Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 27
Filtrar
1.
Fam Cancer ; 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33210232

RESUMO

We present a 24-year-old female patient affected by neurofibromatosis type 1 (NF1) who developed a malignant phyllodes tumor of the breast. The molecular studies showed that the patient carried a heterozygous inactivating deleterious variant in BRCA1 inherited from the father associated with a germline de novo pathogenic alteration in NF1; the tumor presented a biallelic inactivation of both genes. Therefore, tumor analyses helped to establish that the germline NF1 and BRCA1 variants were in cis on the paternal chromosome. This last information is important to provide adequate genetic counselling regarding the risk of recurrence in the offspring, as well as opportunity for early intervention. In conclusion, we present the first case of a malignant phyllodes tumor of the breast in patient carrying pathogenic variants in NF1 and BRCA1. Further studies will be necessary to understand if the phyllodes histotype represents a very rare component of NF1-associated breast cancer.

2.
Acta Neuropathol ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33025139

RESUMO

Schwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often painful neuronal tumors called schwannomas (SWNs). While germline mutations in SMARCB1 or LZTR1, plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q have been identified in a subset of patients, little is known about the epigenomic and genomic alterations that drive SWNTS-related SWNs (SWNTS-SWNs) in a majority of the cases. We performed multiplatform genomic analysis and established the molecular signature of SWNTS-SWNs. We show that SWNTS-SWNs harbor distinct genomic features relative to the histologically identical non-syndromic sporadic SWNs (NS-SWNS). We demonstrate the existence of four distinct DNA methylation subgroups of SWNTS-SWNs that are associated with specific transcriptional programs and tumor location. We show several novel recurrent non-22q deletions and structural rearrangements. We detected the SH3PXD2A-HTRA1 gene fusion in SWNTS-SWNs, with predominance in LZTR1-mutant tumors. In addition, we identified specific genetic, epigenetic, and actionable transcriptional programs associated with painful SWNTS-SWNs including PIGF, VEGF, MEK, and MTOR pathways, which may be harnessed for management of this syndrome.

4.
Cancers (Basel) ; 12(2)2020 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-31991861

RESUMO

Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.

5.
J Mol Diagn ; 20(1): 87-94, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29061375

RESUMO

The efficiency of a novel targeted next-generation sequencing (NGS) test, the Devyser BRCA kit, for a comprehensive analysis of all 48 coding exons of the high-risk breast/ovarian cancer susceptibility genes BRCA1 and BRCA2 has been assessed. The new assay intended to detect nucleotide substitutions, small deletions/insertions, and large deletions/duplications. To document the false-negative and false-positive rates of the NGS assay in the hands of end users, 48 samples with previously identified 444 small variants and seven gross rearrangements were analyzed, showing 100% concordance with gold standards. Furthermore, all other 43 variants (42 single-nucleotide variation or insertion/deletion variation and one copy number variation, whose significance is or may be of clinical value), which were called by the NGS assay in a prospectively analyzed 179-sample set, were confirmed by Sanger sequencing or multiplex ligation probe amplification, according to their nature. We conclude that the Devyser BRCA kit performed satisfactorily for use in a clinical laboratory.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação/genética , Variações do Número de Cópias de DNA/genética , Éxons/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes
6.
J Am Acad Dermatol ; 74(2): 325-32, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26775776

RESUMO

BACKGROUND: Multiple primary melanoma (MPM), in concert with a positive family history, is a predictor of cyclin-dependent kinase (CDK) inhibitor 2A (CDKN2A) germline mutations. A rule regarding the presence of either 2 or 3 or more cancer events (melanoma and pancreatic cancer) in low or high melanoma incidence populations, respectively, has been established to select patients for genetic referral. OBJECTIVE: We sought to determine the CDKN2A/CDK4/microphthalmia-associated transcription factor mutation rate among Italian patients with MPM to appropriately direct genetic counseling regardless of family history. METHODS: In all, 587 patients with MPM and an equal number with single primary melanomas and control subjects were consecutively enrolled at the participating centers and tested for CDKN2A, CDK4, and microphthalmia-associated transcription factor. RESULTS: CDKN2A germline mutations were found in 19% of patients with MPM versus 4.4% of patients with single primary melanoma. In familial MPM cases the mutation rate varied from 36.6% to 58.8%, whereas in sporadic MPM cases it varied from 8.2% to 17.6% in patients with 2 and 3 or more melanomas, respectively. The microphthalmia-associated transcription factor E318K mutation accounted for 3% of MPM cases altogether. LIMITATIONS: The study was hospital based, not population based. Rare novel susceptibility genes were not tested. CONCLUSION: Italian patients who developed 2 melanomas, even in situ, should be referred for genetic counseling even in the absence of family history.


