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‣ Atributos fenológicos, agronômicos e expressão gênica durante a frutificação do cafeeiro; Phenological and agronomic attributes and gene expression during the fruit development of the coffee tree

Gaspari-Pezzopane, Cristiana de
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 31/01/2008 Português
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As características relacionadas à frutificação do cafeeiro são altamente influenciadas pelo ambiente. Portanto, a associação de análises agronômicas, fenológicas e genômicas são necessárias para o entendimento desse processo. Esses estudos fazem parte do programa de melhoramento genético do café, com o objetivo de obter plantas com maior uniformidade de maturação, duração de ciclo e bebidas específicas. Nesse contexto, os objetivos desse trabalho foram estabelecer padrões agronômicos e fenológicos comparativos entre diferentes cultivares e safras de café, caracterizar genes diferencialmente expressos durante o desenvolvimento dos frutos de cafeeiro arábica e correlacionar genes diferencialmente expressos com atributos fenológicos e agronômicos. Os estudos foram realizados no Centro de Café do IAC em Campinas, SP. As cultivares de Coffea arabica utilizadas foram: Mundo Novo, Catuaí Vermelho, Icatu Vermelho, Obatã e Icatu Precoce, nas safras de 2004/2005 e 2005/2006. Os atributos fenológicos foram avaliados com base no desenvolvimento do ciclo fenológico e na porcentagem de frutos maduros na colheita. As avaliações agronômicas foram avaliadas baseadas nas características tecnológicas do produto como...

‣ Análise da expressão de proteínas envolvidas no controle do ciclo celular, apoptose, angiogênese, invasão e migração de células C6 in vitro e in vivo, após o tratamento com o ácido g-linolênico (GLA) e com um novo complexo dirutênico contendo Ibuprofeno (Ru-Ibp).; Analysis of the expression of proteins involved in cell cycle control, apoptosis, angiogenesis, migration and invasion of C6 rat glioma cells in vitro and in vivo, after treatment with g-linolenic acid (GLA) and a novel diruthenium containing ibuprofen complex (Ru-Ibp).

Benadiba, Marcel
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 12/11/2008 Português
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Os gliomas são tumores cerebrais intracraniais caracterizados pelo seu rápido crescimento e pela sua resistência à quimioterapia e radioterapia atuais. Assim, a procura por novos agentes terapêuticos com múltiplos mecanismos de ação têm identificado o ácido g-linolênico (GLA), antiinflamatórios não esteroidais (AINEs) e compostos contendo rutênio como possíveis candidatos. Dessa forma, a principal proposta deste projeto foi entender melhor o mecanismo de ação dessas drogas sobre as células C6 de glioma de rato. Foram analisadas proteínas envolvidas no controle do ciclo celular, apoptose, angiogênese, invasão e migração através de RT-PCR e Western Blotting após tratamento in vitro e in vivo. Alterações da expressão de ciclina D1, E2F-1, pRb, p27, p21, p16, p65, c-myc, ERK1/2, nm23 e b, MMP-2, Brevican GPI e Secretado, Tenascina-R, Tenascina-C, VEGF-A, Flt1, Flk1, Bax, PPARg, p53, COX-2, EP1, 2, 3 e 4, Ku70 e 80 foram encontradas. Em conclusão, o GLA e o complexo Rutênio-Ibuprofeno possuem múltiplos alvos que levam à inibição da proliferação celular.; Gliomas are intracranial tumors of cerebral origin characterized for its rapid growth and resistance to both conventional chemotherapy and radiotherapy. The search for new therapeutics agents with multiple mechanisms of action has identified g-linolenic acid (GLA)...

