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1.
Sci Adv ; 5(5): eaau8857, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31123703

RESUMO

Optimal autophagic activity is crucial to maintain muscle integrity, with either reduced or excessive levels leading to specific myopathies. LGMD2H is a muscle dystrophy caused by mutations in the ubiquitin ligase TRIM32, whose function in muscles remains not fully understood. Here, we show that TRIM32 is required for the induction of muscle autophagy in atrophic conditions using both in vitro and in vivo mouse models. Trim32 inhibition results in a defective autophagy response to muscle atrophy, associated with increased ROS and MuRF1 levels. The proautophagic function of TRIM32 relies on its ability to bind the autophagy proteins AMBRA1 and ULK1 and stimulate ULK1 activity via unanchored K63-linked polyubiquitin. LGMD2H-causative mutations impair TRIM32's ability to bind ULK1 and induce autophagy. Collectively, our study revealed a role for TRIM32 in the regulation of muscle autophagy in response to atrophic stimuli, uncovering a previously unidentified mechanism by which ubiquitin ligases activate autophagy regulators.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Autofagia , Ubiquitina-Proteína Ligases/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular , Transdiferenciação Celular , Humanos , Lisina/metabolismo , Camundongos , Camundongos Knockout , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Distrofia Muscular do Cíngulo dos Membros/patologia , Mioblastos/citologia , Mioblastos/metabolismo , Ligação Proteica , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
2.
Clin Genet ; 93(6): 1254-1256, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29368331

RESUMO

Identification of a novel compound heterozygous of GNB5 in a patient with intellectual developmental disorder with cardiac arrhytmia (IDDCA), from non-consaguineous family. Three-dimensional modelling and in silico predictions suggest that GNB5 variants are causative of the phenotype, extending the number of IDDCA patients so far identified.


Assuntos
Arritmias Cardíacas/complicações , Arritmias Cardíacas/genética , Subunidades beta da Proteína de Ligação ao GTP/genética , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Mutação/genética , Sequência de Aminoácidos , Pré-Escolar , Evolução Molecular , Subunidades beta da Proteína de Ligação ao GTP/química , Heterozigoto , Humanos , Lactente , Masculino , Linhagem
3.
Genet Couns ; 26(3): 327-32, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26625664

RESUMO

Myoclonicastatic epilepsy (MAE) is a rare form of symptomatic generalized epilepsy of uncertain etiology. To search the possible genetic basis of the disorder, here we investigate a 15 year-old patient with MAE, who is the only person presenting epilepsy in the family. High resolution array-CGH analysis was conducted on DNA extracted from peripheral blood of the patient and the parents. The copy number variant(s) (CNVs) identified were further confirmed by Fluorescent In Situ Hybridization (FISH). The array-CGH identified a de novo microduplication of about 778 Kb in the chromosome region 4q21.22-q21.23, involving 11 genes. This is the first report of a de novo CNV in MAE. The genes involved in the duplication are potential candidates that can be investigated in the future to determine their exact role in the etiopathogenesis of the disorder. However, we suggest performing microarray chromosomal analysis in patients with MAE, since rare de novo CNVs could be identified, and this is known to affect the diagnostic process and recurrence risk assessment.


Assuntos
Epilepsias Mioclônicas/genética , Trissomia/genética , Adolescente , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 4/genética , Humanos , Masculino
4.
Br J Cancer ; 111(12): 2361-8, 2014 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-25393370