Assuntos
Aconselhamento Genético , Melanoma/genética , Neoplasias Primárias Múltiplas/genética , Seleção de Pacientes , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase 4 Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Mutação em Linhagem Germinativa , Humanos , Itália , Fator de Transcrição Associado à Microftalmia/genética , Pessoa de Meia-Idade , Taxa de Mutação , Adulto Jovem
7.
Epigenetics ; 9(10): 1431-8, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25437057

RESUMO

Lynch syndrome (LS) is a tumor predisposing condition caused by constitutional defects in genes coding for components of the mismatch repair (MMR) apparatus. While hypermethylation of the promoter of the MMR gene MLH1 occurs in about 15% of colorectal cancer samples, it has also been observed as a constitutional alteration, in the absence of DNA sequence mutations, in a small number of LS patients. In order to obtain further insights on the phenotypic characteristics of MLH1 epimutation carriers, we investigated the somatic and constitutional MLH1 methylation status of 14 unrelated subjects with a suspicion of LS who were negative for MMR gene constitutional mutations and whose tumors did not express the MLH1 protein. A novel case of constitutional MLH1 epimutation was identified. This patient was affected with multiple primary tumors, including breast cancer, diagnosed starting from the age of 55 y. Investigation of her offspring by allele specific expression revealed that the epimutation was not stable across generations. We also found MLH1 hypermethylation in cancer samples from 4 additional patients who did not have evidence of constitutional defects. These patients had some characteristics of LS, namely early age at onset and/or positive family history, raising the possibility of genetic influences in the establishment of somatic MLH1 methylation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Metilação de DNA , Proteínas Nucleares/genética , Adulto , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Linhagem , Regiões Promotoras Genéticas
8.
J Mol Diagn ; 16(4): 393-9, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24815379

RESUMO

Somatic mosaicism represents the coexistence of two or more cell populations with different genotypes in one person, and it is involved in >30 monogenic disorders. Somatic mosaicism characterizes approximately 25% to 33% of patients with de novo neurofibromatosis type 2 (NF2). The identification of mosaicism is crucial to patients and their families because the clinical course of the disease and its transmission risk is influenced by the degree and distribution of mutated cells. Moreover, in NF2, the capability of discriminating patients with mosaicism is especially important to make differential diagnosis with schwannomatosis. However, the identification of mosaic variants is considerably difficult, and the development of specific molecular techniques to detect low levels of unknown molecular alterations is required. Co-amplification at lower denaturation temperature (COLD)-PCR has been described as a powerful method to selectively amplify minority alleles from mixtures of wild-type and mutation-containing sequences. Here, we applied COLD-PCR to molecular analysis of patients with NF2 mosaicism. With the use of COLD-PCR, followed by direct sequencing, we were able to detect NF2 mutations in blood DNA of three patients with NF2 mosaicism. Our study has shown the capability of COLD-PCR in enriching low-represented mutated allele in blood DNA sample, making it usable for molecular diagnosis of patients with mosaicism.


Assuntos
Análise Mutacional de DNA/métodos , Mosaicismo , Neurofibromatose 2/genética , Neurofibromina 2/genética , Reação em Cadeia da Polimerase/métodos , Temperatura Baixa , Feminino , Genes da Neurofibromatose 2 , Humanos , Neurofibromatose 2/sangue , Neurofibromatose 2/diagnóstico , Neurofibromina 2/sangue , Sensibilidade e Especificidade
10.
J Am Acad Dermatol ; 61(5): 775-82, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19500876