‣ Angioqueratoma como marcador para o diagnóstico de doença de Fabry; Angiokeratoma: a marker for the diagnosis of Fabry disease

Kelmann, Samantha Vernaschi
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 19/11/2013 Português
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INTRODUÇÃO: A Doença de Fabry (DF) é uma doença lisossomal de herança ligada ao X, causada pela deficiência da enzima alfa-galactosidase A (alfa-Gal A), que leva ao acúmulo gradual de glicoesfingolipídeos, em especial a globotriaosilceramida, nos lisossomos do endotélio vascular de tecidos cardíaco, renal, cerebral, olhos e pele. Os principais sintomas iniciais são: dores neuropáticas de extremidades, hipoidrose, dores abdominais recorrentes, angioqueratomas e córnea verticillata. As complicações, que aparecem a partir da terceira década de vida, incluem morte prematura por insuficiência renal, cardíaca e alterações cerebrovasculares. Angioqueratomas são uma das manifestações mais precoces da DF. OBJETIVOS: detectar os portadores da DF a partir de casos de angioqueratoma diagnosticados através de exames anatomopatológicos de biópsia cutânea; descrever o quadro clínico dos afetados e portadoras heterozigotas; realizar aconselhamento genético. MÉTODOS: Uma revisão sistemática de biópsias de pele de 2003 a 2012 foi feita em quatro hospitais universitários. Os pacientes foram convocados para anamnese, exame físico e coleta de história familial. A dosagem enzimática de alfa-Gal A por papel filtro e em leucócitos em homens e a análise molecular por PCR e sequenciamento do gene GLA em homens e mulheres foram realizados naqueles com suspeita de DF. RESULTADOS: Foram localizados 125 registros de angioqueratomas...

‣ Detecção de mutações em pacientes brasileiros com Doença de Fabry; Mutation detection of Brazilian patients with Fabry Disease

Pereira, Fernanda dos Santos
Fonte: Universidade Federal do Rio Grande do Sul Publicador: Universidade Federal do Rio Grande do Sul
Tipo: Dissertação Formato: application/pdf
Português
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A Doença de Fabry (DF) é uma desordem lisossomal ligada ao X causada pela deficiência da enzima alfa-galactosidase A, que provoca acúmulo de globotriaosilceramida (Gb3). O gene que codifica essa enzima está localizado no braço longo do cromossomo X, na região Xq21.33-Xq22, chama-se gene GLA e é composto por 12Kb divididos em sete exons. As manifestações clínicas incluem hipohidrose, angioqueratomas, acroparestesias e opacidade corneana. A progressão da doença leva a doenças vasculares secundárias envolvendo rins, coração e sistema nervoso central. A detecção de mulheres portadoras baseada somente na análise enzimática muitas vezes é inconclusiva. Portanto, a análise de mutações é uma ferramenta fundamental para diagnóstico e aconselhamento genético. A heterogeneidade da DF é alta e a maioria das mutações são privadas. Neste estudo nós descrevemos a análise molecular de seis pacientes homens pertencentes a quatro famílias diferentes e suas mães. O seqüenciamento automatizado dos sete exons do gene GLA revelou a presença de três mutações não conhecidas e uma descrita anteriormente em outra família brasileira. Aparentemente, ambas as famílias não são relacionadas, mas estudos futuros utilizando análise de haplótipos esclarecerão esta situação. Uma mãe era portadora...

‣ Genomic analysis of Brazilian patients with fabry disease

Pereira, Fernanda dos Santos; Jardim, Laura Bannach; Netto, Cristina Brinckmann Oliveira; Burin, Maira Graeff; Cecchin, Cláudia Rafaela; Giugliani, Roberto; Matte, Ursula da Silveira
Fonte: Universidade Federal do Rio Grande do Sul Publicador: Universidade Federal do Rio Grande do Sul
Tipo: Artigo de Revista Científica Formato: application/pdf
Português
Relevância na Pesquisa
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Fabry disease is an X-linked lysosomal disorder due to α-galactosidase A deficiency that causes storage of globotriaosylceramide. The gene coding for this lysosomal enzyme is located on the long arm of the X chromosome, in region Xq21.33-Xq22. Disease progression leads to vascular disease secondary to involvement of kidney, heart and the central nervous system. Detection of female carriers based solely on enzyme assays is often inconclusive. Therefore, mutation analysis is a valuable tool for diagnosis and genetic counseling. Many mutations of the α-galactosidase A gene have been reported with high genetic heterogeneity, being most mutations private found in only one family. The disease is panethnic, and estimates of incidence range from about 1 in 40,000 to 60,000 males. Our objective was to describe the analysis of 6 male and 7 female individuals belonging to 4 different Fabry disease families by automated sequencing of the seven exons of the α-galactosidase gene. Sequencing was performed using PCR fragments for each exon amplified from DNA extracted from peripheral blood. Three known mutations and one previously described in another Brazilian family were detected. Of 7 female relatives studied, 4 were carriers. Although the present study confirms the heterogeneity of mutations in Fabry disease...