RESUMO

BACKGROUND: Gender-associated epigenetic alterations are poorly investigated in male and female familial breast cancer (fBC). MicroRNAs may contribute to the different biology in men and women particularly related to RASSF1A pathways. METHODS: Microarray technology was used to evaluate miRNA profile in 24 male and 43 female fBC. Key results were validated using RT-qPCR in an external samples set. In vitro studies were carried out to verify microRNA-target gene interaction. RESULTS: Pathway enrichment analysis with the 287 differentially expressed microRNAs revealed several signalling pathways differently regulated in male and female cases. Because we previously hypothesised a peculiar involvement of RASSF1A in male fBC pathogenesis, we focussed on the MAPK and the Hippo signalling pathways that are regulated by RASSF1A. Male miR-152 and miR-497 upregulation and RASSF1A and NORE1A interacting gene downregulation were observed, confirming a possible indirect interaction between miRNAs and the two genes. CONCLUSIONS: For the first time, a different microRNA expression pattern in male and female fBC has been shown. Moreover, the importance of RASSF1A pathway in male fBC carcinogenesis has been confirmed, highlighting a possible role for miR-152 and miR-497 in controlling MAPK and Hippo signalling pathways, regulated by RASSF1A.


Assuntos
Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Análise em Microsséries , Transdução de Sinais
5.
Cell Death Dis ; 5: e1076, 2014 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-24556691

RESUMO

Understanding of BRCA1/2 interaction with the base excision repair (BER) pathway could improve therapy based on 'synthetic lethality', whose effectiveness is based on homologous recombination deficiency in cells lacking functional BRCA genes. However, poly (ADP-ribose) polymerase (PARP) inhibitors failed in some patients and for this reason we explored BER key enzyme expression. In this study, the expression of BER enzymes (redox factor 1/apurinic-apyrimidinic endonuclease 1 (REF1/APEX1), NTH endonuclease III-like 1 (NTHL1), 8-oxoguanine DNA glycosylase (OGG1), PARP1) and of the scaffold protein XRCC1 (X-ray repair complementing defective repair in Chinese hamster cells 1) were investigated in familial (BRCA-related and not) and sporadic breast cancer cases. Furthermore, miR17 expression was measured because of its role in the epigenetic regulation of BRCA1. Gene expression was evaluated in BRCA1-mutated cell lines, SUM149PT and SUM1315MO2, and in a BRCA1-proficient triple-negative MDA-MB-231 cell line. A cohort of 27 familial and 16 sporadic breast cancer patients was then examined to confirm results obtained from the cell line model. APEX1/REF1 was found to be upregulated in familial BRCA-wild-type and sporadic cases, indicating this enzyme as a potential therapeutic target. Furthermore, XRCC1 was overexpressed in BRCAX patients; consequently, we suggest to test the effectiveness of inhibitors targeting two different BER components in preclinical studies. XRCC1, which is also involved in the non-homologous end-joining pathway, was found to be downregulated in BRCA2-related patients concurrently with no change in PARP1 expression. Interestingly, no difference in PARP1 and miR17 expression was found in BRCA-related and sporadic breast cancer cases. PARP1 and miR17 could therefore be further investigated as molecular biomarkers of 'BRCAness' phenotype, indicating patients which could really benefit from PARP inhibitor therapies.


Assuntos
Biomarcadores Tumorais/metabolismo , Reparo do DNA , MicroRNAs/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto , Idoso , Animais , Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Biologia Computacional , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , Reparo do DNA/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Bases de Dados Genéticas , Desoxirribonuclease (Dímero de Pirimidina)/genética , Desoxirribonuclease (Dímero de Pirimidina)/metabolismo , Feminino , Predisposição Genética para Doença , Células HEK293 , Humanos , Camundongos , Pessoa de Meia-Idade , Mutação , Fenótipo , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Transfecção , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Proteína 1 Complementadora Cruzada de Reparo de Raio-X
6.
Mol Syndromol ; 4(3): 143-7, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23653586

RESUMO

Williams-Beuren syndrome is a rare multisystem neurodevelopmental disorder caused by a 1.55-1.84-Mb hemizygous deletion on chromosome 7q11.23. The classical phenotype consists of characteristic facial features, supravalvular aortic stenosis, intellectual disability, overfriendliness, and visuospatial impairment. So far, 26-28 genes have been shown to contribute to the multisystem phenotype associated with Williams-Beuren syndrome. Among them, haploinsufficiency of the ELN gene has been shown to cause the cardiovascular anomalies. Identification of patients with atypical deletions has provided valuable information for genotype-phenotype correlation, in which other genes such as LIMK1,CLIP2, GTF2IRD1, or GTF2I have been correlated with specific cognitive profiles or craniofacial features. Here, we report the clinical and molecular characteristics of a patient with an atypical deletion that does not include the GTF2I gene and only partially includes the GTF2IRD1 gene.