RESUMO

BACKGROUND: The Italian Society of Human Genetics' (SIGU) recommendations on genetic counseling and testing for hereditary melanoma state that clinical genetic testing can be offered to Italian melanoma families with at least two affected members. OBJECTIVE: In the framework of a cooperative study, we sought to establish the frequency of cyclin-dependent kinase inhibitor 2A mutations in melanoma families that underwent clinical genetic counseling and testing in accordance with the SIGU recommendations at 9 centers in different Italian regions. METHODS: Cyclin-dependent kinase inhibitor 2A testing was conducted by direct sequencing and multiplex ligation-dependent probe amplification analysis in melanoma families with at least two affected members. RESULTS: A total of 33% (68/204) of the families harbored cyclin-dependent kinase inhibitor 2A mutations. In the 145 families with two affected members the mutation frequency was 25%. Three novel mutations, L94P, A86T, and c.407dupG, were identified among the cases and not in 200 controls. LIMITATIONS: We were unable to perform separate analyses for individual centers, as in some cases the number of families was too small. CONCLUSIONS: The availability of clinical genetic testing for melanoma to families with just two affected members in the same branch is justified in Italy in terms of the likelihood of identifying a mutation.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Saúde da Família , Testes Genéticos , Melanoma/genética , Neoplasias Cutâneas/genética , Frequência do Gene , Aconselhamento Genético , Humanos , Itália/epidemiologia , Melanoma/epidemiologia , Neoplasias Primárias Múltiplas/epidemiologia , Neoplasias Primárias Múltiplas/genética , Mutação Puntual , Neoplasias Cutâneas/epidemiologia
11.
Melanoma Res ; 18(6): 431-7, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19011513

RESUMO

Predisposition to familial cutaneous malignant melanoma has been associated with mutations in the CDKN2A and CDK4 genes. However, only a small subgroup of melanoma pedigrees harbour CDKN2A or CDK4 germline mutations. It is possible that other types of CDKN2A rearrangements, not detectable by routine PCR-based approaches, are involved in a fraction of melanoma cases negative for point sequence changes. In order to gain insights on the possible role of CDKN2A large deletions or duplications in melanoma susceptibility in the Italian population, we screened a series of 124 cutaneous malignant melanoma families referred to five national medical/cancer genetics centres. All probands were negative for point mutations in CDKN2A and CDK4. All samples were tested by MLPA (multiplex ligation-dependent probe amplification), and the results were confirmed by real-time quantitative PCR in a subset of 53 cases. No genomic rearrangements were detected in this series, one of the largest so far investigated. These data suggest that large deletions/duplications in the CDKN2A locus are infrequently involved in the development of familial melanoma in the Italian population. Based on these results, routine search for these rearrangements in CDKN2A- and CDK4-mutation negative melanoma families is not warranted, although it would be reasonable to pursue it in selected cases with very strong family history and/or showing linkage to 9p21.


Assuntos
Quinase 4 Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Deleção de Genes , Predisposição Genética para Doença , Humanos , Itália , Células Jurkat , Linhagem , Mutação Puntual/genética
12.
Melanoma Res ; 17(6): 387-92, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17992122

RESUMO

We have investigated the frequency and spectrum of CDKN2A/CDK4 mutations in 23 cutaneous melanoma families from Central Italy (Tuscany). Three distinct mutations were identified in five families. One mutation, p.G23S, was present in three families. Several lines of evidence indicate that p.G23S is a pathogenic mutation: it is located in the functionally important first ankyrinic domain of p16, it was not detected in a sample of 100 control individuals, and it was present in all tested affected individuals from the three families. Haplotype analysis showed a common ancestral origin of the p.G23S mutation. Our data show that the p.G23S mutation is an important cause of hereditary melanoma in Tuscany.


Assuntos
Genes p16 , Melanoma/genética , Mutação , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Linhagem
13.
PLoS One ; 2(6): e495, 2007 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-17551576

RESUMO

BACKGROUND: Hyperhomocysteinemia has been suggested to play a role in the NonValvular Atrial Fibrillation (NVAF) pathogenesis. Polymorphisms in genes coding for homocysteine (Hcy) metabolism enzymes may be associated with hyperhomocysteinemia and NVAF. METHODOLOGIES: 456 NVAF patients and 912 matched controls were genotyped by an electronic microchip technology for C677T and A1298C MTHFR, A2756G MTR, and -786C/T eNOS gene polymorphisms. Hcy was determined by an immunoassay method. PRINCIPAL FINDINGS: The genotype distribution of the four polymorphisms as well as genotype combinations did not differ in patients and controls. Hcy was higher in patients than in controls (15.2, 95%CI 14.7-15.7 vs 11.3, 95%CI 11.0-11.6 micromol/L; p<0.0001). In both populations, a genotype-phenotype association (p<0.0001) between Hcy and C677T MTHFR polymorphism was observed; in controls a significant (p = 0.029) association between tHcy and -786C/T eNOS polymorphism was also observed. At the multivariate analysis the NVAF risk significantly increased in the upper quartiles of Hcy compared to the lowest: OR from 2.8 (1.68-4.54 95%CI) in Q2 to 12.9 (7.96-21.06 95%CI) in Q4. CONCLUSIONS: Our data demonstrated the four polymorphisms, although able, at least in part, to affect Hcy, were not associated with an increased risk of NVAF per se or in combination.