‣ Mutations of the GLA gene in young patients with stroke: the PORTYSTROKE study--screening genetic conditions in Portuguese young stroke patients

Baptista, MV; Ferreira, S; Pinho-e-Melo, T; Carvalho, M; Cruz, VT; Carmona, C; Silva, FA; Tuna, A; Rodrigues, M; Ferreira, C; Pinto, AA; Leitão, A; Gabriel, JP; Calado, S; Oliveira, JP; Ferro, JM
Fonte: Repositório Comum de Portugal Publicador: Repositório Comum de Portugal
Tipo: Artigo de Revista Científica
Publicado em //2010 Português
Relevância na Pesquisa
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BACKGROUND AND PURPOSE: Fabry disease is an X-linked monogenic disorder caused by mutations in the GLA gene. Recent data suggest that stroke in young adults may be associated with Fabry disease. We aimed to ascertain the prevalence of this disorder among young adult patients with stroke in Portugal by GLA genotyping. METHODS: During 1 year, all patients aged 18 to 55 years with first-ever stroke, who were admitted into any of 12 neurology hospital departments in Portugal, were prospectively enrolled (n=625). Ischemic stroke was classified according to Trial of Org 10172 in Acute Stroke Treatment criteria. Alpha-galactosidase activity was further assayed in all patients with GLA mutations. RESULTS: Four hundred ninety-three patients (mean age, 45.4 years; 61% male) underwent genetic analyses: 364 with ischemic stroke, 89 with intracerebral hemorrhage, 26 with subarachnoid hemorrhage, and 14 with cerebral venous thrombosis. Twelve patients had missense GLA mutations: 9 with ischemic stroke (p.R118C: n=4; p.D313Y: n=5), including 5 patients with an identified cause of stroke (cardiac embolism: n=2; small vessel disease: n=2; other cause: n=1), 2 with intracerebral hemorrhage (p.R118C: n=1; p.D313Y: n=1), and one with cerebral venous thrombosis (p.R118C: n=1). Leukocyte alpha-galactosidase activity was subnormal in the hemizygous males and subnormal or low-normal in the heterozygous females. Estimated prevalence of missense GLA mutations was 2.4% (95% CI...

‣ Mutations of the GLA gene in young patients with stroke: the PORTYSTROKE study-screening genetic conditions in Portuguese young stroke patients

Baptista, V; Ferreira, S; Pinho-e-Melo, T; Carvalho, M; Cruz, V; Carmona, C; Silva, F; Tuna, A; Rodrigues, M; Ferreira, C; Pinto, A; Leitão, A; Gabriel, J; Calado, S; Oliveira, J; Ferro, J
Fonte: American Heart Association Publicador: American Heart Association
Tipo: Artigo de Revista Científica
Publicado em //2010 Português
Relevância na Pesquisa
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BACKGROUND AND PURPOSE: Fabry disease is an X-linked monogenic disorder caused by mutations in the GLA gene. Recent data suggest that stroke in young adults may be associated with Fabry disease. We aimed to ascertain the prevalence of this disorder among young adult patients with stroke in Portugal by GLA genotyping. METHODS: During 1 year, all patients aged 18 to 55 years with first-ever stroke, who were admitted into any of 12 neurology hospital departments in Portugal, were prospectively enrolled (n=625). Ischemic stroke was classified according to Trial of Org 10172 in Acute Stroke Treatment criteria. Alpha-galactosidase activity was further assayed in all patients with GLA mutations. RESULTS: Four hundred ninety-three patients (mean age, 45.4 years; 61% male) underwent genetic analyses: 364 with ischemic stroke, 89 with intracerebral hemorrhage, 26 with subarachnoid hemorrhage, and 14 with cerebral venous thrombosis. Twelve patients had missense GLA mutations: 9 with ischemic stroke (p.R118C: n=4; p.D313Y: n=5), including 5 patients with an identified cause of stroke (cardiac embolism: n=2; small vessel disease: n=2; other cause: n=1), 2 with intracerebral hemorrhage (p.R118C: n=1; p.D313Y: n=1), and one with cerebral venous thrombosis (p.R118C: n=1). Leukocyte alpha-galactosidase activity was subnormal in the hemizygous males and subnormal or low-normal in the heterozygous females. Estimated prevalence of missense GLA mutations was 2.4% (95% CI...

