; Baumgartner, Matthias R.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/2014 Português
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Methylmalonyl-CoA mutase (MUT) is an essential enzyme in propionate catabolism that requires adenosylcobalamin as a cofactor. Almost 250 inherited mutations in the MUT gene are known to cause the devastating disorder methylmalonic aciduria; however, the mechanism of dysfunction of these mutations, more than half of which are missense changes, has not been thoroughly investigated. Here, we examined 23 patient missense mutations covering a spectrum of exonic/structural regions, clinical phenotypes, and ethnic populations in order to determine their influence on protein stability, using two recombinant expression systems and a thermostability assay, and enzymatic function by measuring MUT activity and affinity for its cofactor and substrate. Our data stratify MUT missense mutations into categories of biochemical defects, including (1) reduced protein level due to misfolding, (2) increased thermolability, (3) impaired enzyme activity, and (4) reduced cofactor response in substrate turnover. We further demonstrate the stabilization of wild-type and thermolabile mutants by chemical chaperones in vitro and in bacterial cells. This in-depth mutation study illustrates the tools available for MUT enzyme characterization, guides future categorization of further missense mutations...

‣ In silico prediction of tumor antigens derived from functional missense mutations of the cancer gene census

Khalili, Jahan S.; Hanson, Russell W.; Szallasi, Zoltan
Fonte: Landes Bioscience Publicador: Landes Bioscience
Tipo: Artigo de Revista Científica
Português
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Antigen-specific immune responses against peptides derived from missense gene mutations have been identified in multiple cancers. The application of personalized peptide vaccines based on the tumor mutation repertoire of each cancer patient is a near-term clinical reality. These peptides can be identified for pre-validation by leveraging the results of massive gene sequencing efforts in cancer. In this study, we utilized NetMHC 3.2 to predict nanomolar peptide binding affinity to 57 human HLA-A and B alleles. All peptides were derived from 5,685 missense mutations in 312 genes annotated as functionally relevant in the Cancer Genome Project. Of the 26,672,189 potential 8–11 mer peptide-HLA pairs evaluated, 0.4% (127,800) display binding affinities < 50 nM, predicting high affinity interactions. These peptides can be segregated into two groups based on the binding affinity to HLA proteins relative to germline-encoded sequences: peptides for which both the mutant and wild-type forms are high affinity binders, and peptides for which only the mutant form is a high affinity binder. Current evidence directs the attention to mutations that increase HLA binding affinity, as compared with cognate wild-type peptide sequences, as these potentially are more relevant for vaccine development from a clinical perspective. Our analysis generated a database including all predicted HLA binding peptides and the corresponding change in binding affinity as a result of point mutations. Our study constitutes a broad foundation for the development of personalized peptide vaccines that hone-in on functionally relevant targets in multiple cancers in individuals with diverse HLA haplotypes.

‣ Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM

Friend, K.; Crimmins, D.; Phan, T.; Sue, C.; Colley, A.; Fung, V.; Morris, J.; Sutherland, G.; Richards, R.
Fonte: SPRINGER VERLAG Publicador: SPRINGER VERLAG
Tipo: Artigo de Revista Científica
Publicado em //1999 Português
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Mutations in the brain specific P/Q type Ca2+ channel alpha1 subunit gene, CACNA1A, have been identified in three clinically distinct disorders, viz. episodic ataxia type 2 (EA-2), familial hemiplegic migraine (FHM) and spinocerebellar ataxia 6 (SCA6). For individuals with EA-2, the mutations described thus far are presumed to result in a truncated protein product. Several different missense mutations have been identified in patients with FHM. At least two of these mutations have been identified on two different chromosome 19p13 haplotypes and thus represent recurrent mutations. In the present study, we have screened several individuals for mutations in all 47 exons in the CACNA1A gene by single-strand conformation analysis. We have characterised a novel missense mutation, G5260A, in exon 32 in a family segregating for EA-2. The consequence of this mutation is an amino acid substitution at a highly conserved position within the CACNA1A gene. This represents the first point mutation not resulting in a proposed truncated protein. Furthermore, this mutation has been detected in a family member with mild clinical signs including only migraine. Additionally, a second previously identified recurrent muta tion, C2272T, in exon 16 has been discovered in a patient with FHM.; Friend...