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Fibrilação Atrial/genética , Predisposição Genética para Doença , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo de Nucleotídeo Único/genética , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/sangue , Fibrilação Atrial/patologia , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/genética , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/sangue , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo III/sangue , Prognóstico , Fatores de Risco , Adulto Jovem
14.
Int J Cardiol ; 120(1): 59-65, 2007 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-17113662

RESUMO

BACKGROUND: An involvement of the renin angiotensin system in atrial fibrillation (AF) has been hypothesized, and ACE DD genotype has been suggested to influence the predisposition to AF. The aim of this study was to investigate the role of the ACE I/D polymorphism in relation to the different clinical forms of AF, lone and secondary nonvalvular atrial fibrillation (NVAF). METHODS: 510 consecutive patients with documented NVAF (106 patients had lone, and 404 secondary NVAF), and 520 controls with a negative history of cardiovascular disease have been studied. RESULTS: A significant difference in allele frequency between lone and secondary NVAF (p=0.002) has been found. The ACE D allele was associated with the predisposition to lone NVAF under a dominant, recessive and additive model, both at univariate and multivariate analysis, after adjustment for age and gender (multivariate analysis: dominant OR=2.87, p=0.02; recessive OR=2.01, p=0.003; additive OR=4.47, p<0.0001). ACE D allele was significantly associated with secondary NVAF at both univariate and multivariate analysis under a recessive and additive, but not dominant, model (multivariate analysis: recessive OR=1.89, p=0.001; additive OR=2.50, p<0.0001). CONCLUSIONS: This study highlights the role of ACE gene in predisposing to both lone and secondary NVAF, further contributing to penetrate the genetic mechanisms responsible for this complex disease. The clinical relevance of our results may be related to the possible characterization of subjects predisposed to NVAF in the absence of traditional risk factors, and to the use of ACE-inhibitors therapy able to improve the arrhythmogenic substrate.


Assuntos
Fibrilação Atrial/genética , Peptidil Dipeptidase A/genética , Polimorfismo Genético/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Fatores de Risco
15.
J Hypertens ; 24(9): 1823-9, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16915032

RESUMO

OBJECTIVES: Pre-eclampsia is associated with vascular endothelial dysfunction, adverse pregnancy outcome and cardiovascular disease in later life. An inadequate nitric oxide availability related to polymorphisms in the endothelial nitric oxide synthase gene (eNOS) might predispose to the disease. METHODS: We investigated the role of eNOS T-786C, G894T and 4a4b polymorphisms in predisposing to both pre-eclampsia and the recurrence of negative pregnancy events, per se and in the presence of angiotensin-converting enzyme (ACE) DD genotype, and investigated their influence on maternal-fetal flow in 106 non-thrombophilic women with a history of pre-eclampsia, compared with 106 women with a history of normal pregnancy. RESULTS: No association between eNOS polymorphisms and predisposition to pre-eclampsia was found; nevertheless, the contemporary presence of eNOS 894TT and -786CC genotypes represented a susceptibility factor to the disease. In 48 out of 106 women, documented complications (pre-eclampsia and fetal growth restriction) were present in the current pregnancy. The eNOS 894TT genotype influenced the risk of recurrence of negative events (odds ratio = 5.45), particularly in contemporary women homozygous for both eNOS 894TT and ACE DD genotypes (odds ratio = 11.4). Throughout the pregnancy, a progressive alteration of maternal-fetal flow indices was found in women carrying the eNOS 894TT genotype, and this effect was strengthened in women with the contemporary presence of the ACE DD genotype. CONCLUSIONS: An original finding is the increased risk of pre-eclampsia and recurrence of pregnancy negative events, probably by modulating the maternal-fetal flow, in women homozygous for the eNOS 894T allele previously analyzed for the ACE I/D polymorphism.