‣ Gla-rich protein (GRP), a new vitamin K-dependent protein identified from sturgeon cartilage and highly conserved in vertebrates

Viegas, C. S. B.; Simes, Dina; Laizé, Vincent; Williamson, M. K.; Price, P. A.; Cancela, Leonor
Fonte: The American Society for Biochemistry and Molecular Biology Publicador: The American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em 26/12/2008 Português
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We report the isolation of a novel vitamin K-dependent protein from the calcified cartilage of Adriatic sturgeon (Acipenser nacarii). This 10.2-kDa secreted protein contains 16 -carboxyglutamic acid (Gla) residues in its 74-residue sequence, the highest Gla percent of any known protein, and we have therefore termed it Gla-rich protein (GRP). GRP has a high charge density (36 negative 16 positive 20 net negative) yet is insoluble at neutral pH. GRP has orthologs in all taxonomic groups of vertebrates, and a paralog (GRP2) in bony fish; no GRP homolog was found in invertebrates. There is no significant sequence homology between GRP and the Gla-containing region of any presently known vitamin K-dependent protein. Forty-seven GRP sequences were obtained by a combination of cDNA cloning and comparative genomics: all 47 have a propeptide that contains a -carboxylase recognition site and a mature protein with 14 highly conserved Glu residues, each of them being carboxylated in sturgeon. The protein sequence of GRP is also highly conserved, with 78% identity between sturgeon and human GRP. Analysis of the corresponding gene structures suggests a highly constrained organization, particularly for exon 4, which encodes the core Gla domain. GRP mRNA is found in virtually all rat and sturgeon tissues examined...

‣ Genomic analysis of Brazilian patients with Fabry disease

Pereira,F.S.; Jardim,L.B.; Netto,C.B.; Burin,M.G.; Cecchin,C.; Giugliani,R.; Matte,U.S.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/12/2007 Português
Relevância na Pesquisa
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Fabry disease is an X-linked lysosomal disorder due to a-galactosidase A deficiency that causes storage of globotriaosylceramide. The gene coding for this lysosomal enzyme is located on the long arm of the X chromosome, in region Xq21.33-Xq22. Disease progression leads to vascular disease secondary to involvement of kidney, heart and the central nervous system. Detection of female carriers based solely on enzyme assays is often inconclusive. Therefore, mutation analysis is a valuable tool for diagnosis and genetic counseling. Many mutations of the a-galactosidase A gene have been reported with high genetic heterogeneity, being most mutations private found in only one family. The disease is panethnic, and estimates of incidence range from about 1 in 40,000 to 60,000 males. Our objective was to describe the analysis of 6 male and 7 female individuals belonging to 4 different Fabry disease families by automated sequencing of the seven exons of the a-galactosidase gene. Sequencing was performed using PCR fragments for each exon amplified from DNA extracted from peripheral blood. Three known mutations and one previously described in another Brazilian family were detected. Of 7 female relatives studied, 4 were carriers. Although the present study confirms the heterogeneity of mutations in Fabry disease...