‣ Mutationsanalyse des HFE-Genes mittels DHPLC bei Hämochromatose-Patienten und Parkinson-Patienten; Screening for mutations of the HFE-gene by the method of DHPLC in hemochromatosis patients and Parkinson’s disease patients

Akbas, Nilgün
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
Português
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Bei der HFE-assoziierten Hereditären Hämochromatose (HH1) handelt es sich um ein monogen vererbtes Krankheitssyndrom, bei welchem es aufgrund von Sequenzvariationen im HFE-Gen zu einer exzessiven Eisenspeicherung mit folgender Schädigung diverser Organsysteme kommt. Die wichtigsten, mit dieser Erkrankung assoziierten Genotypen sind dabei die homozygote C282Y-Mutation in Exon 4, die homozygote H63D-Mutation in Exon 2 und die Compound-Heterozygotie für diese zwei Mutationen. Diese Genotypen können bei vielen Individuen, aber bei weitem nicht allen Individuen mit entsprechendem Phänotyp nachgewiesen werden. Auch bei der routinemäßig durchgeführten molekulargenetischen Analyse des hier untersuchten HH1-Kollektives konnte nur für einen Teil der insgesamt 116 Patienten ein entsprechender Genotyp festgestellt werden. Daher wurden im Rahmen dieser Arbeit alle 6 Exons des HFE-Genes innerhalb dieses Kollektives mittels DHPLC und Sequenzierung untersucht. Hierbei konnte das Vorliegen der zwei Hauptmutationen der HH1 als exonische missense-Mutationen und eine intronische Sequenzvariation (IVS2/3889*T>C) nachgewiesen werden, über deren Bedeutung noch keinerlei Klarheit besteht. Mit Hilfe einer Stammbaumanalyse konnte außerdem eine Kopplung der H63D-Mutation mit dieser intronischen Sequenzvariation festgestellt werden. Neben der genetischen Untersuchung wurde retrospektiv für jeden Patienten die vorliegende Klinik anhand eines Patientenbogens erhoben. So konnten Vergleiche zwischen dem vorliegenden Genotyp und Phänotyp durchgeführt werden. Hierzu wurden die Patienten...

‣ BCR-ABL1 compound mutations in tyrosine kinase inhibitor–resistant CML: frequency and clonal relationships

Khorashad, Jamshid S.; Kelley, Todd W.; Szankasi, Philippe; Mason, Clinton C.; Soverini, Simona; Adrian, Lauren T.; Eide, Christopher A.; Zabriskie, Matthew S.; Lange, Thoralf; Estrada, Johanna C.; Pomicter, Anthony D.; Eiring, Anna M.; Kraft, Ira L.; And
Fonte: American Society of Hematology Publicador: American Society of Hematology
Tipo: Artigo de Revista Científica
Publicado em 17/01/2013 Português
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BCR-ABL1 compound mutations can confer high-level resistance to imatinib and other ABL1 tyrosine kinase inhibitors (TKIs). The third-generation ABL1 TKI ponatinib is effective against BCR-ABL1 point mutants individually, but remains vulnerable to certain BCR-ABL1 compound mutants. To determine the frequency of compound mutations among chronic myeloid leukemia patients on ABL1 TKI therapy, in the present study, we examined a collection of patient samples (N = 47) with clear evidence of 2 BCR-ABL1 kinase domain mutations by direct sequencing. Using a cloning and sequencing method, we found that 70% (33/47) of double mutations detected by direct sequencing were compound mutations. Sequential, branching, and parallel routes to compound mutations were common. In addition, our approach revealed individual and compound mutations not detectable by direct sequencing. The frequency of clones harboring compound mutations with more than 2 missense mutations was low (10%), whereas the likelihood of silent mutations increased disproportionately with the total number of mutations per clone, suggesting a limited tolerance for BCR-ABL1 kinase domain missense mutations. We conclude that compound mutations are common in patients with sequencing evidence for 2 BCR-ABL1 mutations and frequently reflect a highly complex clonal network...

‣ Fabry disease: Identification of 50 novel α-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations

Shabbeer, Junaid; Yasuda, Makiko; Benson, Stacy D; Desnick, Robert J
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 01/03/2006 Português
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Fabry disease, an X-linked recessive inborn error of glycosphingolipid catabolism, results from the deficient activity of the lysosomal exoglycohydrolase, α-galactosidase A (EC 3.2.1.22; α-Gal A). The molecular lesions in the α-Gal A gene causing the classic phenotype of Fabry disease in 66 unrelated families were determined. In 49 families, 50 new mutations were identified, including: 29 missense mutations (N34K, T41I, D93V, R112S, L166G, G171D, M187T, S201Y, S201F, D234E, W236R, D264Y, M267R, V269M, G271S, G271V, S276G, Q283P, A285P, A285D, M290I, P293T, Q312H, Q321R, G328V, E338K, A348P, E358A, Q386P); nine nonsense mutations (C56X, E79X, K127X, Y151X, Y173X, L177X, W262X, Q306X, E338X); five splicing defects (IVS4-1G > A, IVS5-2A > G, IVS5 + 3A > G, IVS5 + 4A > G, IVS6-1G > C); four small deletions (18delA, 457delGAC, 567delG, 1096delACCAT); one small insertion (996insC); one 3.1 kilobase Alu-Alu deletion (which included exon 2); and one complex mutation (K374R, 1124delGAG). In 18 families, 17 previously reported mutations were identified, with R112C occurring in two families. In two classically affected families, affected males were identified with two mutations: one with two novel mutations, D264Y and V269M and the other with one novel (Q312H) and one previously reported (A143T) mutation. Transient expression of the individual mutations revealed that D264Y and Q312H were localised in the endoplasmic reticulum and had no detectable or markedly reduced activity...

‣ Nonsense but not missense mutations can decrease the abundance of nuclear mRNA for the mouse major urinary protein, while both types of mutations can facilitate exon skipping.

Belgrader, P; Maquat, L E
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1994 Português
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In an effort to understand the mechanisms by which nonsense codons affect RNA metabolism in mammalian cells, nonsense mutations were generated within the gene for the secretory major urinary protein (MUP) of mice. The translation of MUP mRNA normally begins within exon 1 and terminates within exon 6, the penultimate exon. Through the use of Northern (RNA) blot hybridization and assays that couple reverse transcription and PCR, a nonsense mutation within codon 50 of exon 2 or codon 143 of exon 5 was found to reduce the abundance of fully spliced, nuclear MUP mRNA to 10 to 20% of normal without an additional reduction in the abundance of cytoplasmic mRNA. In contrast, a nonsense mutation within codon 172 of exon 5 was found to have no effects on the abundance of MUP mRNA. These findings suggest that a boundary between nonsense mutations that do and do not reduce the abundance of nuclear mRNA exists within the exon preceding the exon that harbors the normal site of translation termination. In this way, the boundary is analogous to the boundary that exists within the penultimate exon of the human gene for the cytosolic enzyme triosephosphate isomerase. Assays for exon skipping, i.e., the removal of an exon as a part of the flanking introns during the process of splicing...

‣ Genética molecular de hemofilia: caracterización de mutaciones en hemofilia B, expresión de hemofilia en mujeres y desarrollo de nuevos métodos de análisis de inversiones; Molecular genetics of hemophilia: characterization of hemophilia B mutations, expression of hemophilia in women and development of new methods for inversion analysis

Radic, Claudia Pamela
Fonte: Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires Publicador: Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires
Tipo: info:eu-repo/semantics/doctoralThesis; tesis doctoral; info:eu-repo/semantics/publishedVersion Formato: application/pdf
Publicado em //2010 Português
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Las hemofilias A (HA) y B (HB) son coagulopatías hereditarias, ligadas al cromosoma X (X), sufridas por varones (1:5000) y raramente por mujeres, causada por defectos génicos del factor VIII (F8) y IX (F9), respectivamente. Para caracterizar el espectro de mutaciones causales de HB en Argentina se aplicó un esquema original de 12 amplímeros para el F9, incluyendo un screening por CSGE (conformation sensitive gel electrophoresis), en 49 familias, y se identificaron 29 cambios missense (60%), 7 nonsense (14%), 4 defectos de splicing (8%), 2 pequeñas inserciones‐deleciones (4%), 6 grandes deleciones (12%) y un cambio en región promotora del F9. Dos cambios missense no reportados mostraron, uno la disrupción de un puente disulfuro y otro la destrucción de un sitio de γ‐carboxilación condicionando el fenotipo de HB severa. Para mejorar la estrategia de detección de grandes rearreglos que involucran int22h e int1h en el F8, causales del 50% de las HA severas, se desarrolló un abordaje nuevo, inverse‐shifting‐PCR (IS‐PCR). Mediante el uso de un test diagnóstico para la inversión del intron 22 (Inv22), los resultados de IS‐PCR fueron validados por perfecta concordancia en 32 y 43 casos previamente estudiados por Southern blot y PCR inversa...