7.
Mol Syndromol ; 4(3): 152-6, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23653588

RESUMO

Kabuki syndrome (also known as Niikawa-Kuroki syndrome) is a rare autosomal disorder, characterized by an unusual face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, mental retardation, and immunological defects. Point mutations and large intragenic deletions and duplications of the mixed lineage leukemia 2 (MLL2) and exons deletions of lysine demethylase 6A (-KDM6A) genes have been identified as its underlying causes. We report on the first description of a Moroccan Kabuki syndrome patient with typical facial features, developmental delay, finger pads, and other anomalies carrying a novel splice site mutation in the MLL2 gene that produces a truncated and likely pathogenetic form of MLL2 protein.

10.
J Med Genet ; 43(3): 266-73, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15994861

RESUMO

OBJECTIVE: To develop and compare two new technologies for diagnosing a contiguous gene syndrome, the Williams-Beuren syndrome (WBS). METHODS: The first proposed method, named paralogous sequence quantification (PSQ), is based on the use of paralogous sequences located on different chromosomes and quantification of specific mismatches present at these loci using pyrosequencing technology. The second exploits quantitative real time polymerase chain reaction (QPCR) to assess the relative quantity of an analysed locus. RESULTS: A correct and unambiguous diagnosis was obtained for 100% of the analysed samples with either technique (n = 165 and n = 155, respectively). These methods allowed the identification of two patients with atypical deletions in a cohort of 182 WBS patients. Both patients presented with mild facial anomalies, mild mental retardation with impaired visuospatial cognition, supravalvar aortic stenosis, and normal growth indices. These observations are consistent with the involvement of GTF2IRD1 or GTF2I in some of the WBS facial features. CONCLUSIONS: Both PSQ and QPCR are robust, easy to interpret, and simple to set up. They represent a competitive alternative for the diagnosis of segmental aneuploidies in clinical laboratories. They have advantages over fluorescence in situ hybridisation or microsatellites/SNP genotyping for detecting short segmental aneuploidies as the former is costly and labour intensive while the latter depends on the informativeness of the polymorphisms.


Assuntos
Aneuploidia , Síndrome de Williams/genética , Diagnóstico Diferencial , Humanos , Hibridização in Situ Fluorescente , Reação em Cadeia da Polimerase , Polimorfismo Genético , Deleção de Sequência , Síndrome de Williams/classificação , Síndrome de Williams/diagnóstico
11.
J Med Genet ; 41(12): 908-15, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15591276

RESUMO

BACKGROUND: Chromosomal aneuploidies are a common cause of congenital disorders associated with cognitive impairment and multiple dysmorphic features. Pre-natal diagnosis of aneuploidies is most commonly performed by the karyotyping of fetal cells obtained by amniocentesis or chorionic villus sampling, but this method is labour intensive and requires about 14 days to complete. METHODS: We have developed a PCR based method for the detection of targeted chromosome number abnormalities termed paralogous sequence quantification (PSQ), based on the use of paralogous genes. Paralogous sequences have a high degree of sequence identity, but accumulate nucleotide substitutions in a locus specific manner. These sequence differences, which we term paralogous sequence mismatches (PSMs), can be quantified using pyrosequencing technology, to estimate the relative dosage between different chromosomes. We designed 10 assays for the detection of trisomies of chromosomes 13, 18, and 21 and sex chromosome aneuploidies. RESULTS: We evaluated the performance of this method on 175 DNAs, highly enriched for abnormal samples. A correct and unambiguous diagnosis was given for 119 out of 120 aneuploid samples as well as for all the controls. One sample which gave an intermediate value for the chromosome 13 assays could not be diagnosed. CONCLUSIONS: Our data suggests that PSQ is a robust, easy to interpret, and easy to set up method for the diagnosis of common aneuploidies, and can be performed in less than 48 h, representing a competitive alternative for widespread use in diagnostic laboratories.