‣ Gla-rich Protein (GRP), A New Vitamin K-dependent Protein Identified from Sturgeon Cartilage and Highly Conserved in Vertebrates*S⃞

Viegas, Carla S. B.; Simes, Dina C.; Laizé, Vincent; Williamson, Matthew K.; Price, Paul A.; Cancela, M. Leonor
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em 26/12/2008 Português
Relevância na Pesquisa
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We report the isolation of a novel vitamin K-dependent protein from the calcified cartilage of Adriatic sturgeon (Acipenser nacarii). This 10.2-kDa secreted protein contains 16 γ-carboxyglutamic acid (Gla) residues in its 74-residue sequence, the highest Gla percent of any known protein, and we have therefore termed it Gla-rich protein (GRP). GRP has a high charge density (36 negative + 16 positive = 20 net negative) yet is insoluble at neutral pH. GRP has orthologs in all taxonomic groups of vertebrates, and a paralog (GRP2) in bony fish; no GRP homolog was found in invertebrates. There is no significant sequence homology between GRP and the Gla-containing region of any presently known vitamin K-dependent protein. Forty-seven GRP sequences were obtained by a combination of cDNA cloning and comparative genomics: all 47 have a propeptide that contains a γ-carboxylase recognition site and a mature protein with 14 highly conserved Glu residues, each of them being γ-carboxylated in sturgeon. The protein sequence of GRP is also highly conserved, with 78% identity between sturgeon and human GRP. Analysis of the corresponding gene structures suggests a highly constrained organization, particularly for exon 4, which encodes the core Gla domain. GRP mRNA is found in virtually all rat and sturgeon tissues examined...

‣ Effects of a chemical chaperone on genetic mutations in α-galactosidase A in Korean patients with Fabry disease

Park, Jung-Young; Kim, Gu-Hwan; Kim, Sung-Su; Ko, Jung Min; Lee, Jin-Joo; Yoo, Han-Wook
Fonte: Korean Society of Medical Biochemistry and Molecular Biology Publicador: Korean Society of Medical Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Português
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Fabry disease is an X-linked inborn error of glycosphingolipid catabolism that results from mutations in the gene encoding the α-galactosidase A (GLA) enzyme. We have identified 15 distinct mutations in the GLA gene in 13 unrelated patients with classic Fabry disease and 2 unrelated patients with atypical Fabry disease. Two of the identified mutations were novel (i.e., the D231G missense mutation and the L268delfsX1 deletion mutation). This study evaluated the effects of the chemical chaperones 1-deoxygalactonojirimycin (DGJ) on the function of GLA in vitro, in cells containing missense mutations in the GLA gene. Nine missense and a nonsense mutations, including one novel mutation were cloned into mammalian expression vectors. After transient expression in COS-7 cells, GLA enzyme activity and protein expression were analyzed using fluorescence spectrophotometry and Western blot analysis, respectively. DGJ enhanced GLA enzyme activity in the M42V, I91T, R112C and F113L mutants. Interestingly, the I91T and F113L mutations are associated with the atypical form of Fabry disease. However, DGJ treatment did not have any significant effect on the GLA enzyme activity and protein expression of other mutants, including C142W, D231G, D266N, and S297F. Of note...

‣ FUNCTIONAL STUDIES OF NEW GLA GENE MUTATIONS LEADING TO CONFORMATIONAL FABRY DISEASE

Filoni, C.; Caciotti, A.; Carraresi, L.; Cavicchi, C.; Parini, R.; Antuzzi, D.; Zampetti, A.; Feriozzi, S.; Poisetti, P.; Garman, S.C.; Guerrini, R.; Zammarchi, E.; Donati, M.A.; Morrone, A.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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Fabry Disease (FD) is an X-linked multisystemic lysosomal disorder caused by mutations of α-galactosidase (GLA) gene. Only a few of the 450 genetic lesions identified so far have been characterised by in vitro expression studies. Thus the significance of newly identified GLA nucleotide variants sin FD patients which lead to α-galactosidase (GAL-A) amino acid substitutions or intronic changes can be uncertain.