‣ RB1 gene mutation up-date, a meta-analysis based on 932 reported mutations available in a searchable database

Valverde, José R.; Alonso García de la Rosa, Francisco Javier; Palacios, Itziar; Pestaña, Ángel
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artículo Formato: 406983 bytes; application/pdf
Português
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[Background] Retinoblastoma, a prototype of hereditary cancer, is the most common intraocular tumour in children and potential cause of blindness from therapeutic eye ablation, second tumours in germ line carrier's survivors, and even death when left untreated. The molecular scanning of RB1 in search of germ line mutations lead to the publication of more than 900 mutations whose knowledge is important for genetic counselling and the characterization of phenotypic-genotypic relationships.; [Results] A searchable database (RBGMdb) has been constructed with 932 published RB1 mutations. The spectrum of these mutations has been analyzed with the following results: 1) the retinoblastoma protein is frequently inactivated by deletions and nonsense mutations while missense mutations are the main inactivating event in most genetic diseases. 2) Near 40% of RB1 gene mutations are recurrent and gather in sixteen hot points, including twelve nonsense, two missense and three splicing mutations. The remainder mutations are scattered along RB1, being most frequent in exons 9, 10, 14, 17, 18, 20, and 23. 3) The analysis of RB1 mutations by country of origin of the patients identifies two groups in which the incidence of nonsense and splicing mutations show differences extremely significant...

‣ An integrated computational approach can classify VHL missense mutations according to risk of clear cell Renal carcinoma

Gossage, Lucy; Pires, Douglas E. V.; Olivera-Nappa, ?lvaro; Asenjo, Juan A.; Bycroft, Mark; Blundell, Tom L.; Eisen, Tim
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Article; published version
Português
Relevância na Pesquisa
48.363027%
This is the final published version, also available from the publisher website at at: http://hmg.oxfordjournals.org/content/early/2014/06/26/hmg.ddu321.long; Mutations?in?the?von?Hippel?Lindau?(VHL)?gene?are?pathogenic?in?VHL?disease,?congenital? polycythaemia?and?clear?cell?renal?carcinoma.?pVHL?forms?a?ternary?complex?with?Elongin?C? and?Elongin?B,?critical?for?pVHL?stability?and?function,?which?interacts?with?Cullin?2?and? RING?box?protein?1?to?target?Hypoxia?inducible?factor?for?polyubiquitination?and? proteasomal?degradation.?We?describe?a?comprehensive?database?of?missense?VHL? mutations?linked?to?experimental?and?clinical?data.?We?use?predictions?from?in?silico?tools?to? link?the?functional?effects?of?missense?VHL?mutations?to?phenotype.?The?risk?of?clear?cell? renal?carcinoma?in?VHL?disease?is?linked?to?the?degree?of?destabilisation?resulting?from? missense?mutations.?An?optimised?binary?classification?system?(Symphony),?which?integrates? predictions?from?five?in?silico?methods,?can?predict?the?risk?of?ccRCC?associated?with?VHL? missense?mutations?with?high?sensitivity?and?specificity.?We?use?Symphony?to?generate? predictions?for?risk?of?ccRCC?for?all?possible?VHL?missense?mutations?and?present?these? predictions...

‣ Comparison of predicted and actual consequences of missense mutations

Miosge, Lisa; Field, Matthew; Sontani, Yovina; Cho, Eun; Johnson, Simon; Palkova, Anna; Balakishnan, Bhavani; Liang, Rong; Zhang, Yafei; Lyon, Stephen; Beutler, Bruce; Whittle, Belinda; Bertram, Edward; Enders, Anselm; Goodnow, Christopher; Andrews, Thoma
Fonte: National Academy of Sciences (USA) Publicador: National Academy of Sciences (USA)
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
48.363027%
Each person's genome sequence has thousands of missense variants. Practical interpretation of their functional significance must rely on computational inferences in the absence of exhaustive experimental measurements. Here we analyzed the efficacy of these inferences in 33 de novo missense mutations revealed by sequencing in first-generation progeny of N-ethyl-N-nitrosourea- treated mice, involving 23 essential immune system genes. Poly- Phen2, SIFT, MutationAssessor, Panther, CADD, and Condel were used to predict each mutation's functional importance, whereas the actual effect was measured by breeding and testing homozygotes for the expected in vivo loss-of-function phenotype. Only 20% of mutations predicted to be deleterious by PolyPhen2 (and 15% by CADD) showed a discernible phenotype in individual homozygotes. Half of all possible missense mutations in the same 23 immune genes were predicted to be deleterious, and most of these appear to become subject to purifying selection because few persist between separate mouse substrains, rodents, or primates. Because defects in immune genes could be phenotypically masked in vivo by compensation and environment, we compared inferences by the same tools with the in vitro phenotype of all 2...