Assuntos
Aneuploidia , Testes Genéticos/métodos , Reação em Cadeia da Polimerase/métodos , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 18 , Cromossomos Humanos Par 21 , Cromossomos Humanos X , Cromossomos Humanos Y , DNA , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Homologia de Sequência do Ácido Nucleico
12.
Oncogene ; 20(47): 6881-90, 2001 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-11687967

RESUMO

PRUNE, the human homologue of the Drosophila gene, is located in 1q21.3, a region highly amplified in human sarcomas, malignant tumours of mesenchymal origin. Prune protein interacts with the metastasis suppressor nm23-H1, but shows impaired affinity towards the nm23-H1 S120G mutant associated with advanced neuroblastoma. Based on these observations, we previously suggested that prune may act as a negative regulator of nm23-H1 activity. We found amplification of PRUNE in aggressive sarcoma subtypes, such as leiomyosarcomas and malignant fibrous histiocytomas (MFH) as well as in the less malignant liposarcomas. PRUNE amplification was generally accompanied by high mRNA and moderate to high protein levels. The sarcoma samples expressed nm23-H1 mostly at low or moderate levels, whereas mRNA and protein levels were moderate to high in breast carcinomas. For the more aggressive sarcoma subtypes, 9/13 patients with PRUNE amplification developed metastases. A similar situation was observed in all breast carcinomas with amplification of PRUNE. Infection of NIH3T3 cells with a PRUNE recombinant retrovirus increased cell proliferation. Possibly, amplification and overexpression of PRUNE has the same effect in the tumours. We suggest that amplification and overexpression of PRUNE could be a mechanism for inhibition of nm23-H1 activity that affect the development or progression of these tumours.


Assuntos
Neoplasias da Mama/genética , Carcinoma/genética , Proteínas de Transporte/genética , Proteínas de Drosophila , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Proteínas de Insetos/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Núcleosídeo-Difosfato Quinase , Sarcoma/genética , Fatores de Transcrição/metabolismo , Células 3T3 , Animais , Neoplasias da Mama/patologia , Células COS , Carcinoma/patologia , Proteínas de Transporte/fisiologia , Divisão Celular , Feminino , Humanos , Proteínas de Insetos/fisiologia , Camundongos , Proteínas Monoméricas de Ligação ao GTP/genética , Nucleosídeo NM23 Difosfato Quinases , Metástase Neoplásica , Monoéster Fosfórico Hidrolases , RNA Neoplásico/biossíntese , Sarcoma/patologia , Fatores de Transcrição/genética
13.
EMBO J ; 20(9): 2140-51, 2001 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-11331580

RESUMO

A functional genomic approach, based on systematic data gathering, was used to characterize a family of proteins containing a tripartite motif (TRIM). A total of 37 TRIM genes/proteins were studied, 21 of which were novel. The results demonstrate that TRIM proteins share a common function: by means of homo-multimerization they identify specific cell compartments.


Assuntos
Motivos de Aminoácidos/fisiologia , Proteínas de Transporte , Compartimento Celular/fisiologia , Família Multigênica/genética , Proteínas do Tecido Nervoso , Proteínas/fisiologia , Animais , Northern Blotting , Linhagem Celular , Mapeamento Cromossômico , Clonagem Molecular , Bases de Dados Factuais , Embrião de Mamíferos , Humanos , Hibridização In Situ , Camundongos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Especificidade de Órgãos , Ligação Proteica/fisiologia , Estrutura Terciária de Proteína/fisiologia , Homologia de Sequência de Aminoácidos , Frações Subcelulares/metabolismo , Técnicas do Sistema de Duplo-Híbrido , Ubiquitina-Proteína Ligases
14.
Hum Mol Genet ; 10(6): 617-27, 2001 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-11230181