‣ Multifocal White Matter Lesions Associated with the D313Y Mutation of the α-Galactosidase A Gene

Lenders, Malte; Duning, Thomas; Schelleckes, Michael; Schmitz, Boris; Stander, Sonja; Rolfs, Arndt; Brand, Stefan-Martin; Brand, Eva
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 05/02/2013 Português
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White matter lesions (WML) are clinically relevant since they are associated with strokes, cognitive decline, depression, or epilepsy, but the underlying etiology in young adults without classical risk factors still remains elusive. Our aim was to elucidate the possible clinical diagnosis and mechanisms leading to WML in patients carrying the D313Y mutation in the α-galactosidase A (GLA) gene, a mutation that was formerly described as nonpathogenic. Pathogenic GLA mutations cause Fabry disease, a vascular endothelial glycosphingolipid storage disease typically presenting with a symptom complex of renal, cardiac, and cerebrovascular manifestations. We performed in-depths clinical, biochemical and genetic examinations as well as advanced magnetic resonance imaging analyses in a pedigree with the genetically determined GLA mutation D313Y. We detected exclusive neurologic manifestations of the central nervous system of the “pseudo”-deficient D313Y mutation leading to manifest WML in 7 affected adult family members. Furthermore, two family members that do not carry the mutation showed no WML. The D313Y mutation resulted in a normal GLA enzyme activity in leukocytes and severely decreased activities in plasma. In conclusion, our results provide evidence that GLA D313Y is potentially involved in neural damage with significant WML...

‣ Development of a Highly Sensitive Immuno-PCR Assay for the Measurement of α-Galactosidase A Protein Levels in Serum and Plasma

Nakano, Sachie; Morizane, Yoshihito; Makisaka, Noriko; Suzuki, Toshihiro; Togawa, Tadayasu; Tsukimura, Takahiro; Kawashima, Ikuo; Sakuraba, Hitoshi; Shibasaki, Futoshi
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 13/11/2013 Português
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Fabry disease is an X-linked genetic disorder caused by defects in the α-galactosidase A (GLA) gene, and heterogeneous mutations lead to quantitative and/or qualitative defects in GLA protein in male patients with Fabry disease. Random X-chromosomal inactivation modifies the clinical and biochemical features of female patients with Fabry disease. Functional polymorphisms have been frequently reported in recent times, and these increase the difficulty of understanding the pathogenetic basis of the disease. To date, GLA protein level has been measured using an enzyme-linked immunosorbent assay (ELISA). However, ELISA is not highly sensitive due to the high background noise. In this paper, we introduce a novel application of the immuno-polymerase chain reaction (PCR) method (termed Multiple Simultaneous Tag [MUSTag]) for measurement of the GLA protein level in blood samples. We compared the sensitivities of the MUSTag method with plates or magnetic beads with those of ELISA for recombinant human GLA and found that the apparent maximal sensitivity was higher for the former than for the latter. We then measured the GLA concentrations in serum and plasma from male patients with classic Fabry disease (Male Fabry), females with Fabry disease (Female Fabry)...

‣ Renal variant of Fabry disease with sporadic GLA gene mutation: role of early renal biopsy

Al-Salam, Suhail; Chaaban, Ahmed; Al-Jasmi, Fatima; Amann, Kerstin; Abouchacra, Samra
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Publicado em /10/2012 Português
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Fabry disease (FD) is a rare, X-linked inherited disease of glycosphingolipid metabolism due to deficiency of lysosomal α-galactosidase A activity. Scarce activity of lysosomal α-galactosidase A results in progressive accumulation of globotriaosylceramide (Gb3) within lysosomes, believed to trigger a flow of cellular changes that lead to the clinical manifestation of the disease. We present a 23-year-old male with renal variant of FD who was born from non-affected parents, which, to the best of our knowledge, has not been reported in the literature so far. In conclusion, FD can occur due to sporadic GLA gene mutation. Pure renal involvement might be associated with progressive disease which leads to end-stage renal disease within a short period. Physicians should have a high index of suspicion for FD especially in male cases with unexplained renal failure that are slowly progressive in nature, even in the absence of a clear hereditary component. Early renal biopsy is recommended in any progressive renal impairment.

