RESUMO

Cystic fibrosis (CF) is the most common autosomal recessive disease of the Caucasian population. Among the various CF mutations, p.F508del is the most frequent, accounting for two-thirds of the global CF chromosomes, although showing great variability among populations. We have studied 115 unrelated CF patients from a mixed population of Minas Gerais (Brazil). To evaluate part of the DNA sequence of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, blood DNA was obtained and PCR was performed using two pairs of primers that anneal to exons 10 and 24 of the CFTR gene. The PCR product was then submitted to automatic sequencing using the ABI PRISM 310 Genetic Analyzer. The p.F508del mutation was found in 50 (21.7%) of 230 unrelated CF alleles. Fifteen (13.0%) patients were homozygous for this mutation, while 20 (17.4%) were heterozygous; the remaining 80 (69.6%) patients did not carry the p.F508del mutation. Exon 24 sequence had no change in 75 (65.2%) patients, 21 (18.3%) had the sequence variation 4521G/A, 11 (9.6%) had a not yet described sequence variation 4407T/A and 8 (7.0%) patients had both sequence variations (4521G/A and 4407T/A). The polymorphism 4407T/A results in an amino acid modification from aspartic acid to glutamic acid, which will probably have no function effect in CFTR. This low p.F508del prevalence can be due to the variable ethnic origin of this population from Minas Gerais, which may have a high diversity of CF rare mutations.

Assuntos

Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Mutação/genética , Brasil/etnologia , Fibrose Cística/sangue , Feminino , Frequência do Gene , Humanos , Masculino , Reação em Cadeia da Polimerase , Análise de Sequência de DNA

RESUMO

Cystic fibrosis (CF) is the most common autosomal recessive disease of the Caucasian population. Among the various CF mutations, p.F508del is the most frequent, accounting for two-thirds of the global CF chromosomes, although showing great variability among populations. We have studied 115 unrelated CF patients from a mixed population of Minas Gerais (Brazil). To evaluate part of the DNA sequence of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, blood DNA was obtained and PCR was performed using two pairs of primers that anneal to exons 10 and 24 of the CFTR gene. The PCR product was then submitted to automatic sequencing using the ABI PRISM 310 Genetic Analyzer. The p.F508del mutation was found in 50 (21.7 percent) of 230 unrelated CF alleles. Fifteen (13.0 percent) patients were homozygous for this mutation, while 20 (17.4 percent) were heterozygous; the remaining 80 (69.6 percent) patients did not carry the p.F508del mutation. Exon 24 sequence had no change in 75 (65.2 percent) patients, 21 (18.3 percent) had the sequence variation 4521G/A, 11 (9.6 percent) had a not yet described sequence variation 4407T/A and 8 (7.0 percent) patients had both sequence variations (4521G/A and 4407T/A). The polymorphism 4407T/A results in an amino acid modification from aspartic acid to glutamic acid, which will probably have no function effect in CFTR. This low p.F508del prevalence can be due to the variable ethnic origin of this population from Minas Gerais, which may have a high diversity of CF rare mutations.

Assuntos

Feminino , Humanos , Masculino , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Mutação/genética , Brasil/etnologia , Fibrose Cística/sangue , Frequência do Gene , Reação em Cadeia da Polimerase , Análise de Sequência de DNA/métodos

RESUMO

Nephrogenic diabetes insipidus (NDI) is an inherited disorder characterized by renal resistance to the antidiuretic effect of arginine vasopressin (AVP), resulting in polyuria, polydipsia, and hypoosmolar urine. In the vast majority of cases, NDI is associated with germ-line mutations in the vasopressin receptor type 2 gene (AVPR2) and in about 8% of the cases with the water channel aquaporin-2 gene (AQP-2) mutations. To date, approximately 277 families with 185 germ-line mutations in the AVPR2 gene have been described worldwide. In the present study, the AVPR2 gene was genotyped in eight unrelated Brazilian kindred with NDI. In five of these NDI families, novel mutations were noted (S54R, I130L, S187R, 219delT, and R230P), whereas three seemingly unrelated probands were found to harbor previously described AVPR2 gene mutations (R106C, R137H, R337X). Additionally a novel polymorphism (V281V) was detected. In conclusion, although NDI is a rare disease, the findings of mutations scattered over the entire coding region of the AVPR2 gene are a valuable model to determine structure function relationship in G-protein-coupled receptor related diseases. Furthermore, our data indicate that in Brazil the spectrum of AVPR2 gene mutations is "family specific".