RESUMO

Williams-Beuren syndrome (WBS) is a developmental disorder associated with haploinsufficiency of multiple genes at 7q11.23. Here, we report the functional characterization of WBS critical region gene 14 (WBSCR14), a gene contained in the WBS commonly deleted region. It encodes a basic-helix--loop--helix leucine zipper (bHLHZip) transcription factor of the Myc/Max/Mad superfamily. WBSCR14 is expressed in multiple tissues, including regions of the brain and the intestinal tract. WBSCR14 forms heterodimers with the bHLHZip protein Mlx to bind the DNA sequence CACGTG. Like Max, Mlx has no intrinsic transcriptional activity, but its association with Mad1, Mad4, Mnt or WBSCR14 can repress E-box-dependent transcription. Preliminary results suggest a possible role of WBSCR14 in growth control. Our data support the view that the Max-like bHLHZip protein, Mlx, is a key element of a transcription factor network. We thus suggest that WBSCR14 may contribute to some aspects of the WBS pathology.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/genética , Síndrome de Williams/genética , Sequência de Aminoácidos , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Diferenciação Celular/genética , Divisão Celular/genética , Células Cultivadas , Mapeamento Cromossômico , Cromossomos Humanos Par 7 , DNA/metabolismo , Dimerização , Deleção de Genes , Expressão Gênica , Humanos , Camundongos , Dados de Sequência Molecular , Proteínas Nucleares , Homologia de Sequência de Aminoácidos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia , Transcrição Gênica/genética , Transfecção , Síndrome de Williams/metabolismo , Síndrome de Williams/patologia
15.
Oncogene ; 19(29): 3266-77, 2000 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-10918583

RESUMO

The Myc proto-oncogene family members have been identified as the cellular homologs of the transforming oncogene of avian retroviruses. They encode central regulators of mammalian cell proliferation and apoptosis, and they associate with the bHLHZip protein Max to bind specific DNA sequences and regulate the expression of genes important for cell cycle progression. The other family members, Mad1, Mxi1, Mad3, Mad4 and Rox (Mnt) antagonize their activities. The Mads and Rox compete with Myc in heterodimerizing with Max and in binding to the same specific target sequences. These Mads:Max and Rox:Max dimers repress transcription through binding to the mSIN3 corepressor protein and by tethering histone deacetylase-containing complexes to the DNA. In a screen for Rox interactors we isolated Mlx, a bHLHZip protein previously identified in a screen for Mad1 interactors. In the present work we extend the known dimerization partners of Mlx by demonstrating its ability to interact with Rox. Moreover, we show that contrary to previous reports Mlx is able to homodimerize and to bind E-box sequences at low concentration levels. The possible role of Mlx in an emerging regulatory pathway and acting parallel to the Max driven network is discussed.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Genes Supressores , Sequências Hélice-Alça-Hélice , Zíper de Leucina , Proteínas Nucleares/metabolismo , Proteínas Repressoras , Transdução de Sinais , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Fatores de Transcrição de Zíper de Leucina Básica , Células COS , Linhagem Celular Transformada , DNA/metabolismo , DNA Complementar , Proteínas de Ligação a DNA/genética , Dimerização , Expressão Gênica , Células HeLa , Humanos , Dados de Sequência Molecular , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proto-Oncogene Mas , Coelhos , Frações Subcelulares , Fatores de Transcrição/genética
16.
Oncogene ; 18(51): 7244-52, 1999 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-10602478