‣ The Modulatory Effects of the Polymorphisms in GLA 5′-Untranslated Region Upon Gene Expression Are Cell-Type Specific

Ferreira, Susana; Reguenga, Carlos; Oliveira, João Paulo
Fonte: Springer Berlin Heidelberg Publicador: Springer Berlin Heidelberg
Tipo: Artigo de Revista Científica
Publicado em 13/03/2015 Português
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Lysosomal α-galactosidase A (αGal) is the enzyme deficient in Fabry disease (FD). The 5′-untranslated region (5′UTR) of the αGal gene (GLA) shows a remarkable degree of variation with three common single nucleotide polymorphisms at nucleotide positions c.-30G>A, c.-12G>A and c.-10C>T. We have recently identified in young Portuguese stroke patients a fourth polymorphism, at c.-44C>T, co-segregating in cis with the c.-12A allele. In vivo, the c.-30A allele is associated with higher enzyme activity in plasma, whereas c.-10T is associated with moderately decreased enzyme activity in leucocytes. Limited data suggest that c.-44T might be associated with increased plasma αGal activity. We have used a luciferase reporter system to experimentally assess the relative modulatory effects on gene expression of the different GLA 5′UTR polymorphisms, as compared to the wild-type sequence, in four different human cell lines. Group-wise, the relative luciferase expression patterns of the various GLA variant isoforms differed significantly in all four cell lines, as evaluated by non-parametric statistics, and were cell-type specific. Some of the post hoc pairwise statistical comparisons were also significant, but the observed effects of the GLA 5′UTR polymorphisms upon the luciferase transcriptional activity in vitro did not consistently replicate the in vivo observations.

‣ Risk of death in heart disease is associated with elevated urinary globotriaosylceramide

Schiffmann, R.; Forni, S.; Swift, C.; Brignol, N.; Wu, X.; Lockhart, D.J.; Blankenship, D.; Wang, X.; Grayburn, P.A.; Taylor, M.R.G.; Lowes, B.D.; Fuller, M.; Benjamin, E.R.; Sweetman, L.
Fonte: American Heart Association Publicador: American Heart Association
Tipo: Artigo de Revista Científica
Publicado em //2014 Português
Relevância na Pesquisa
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BACKGROUND: Elevated urinary globotriaosylceramide (Gb3) has been considered a hallmark of Fabry disease, an X-linked lysosomal disorder that is a risk factor for most types of heart disease. METHODS AND RESULTS: We screened 1421 consecutive patients with common forms of heart disease for Fabry disease by measuring urinary Gb3 in whole urine using tandem mass spectrometry, α-galactosidase A activity in dried blood spots, and we looked for GLA mutations by parallel sequencing of the whole gene (exons and introns) in pooled genomic DNA samples followed by Sanger sequencing verification. GLA variants were found in 13 patients. In the 1408 patients without GLA mutations, urinary Gb3 levels were significantly higher in heart disease patients compared to 116 apparently healthy controls (median difference=10.0 ng/mL and P<0.001). Urinary lipid profiling showed that levels of 5 other lipids significantly distinguished between urine of patients with Fabry disease (n=7) and heart disease patients with elevated urinary Gb3 (n=6). Sphingomyelin and Gb3 levels were abnormal in the left ventricular wall of patients with ischemic heart failure. Elevated levels of urinary Gb3 were independently associated with increased risk of death in the average follow-up of 17 months (hazard ratio=1.59 for increase in Gb3 of 200...

‣ Increased glycolipid storage produced by the inheritance of a complex intronic haplotype in the α-galactosidase A (GLA) gene