Assuntos

Arginina Vasopressina/metabolismo , Diabetes Insípido Nefrogênico/genética , Diabetes Insípido Nefrogênico/metabolismo , Mutação , Receptores de Vasopressinas/genética , Sequência de Aminoácidos , Substituição de Aminoácidos/genética , Brasil , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Fases de Leitura Aberta/genética , Linhagem , Receptores de Vasopressinas/classificação , Receptores de Vasopressinas/fisiologia

RESUMO

According to WHO, suicide accounts for about 1,000,000 deaths worldwide every year. In view of these dramatic data, several studies have tried to identify possible biological mechanisms and markers of suicide. Genes encoding for proteins involved in the serotonergic transmission are major candidates in association studies of suicidal behavior. The gene that codes for tryptophan hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of serotonin, is one of these candidates. Two polymorphisms in intron 7 of this gene (A218C and A779C) have been described, but their role in suicidal behavior remains uncertain. TPH A218C polymorphism was analyzed in a sample of 248 psychiatric patients and 63 healthy controls. In addition, at least one close relative member was interviewed to assess family suicidal behavior history. Our research confirmed that a positive history of suicide attempts in a family member is associated with the chance of an individual to attempt suicide. Furthermore, we demonstrated that familial suicide attempts are more lethal and frequently more violent. We were not able to find significant differences of the TPH genotype frequencies between patients and controls. The TPH A218C genotypes were not associated with a history of suicide attempt and the lethality of the most lethal lifetime suicide attempt and suicide attempt method. The authors conclude that the A218C polymorphism of the TPH gene may not be a susceptibility factor for suicidal behavior in this group of psychiatric patients but confirm that a family suicidal behavior history increases the proband's suicide attempt risk.

Assuntos

Transtornos Mentais/genética , Tentativa de Suicídio/estatística & dados numéricos , Suicídio , Triptofano Hidroxilase/genética , Adulto , Alcoolismo/genética , Alcoolismo/psicologia , Brasil , Estudos de Casos e Controles , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/psicologia , Saúde da Família , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Transtornos Mentais/psicologia , Pessoa de Meia-Idade , Linhagem , Polimorfismo Genético/genética , Valores de Referência , Esquizofrenia/genética , Psicologia do Esquizofrênico , Suicídio/psicologia , Tentativa de Suicídio/psicologia

RESUMO

Haim-Munk syndrome (HMS) is a rare autosomal recessive disorder characterized clinically by abnormal palmoplantar hyperkeratosis and destruction of the periodontium, with hallmarks of onychogryphosis and arachnodactyly. Germline mutations in the lysosomal protease cathepsin C gene (CTSC) have been described in a single patient with HMS and in several individuals with the clinically related disorder Papillon-Lefevre syndrome (PLS). We describe a patient with HMS. We have analysed the cathepsin C gene in the proband and her mother. Sequence analysis of CTSC in the proband revealed a homozygous mutation at codon 196 (587T-->C) within exon 4 that altered the conserved leucine to proline (Leu196Pro), whereas the patient's mother was heterozygous for that mutation. The same mutation has previously been described in an unrelated Brazilian family with PLS. An identical single missense mutation in the cathepsin C gene may underlie both PLS and HMS. These findings confirm that HMS and PLS are allelic variants of cathepsin C gene mutations and suggest that other factors (environmental or genetic) may be important determinants of the clinical phenotype of HMS and PLS.

Assuntos

Catepsina C/genética , Ceratodermia Palmar e Plantar/genética , Mutação , Adulto , Feminino , Homozigoto , Humanos , Ceratodermia Palmar e Plantar/patologia , Doença de Papillon-Lefevre/genética , Linhagem , Análise de Sequência de DNA , Síndrome

RESUMO

OBJECTIVE: There is compelling evidence that a serotonergic dysfunction may play a major role in suicide behaviour and it has also been demonstrated that suicide is, at least partially, genetically determined. Thus, the serotonin-related genes are the major candidates. Previously a functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was identified and the presence of the short allele (S) was found to be associated with a lower level of expression of the gene and lower levels of 5-HT uptake when compared with the long allele (L). The purpose of this study was to evaluate the association between family suicide behaviour history and probands' suicide attempt (SA) history, SA characteristics and 5-HTTLPR genotype. METHOD: We genotyped 237 probands (major depressed or schizophrenic patients) and used a semistructured interview to determine probands' SA characteristics and first- and second-degree family suicidal behaviour. RESULTS: An association between suicidal family history and proband's SA but not with SA characteristics and probands genotype was found. CONCLUSION: Our results suggest that multiple biological and environmental factors underlie familial transmission of suicidal behaviour.

Assuntos

Comportamento , Família , Polimorfismo Genético , Receptor 5-HT1A de Serotonina/genética , Serotonina/genética , Tentativa de Suicídio/psicologia , Brasil/epidemiologia , Transtorno Depressivo/genética , Predisposição Genética para Doença , Genótipo , Humanos , Esquizofrenia/genética , Serotonina/metabolismo

RESUMO

Thiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs. Low-activity phenotypes are correlated with several mutations in the TPMT gene. Polymorphisms of TPMT have been reported for Caucasians, African-Americans and Asians. Since ethnic differences have been demonstrated worldwide, it remains to be elucidated in Brazil. The Brazilian population is the result of five centuries of interethnic crosses between peoples from almost all continents as well as autochthonous Amerindians, all forming the fifth largest and one of the most heterogeneous populations in the world. The frequency of six allelic variants of the TPMT gene, *2 (G238C) (2.2%), *3A (G460A and A719G) (1.5%), *3B (G460A) (0.2%), *3C (A719G) (1.0%), *5 (0%) and *6 (0%) were determined in Brazilian subjects using polymerase chain reaction (PCR)-RFLP and allele-specific PCR-based assays. This study provides the first analysis of TPMT mutant allele frequency in a sample of the Brazilian population.