RESUMO

We have isolated a human and murine homologue of the Drosophila prune gene through dbEST searches. The gene is ubiquitously expressed in human adult tissues, while in mouse developing embryos a high level of expression is confined to the nervous system particularly in the dorsal root ganglia, cranial nerves, and neural retina. The gene is composed of eight exons and is located in the 1q21.3 chromosomal region. A pseudogene has been sequenced and mapped to chromosomal region 13q12. PRUNE protein retains the four characteristic domains of DHH phosphoesterases. The synergism between prune and awdK-pn in Drosophila has led various authors to propose an interaction between these genes. However, such an interaction has never been supported by biochemical data. By using interaction-mating and in vitro co-immunoprecipitation experiments, we show for the first time the ability of human PRUNE to interact with the human homologue of awd protein (nm23-H1). In contrast, PRUNE is impaired in its interaction with nm-23-H1-S120G mutant, a gain-of-function mutation associated with advanced neuroblastoma stages. Consistently, PRUNE and nm23-H1 proteins partially colocalize in the cytoplasm. The data presented are consistent with the view that PRUNE acts as a negative regulator of the nm23-H1 protein. We discuss how PRUNE regulates nm23-H1 protein and postulate possible implications of PRUNE in neuroblastoma progression.


Assuntos
Biomarcadores Tumorais/genética , Cromossomos Humanos Par 13 , Proteínas de Drosophila , Regulação da Expressão Gênica , Proteínas de Insetos/genética , Proteínas Monoméricas de Ligação ao GTP , Fatores de Transcrição/genética , Adulto , Sequência de Aminoácidos , Animais , Antígenos de Neoplasias/genética , Mapeamento Cromossômico , Drosophila , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Dados de Sequência Molecular , Nucleosídeo NM23 Difosfato Quinases , Núcleosídeo-Difosfato Quinase/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos
19.
Stroke ; 29(2): 399-403, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9472880

RESUMO

BACKGROUND AND PURPOSE: The epsilon4 allele of the apolipoprotein E (apoE) has been related to the occurrence of myocardial infarction, but its association with ischemic stroke is controversial. We have evaluated the relation between apoE alleles and the occurrence of cerebrovascular ischemia. METHODS: The apoE epsilon genotypes of 100 patients with a documented history of ischemic stroke without clinically apparent dementia (stroke+) and 108 subjects without such history (stroke-) were determined. The relative frequency of the apoE alleles and genotypes was estimated in 398 healthy subjects aged < 40 years from the same ethnic background. RESULTS: The frequency of the apoE epsilon4 allele in stroke+ (0.18 [95% CI, 0.12 to 0.25]) was higher than in stroke- (0.07 [95% CI, 0.03 to 0.12]; P<.001) or in healthy subjects (0.09 [95% CI, 0.07 to 0.12]; P<.001). Carriers of the epsilon4 allele differed between stroke+ (0.30 [95% CI, 0.19 to 0.42]) and stroke- (0.12 [95% CI, 0.5 to 0.22]; P=.004) or healthy subjects (0.16 [95% CI; 0.12 to 0.22]; P=.015). Accordingly, epsilon3/epsilon3 homozygotes were less frequent in stroke+ (0.59 [95% CI, 0.45 to 0.71]) than in stroke- (0.72 [95% CI, 0.59 to 0.82]; P=.063) or in healthy subjects (0.73 [95% CI, 0.67 to 0.78]; P=.01). In a multiple logistic regression analysis, age (P<.03), positive family history (P<.04) and apoE (P<.002) independently contributed to a stroke history, with epsilon4 carriers exhibiting a higher estimated risk (odds ratio, 5.05). CONCLUSIONS: Our data show an association between apoE gene and a personal history of ischemic stroke and support the possibility that the apoE gene is a susceptibility locus for the risk of cerebrovascular ischemic disease.


Assuntos
Apolipoproteínas E/genética , Isquemia Encefálica/genética , Sobreviventes , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Apolipoproteínas E/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/epidemiologia , Estudos de Casos e Controles , Demência Vascular/sangue , Demência Vascular/etiologia , Demência Vascular/genética , Feminino , Homozigoto , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Razão de Chances , Valores de Referência , Fatores de Risco
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