Gervas Arruga, Javier; Cebolla, Jorge Javier; Irún Irún, Pilar; Pérez López, Javier; Plaza Mas, Luis; Roche Bueno, José C.; Capablo Liesa, José L.; Rodríguez Rey, José Carlos; Pocoví Mieras, Miguel; Giraldo Castellano, Pilar
Fonte: BioMed Central Publicador: BioMed Central
Tipo: info:eu-repo/semantics/article; publishedVersion
Português
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BACKGROUND: Accumulation of galactosphingolipids is a general characteristic of Fabry disease, a lysosomal storage disorder caused by the deficient activity of α-galactosidase A encoded by the GLA gene. Although many polymorphic GLA haplotypes have been described, it is still unclear whether some of these variants are causative of disease symptoms. We report the study of an inheritance of a complex intronic haplotype (CIH) (c.-10C > T, c.369 + 990C > A, c.370-81_370-77delCAGCC, c.640-16A > G, c.1000-22C > T) within the GLA gene associated with Fabry-like symptoms and galactosphingolipid accumulation. We analysed α-Gal A activity in plasma, leukocytes and skin fibroblasts in patients, and measured accumulation of galactosphingolipids by enzymatic methods and immunofluorescence techniques. Additionally, we evaluated GLA expression using quantitative PCR, EMSA, and cDNA cloning. RESULTS: CIH carriers had an altered GLA expression pattern, although most of the carriers had high residual enzyme activity in plasma, leukocytes and in skin fibroblasts. Nonetheless, CIH carriers had significant galactosphingolipid accumulation in fibroblasts in comparison with controls, and also glycolipid deposits in renal tubules and glomeruli. EMSA assays indicated that the c.-10C > T variant in the promoter affected a nuclear protein binding site. CONCLUSIONS: Thus...

‣ New mutations in the GLA gene in Brazilian families with Fabry disease

Turaca, Lauro Thiago; Pessoa, Juliana Gilbert; Motta, Fabiana Louise; Munoz Rojas, Maria Veronica; Mueller, Karen Barbosa; Lourenço, Charles Marques; Marques Júnior, Wilson; D'Almeida, Vania; Martins, Ana Maria; Pesquero, Joao Bosco
Fonte: NATURE PUBLISHING GROUP; NEW YORK Publicador: NATURE PUBLISHING GROUP; NEW YORK
Tipo: Artigo de Revista Científica
Português
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Fabry disease (FD) is an X-linked inborn error of glycosphingolipid catabolism that results from mutations in the alpha-galactosidase A (GLA) gene. Evaluating the enzymatic activity in male individuals usually performs the diagnosis of the disease, but in female carriers the diagnosis based only on enzyme assays is often inconclusive. In this work, we analyzed 568 individuals from 102 families with suspect of FD. Overall, 51 families presented 38 alterations in the GLA gene, among which 19 were not previously reported in literature. The alterations included 17 missense mutations, 7 nonsense mutations, 7 deletions, 6 insertions and 1 in the splice site. Six alterations (R112C, R118C, R220X, R227X, R342Q and R356W) occurred at CpG dinucleotides. Five mutations not previously described in the literature (A156D, K237X, A292V, I317S, c.1177_1178insG) were correlated with low GLA enzyme activity and with prediction of molecular damages. From the 13 deletions and insertions, 7 occurred in exons 6 or 7 (54%) and 11 led to the formation of a stop codon. The present study highlights the detection of new genomic alterations in the GLA gene in the Brazilian population, facilitating the selection of patients for recombinant enzyme-replacement trials and offering the possibility to perform prenatal diagnosis. Journal of Human Genetics (2012) 57...

‣ Cloning of the Bone Gla Protein gene from the teleost fish Sparus aurata (gilthead seabream). Molecular organization, developmental appearance and evolutionary implications

Pinto, Idílio Jorge Matias Pereira
Fonte: Universidade do Algarve Publicador: Universidade do Algarve
Tipo: Tese de Doutorado
Publicado em //2001 Português
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Tese de Doutoramento, Biologia Molecular, Faculdade de Ciências do Mar e do Ambiente, Universidade do Algarve, 2001; A proteína Bone Gla (BGP, osteocalcina) é uma pequena proteína dependenteda. vitamina K que apresenta resíduos de ácido glutâmico y-carboxilados. A presença destes aminoácidos modificados permite à proteína ligar-se a iões Ca2+ e interagir com os cristais de hidroxiapatite dos tecidos mineralizados.; The Bone Gla Protein (BGP, osleocalcin) is a small vilamin K-dependent protein which presenls Ihree y-carboxylated glutamic acid residues. lhe prcsence oí these modified amino acids enables the protein to bind to Ca2+ ions and to interact with hydroxyapatite ciystals of mineralized tissues.