Assuntos
Regulação Enzimológica da Expressão Gênica , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/fisiologia , Polimorfismo Genético , Pré-Eclâmpsia/diagnóstico , Adulto , Alelos , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Troca Materno-Fetal , Razão de Chances , Peptidil Dipeptidase A/genética , Pré-Eclâmpsia/patologia , Gravidez , Resultado da Gravidez , Recidiva , Trombofilia/genética
16.
Hum Mol Genet ; 15(18): 2682-9, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16893909

RESUMO

Mutations in the CDKN2A gene underlie melanoma susceptibility in as many as 50% of melanoma kindreds in selected populations, and several CDKN2A founder mutations have been described. Inherited mutations in CDKN2A have been found to be associated with other, non-melanoma cancers including pancreatic cancer (PC) and neural system tumors (NST). Here we report a novel germline mutation in exon 1 of the CDKN2A gene, E27X, which we first detected in melanoma patients living in or originally from a small geographic area bordering Liguria in north-western Italy. A subset of melanoma kindreds positive for this mutation displayed PC and neuroblastoma. E27X generates a premature stop codon, leading to dramatically reduced protein levels of p16 and leaving p14ARF unaltered. As PC and NSTs have been postulated to be preferentially associated with CDKN2A mutations located in exon 2 and/or affecting p14ARF alone, the position of E27X in exon 1alpha provides interesting insights towards clarifying the mechanisms by which the CDKN2A/ARF locus is involved in cancer predisposition.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Genes p16 , Mutação em Linhagem Germinativa , Melanoma/genética , Neuroblastoma/genética , Neoplasias Pancreáticas/genética , Proteína Supressora de Tumor p14ARF/genética , Adulto , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Éxons , Feminino , Genótipo , Haplótipos , Humanos , Itália , Masculino , Melanoma/metabolismo , Neuroblastoma/metabolismo , Neoplasias Pancreáticas/metabolismo , Linhagem , Mutação Puntual , Proteína Supressora de Tumor p14ARF/metabolismo
17.
Eur Heart J ; 27(14): 1712-8, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16760206

RESUMO

AIM: Mink protein, a beta-subunit of I(ks) potassium channels modulate cardiac cellular electrophysiology, and experimental data demonstrated that NO is involved in cardiac vagal activity and in the inhibition of sympathetic activity. We evaluated the role of eNOS -786T>C, 894G>T, 4a/4b and of minK S38G polymorphisms as predisposing factors to non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: We studied 331 consecutive patients with documented NVAF and in 441 control subjects, comparable for age and gender. A significant difference in allele frequencies between patients and controls for minK S38G and eNOS -786T>C, but not for eNOS 894G>T and 4a/4b polymorphisms, was observed. The minK 38G allele was significantly associated with susceptibility to NVAF at both univariate and multivariable analysis, according to dominant and recessive genetic model (multivariable analysis, dominant: OR=1.73, P=0.004 and recessive: OR=1.59, P=0.006). The eNOS -786C allele weakly influenced NVAF at univariate analysis, according to the dominant model (OR=1.50, P=0.01). The contemporary presence of minK 38G and eNOS -786C alleles increased the predisposition to NVAF, after adjustment with cardiovascular risk factors (OR minK 38G*eNOS -786C=2.11, P<0.0001; OR=2.58, P=0.003; OR=3.08, P=0.002, according to dominant, recessive, and additive model, respectively). CONCLUSION: Our findings suggest a role for minK and eNOS genes as predisposing factors to NVAF.


Assuntos
Fibrilação Atrial/genética , Predisposição Genética para Doença/genética , Óxido Nítrico Sintase Tipo III/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Reação em Cadeia da Polimerase/métodos , Polimorfismo Genético/genética , Polimorfismo de Fragmento de Restrição
18.
Am J Med Genet A ; 134A(2): 212-4, 2005 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15690400

RESUMO

MYH-associated polyposis (MAP) is a recently described autosomal recessive form of familial adenomatous polyposis (FAP) associated with susceptibility to colorectal carcinoma (CRC). MAP is caused by biallelic inactivating mutations of the MYH gene, a component of the base excision repair (BER) machinery, whose dysfunction leads to an increase in the rate of G > T transversions following DNA oxidative damage. MAP patients can present with either classic or attenuated polyposis. However, the MAP colonic and extracolonic phenotype has yet to be defined. We report on two siblings, born from consanguineous parents, who were found to be homozygotes for an MYH frameshift mutation. The propositus presented with a low number of colonic lesions and an early-onset CRC. Both siblings had a history of pilomatricomas, benign tumors derived from hair follicles, in childhood. The findings presented provide further evidence of phenotypic variability in MAP, and suggest that multiple pilomatricomas may be a useful cutaneous marker of MAP.