Assuntos

Metiltransferases/genética , Polimorfismo Genético/genética , Povo Asiático/etnologia , Povo Asiático/genética , População Negra/etnologia , População Negra/genética , Brasil/etnologia , Frequência do Gene/genética , Humanos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , População Branca/etnologia , População Branca/genética

RESUMO

1. Central serotonergic dysfunction and genetic factors are associated with suicidal behavior in psychiatric patients. The goal of this study was to examine the association between the 5-HT2A gene polymorphism (102T/C) and suicide in a sample of Brazilian psychiatric inpatients. 2. We studied 225 subjects. Genotypic frequencies were obtained after DNA extraction and the region of 5-HT2A/T102C containing the polymorphic site amplified by the polymerase chain reaction and digested with the restriction enzyme HpaII. 3. No differences were found between patients with and without suicide attempt history. Patients with a history of severe suicide attempts also did not exhibit different genotypic frequencies when compared with patients without a suicide attempt history. 4. These results suggest that the 5HT2A gene polymorphism (102T/C) may not be involved in the genetic susceptibility to suicidal behavior.

Assuntos

Química Encefálica/genética , Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Polimorfismo Genético/genética , Receptores de Serotonina/genética , Suicídio , Fatores Etários , Análise Mutacional de DNA , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Feminino , Frequência do Gene/genética , Testes Genéticos , Genótipo , Humanos , Masculino , Receptor 5-HT2A de Serotonina , Serotonina/genética , Fatores Sexuais

RESUMO

Craniopharyngioma is the most common childhood tumor and thought to arise from embryonic remnants of Rathke's pouch. The paucity of published data on the molecular basis of these tumors prompted us to examine 22 adamantinomatous craniopharyngiomas looking for genetic abnormalities. Using the X-linked polymorphic androgen receptor gene as a tool for X-chromosome inactivating analysis, we found that a subset of craniopharyngiomas are monoclonal and therefore are probably due to acquired somatic genetic defects. Thus, we investigated these tumours for mutations within three candidate genes, Gsalpha, Gi2alpha and patched (PTCH). Using single stranded conformational polymorphism (SSCP), denaturing gradient gel electrophoresis and direct sequencing, the presence of somatic mutations in these genes could not be demonstrated in any tumor. Our data indicate that a subset of craniopharyngiomas are monoclonal and the mutations in the PTCH, Gsalpha, and Gi2alpha contribute little if any to craniopharyngioma development.

Assuntos

Adenoma/genética , Neoplasias Encefálicas/genética , Craniofaringioma/genética , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Proteínas Proto-Oncogênicas/genética , Adenoma/patologia , Anticorpos Monoclonais , Neoplasias Encefálicas/patologia , Craniofaringioma/patologia , Primers do DNA , Éxons/genética , Subunidade alfa Gi2 de Proteína de Ligação ao GTP , Humanos , Mutação/genética , Polimorfismo Conformacional de Fita Simples , Desnaturação Proteica , Reação em Cadeia da Polimerase Via Transcriptase Reversa

RESUMO

An odontogenic keratocyst (OKC) is a benign cystic lesion of the jaws that occurs sporadically or in association with nevoid basal cell carcinoma syndrome (NBCCS). Recently, the gene for NBCCS was cloned and shown to be the human homologue of the Drosophila segment polarity gene Patched (PTCH), a tumor suppressor gene. The PTCH gene encodes a transmembrane protein that acts in opposition to the Hedgehog signaling protein, controlling cell fates, patterning, and growth in numerous tissues, including tooth. We investigated three cases of sporadic odontogenic keratocysts and three other cases associated with NBCCS, looking for mutations of the PTCH gene. Non-radioactive single-strand conformational polymorphism and direct sequencing of PCR products revealed a deletion of 5 base pairs (bp) in exon 3 (518delAAGCG) in one sporadic cyst as well as mutations in two cysts associated with NBCCS, a nonsense (C2760A) and a missense (G3499A) alteration. This report is the first to describe a somatic mutation of PTCH in sporadic odontogenic keratocysts as well as two novel mutations in cysts associated with NBCCS, indicating a similar pathogenesis in a subset of sporadic keratocysts.

Assuntos

Proteínas de Membrana/genética , Mutação/genética , Cistos Odontogênicos/genética , Transativadores , Adulto , Substituição de Aminoácidos/genética , Síndrome do Nevo Basocelular/genética , Pareamento de Bases/genética , Códon sem Sentido/genética , Indução Embrionária/genética , Éxons/genética , Feminino , Mutação da Fase de Leitura/genética , Deleção de Genes , Genes Supressores de Tumor/genética , Proteínas Hedgehog , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Receptores Patched , Receptor Patched-1 , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Proteínas/genética , Receptores de Superfície Celular , Análise de Sequência de DNA , Transdução de Sinais/genética