Assuntos
Polipose Adenomatosa do Colo/genética , DNA Glicosilases/genética , Doenças do Cabelo/patologia , Pilomatrixoma/patologia , Neoplasias Cutâneas/patologia , Polipose Adenomatosa do Colo/enzimologia , Polipose Adenomatosa do Colo/patologia , Adulto , Consanguinidade , DNA/química , DNA/genética , Análise Mutacional de DNA , Saúde da Família , Feminino , Mutação da Fase de Leitura , Humanos , Masculino , Linhagem , Polimorfismo Conformacional de Fita Simples , Irmãos
19.
Hypertension ; 45(1): 86-91, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15557391

RESUMO

Data from literature report that angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism affects the recurrence of preeclampsia and that low-molecular-weight heparin (LMWH) prevents adverse outcomes in thrombophilic women. We investigated the effect of LMWH on the pregnancy outcome, on maternal blood pressure values, and on uteroplacental flow in ACE DD nonthrombophilic women with history of preeclampsia. Eighty nonthrombophilic ACE DD women were randomized in 2 groups: 41 treated with dalteparin 5000 IU/day and 39 untreated (control group). Women underwent 24-hour automated blood pressure monitoring in the preconceptional period and every 2 weeks from weeks 8 to 36 and transabdominal color flow/pulsed Doppler examination at weeks 16, 20, and 24. LMWH reduced the risk of clinical negative outcomes (74.1% reduction of preeclampsia and 77.5% reduction of fetal growth restriction) and the severity (88.3% reduction of early onset of preeclampsia and 86.4% reduction of early onset of fetal growth restriction). In treated women, the relative risk for preeclampsia was 0.26 (P=0.02), and the relative risk for fetal growth restriction was 0.14 (P<0.001). Systolic (P=0.002) and diastolic (P=0.002) blood pressures, as well as awake (P=0.04) and asleep (P=0.01) period values, and the resistance indexes of both uterine arteries (P=0.002) were lower in the treated group. LMWH reduces the recurrence of preeclampsia, of negative outcomes, and the resistance of uteroplacental flow, and also prevents maternal blood pressure increase in ACE DD homozygote women with a previous history of preeclampsia.


Assuntos
Anticoagulantes/uso terapêutico , Dalteparina/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Peptidil Dipeptidase A/genética , Pré-Eclâmpsia/prevenção & controle , Adulto , Peso ao Nascer , Ritmo Circadiano , Diástole/efeitos dos fármacos , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Retardo do Crescimento Fetal/epidemiologia , Retardo do Crescimento Fetal/prevenção & controle , Predisposição Genética para Doença , Homozigoto , Humanos , Recém-Nascido , Circulação Placentária/efeitos dos fármacos , Pré-Eclâmpsia/enzimologia , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/genética , Gravidez , Resultado da Gravidez , Recidiva , Risco , Deleção de Sequência , Sístole/efeitos dos fármacos , Resultado do Tratamento , Ultrassonografia Doppler em Cores , Ultrassonografia Doppler de Pulso , Ultrassonografia Pré-Natal , Útero/irrigação sanguínea , Resistência Vascular/efeitos dos fármacos
20.
Biochem Genet ; 42(3-4): 121-7, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15168725

RESUMO

In endothelial cells nitric oxide (NO) is synthesized by endothelial-nitric oxide synthase (e-NOS), constitutively expressed and encoded by a 26-exon gene, located on chromosome 7q35-36. The prevalence of the T rare variant of the G894T polymorphism in exon 7 of the e-NOS gene (Glu-->Asp amino acid substitution) has been reported to be significantly higher in patients with coronary spasm and coronary artery disease. To date G894T polymorphism detection is performed by PCR-RFLP assay. In order to establish a high-speed genotyping method, we have taken advantage of the Light Cycler instrument, a thermal cycler that combines rapid-cycle DNA amplification with a real-time fluorescence monitoring. This technology is based on hybridization of the adjacent fluorescently labeled probes with PCR products. This methodology is considered more accurate and less time-consuming than conventional PCR-RFLP assay. To validate this technique we genotyped 270 healthy subjects. The results were consistent with those obtained from PCR-RFLP assay.


Assuntos
Endotélio Vascular/enzimologia , Éxons , Testes Genéticos/métodos , Óxido Nítrico Sintase/genética , Reação em Cadeia da Polimerase , Polimorfismo Genético , Alelos , Substituição de Aminoácidos , Ácido Aspártico/metabolismo , Fluorescência , Frequência do Gene , Humanos , Reprodutibilidade dos Testes , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...