RESUMO
Char syndrome is an autosomal dominant trait characterized by patent ductus arteriosus, facial dysmorphism and hand anomalies. Using a positional candidacy strategy, we mapped TFAP2B, encoding a transcription factor expressed in neural crest cells, to the Char syndrome critical region and identified missense mutations altering conserved residues in two affected families. Mutant TFAP2B proteins dimerized properly in vitro, but showed abnormal binding to TFAP2 target sequence. Dimerization of both mutants with normal TFAP2B adversely affected transactivation, demonstrating a dominant-negative mechanism. Our work shows that TFAP2B has a role in ductal, facial and limb development and suggests that Char syndrome results from derangement of neural-crest-cell derivatives.
Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Permeabilidade do Canal Arterial/genética , Face/anormalidades , Deformidades Congênitas da Mão/genética , Mutação , Fatores de Transcrição/genética , Células 3T3 , Anormalidades Múltiplas/etiologia , Alanina/genética , Sequência de Aminoácidos , Animais , Ácido Aspártico/genética , Linhagem Celular , Permeabilidade do Canal Arterial/etiologia , Deformidades Congênitas da Mão/etiologia , Camundongos , Dados de Sequência Molecular , Crista Neural/anormalidades , Síndrome , Fator de Transcrição AP-2Assuntos
Neoplasias da Mama/genética , Mutação , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/genética , Fatores de Transcrição/genética , Adulto , Proteína BRCA1 , Feminino , Homozigoto , Humanos , Masculino , Neoplasias/genética , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo Conformacional de Fita SimplesRESUMO
Information about the prenatal exclusion test for Huntington's disease (HD) has been given to an unselected series of couples who attended the genetic counselling clinic from 1986 onwards. Ten couples underwent 13 prenatal tests during this period with expressed intention of stopping a pregnancy if the result indicated a high risk (almost 50%) that the fetus carried the HD gene. Nine fetuses at nearly 50% risk of carrying the HD gene were identified but only six such pregnancies were terminated. In each of three high risk pregnancies which continued, the mother made a "final hour" decision not to undergo the scheduled, first trimester termination. In our experience, late reversal of a previous decision to undergo first trimester pregnancy termination for a genetic indication is uniquely frequent among couples who have undergone the prenatal exclusion test for HD.
Assuntos
DNA/análise , Doença de Huntington/diagnóstico , Doença de Huntington/genética , Adulto , Amostra da Vilosidade Coriônica , Feminino , Aconselhamento Genético , Marcadores Genéticos , Testes Genéticos , Humanos , Masculino , Gravidez , Diagnóstico Pré-Natal , EscóciaAssuntos
Mutação da Fase de Leitura/genética , Genes da Neurofibromatose 1/genética , Mutação em Linhagem Germinativa/genética , Mutagênese Insercional , Neurofibromatose 1/genética , Adulto , Sequência de Bases , DNA/análise , Análise Mutacional de DNA , Éxons/genética , Feminino , Humanos , Dados de Sequência Molecular , Neurofibromina 1 , Ácidos Nucleicos Heteroduplexes , Reação em Cadeia da Polimerase , Proteínas/genéticaRESUMO
A large family is described in which patent ductus arteriosus in association with an unusual facial appearance affected nine family members in three generations. The segregation pattern suggests autosomal dominant inheritance with incomplete penetrance with respect to the PDA. The facial features included a broad, high forehead, flat profile, and short nose with a broad, flattened tip.
Assuntos
Permeabilidade do Canal Arterial/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Expressão Gênica , Genes Dominantes , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Linhagem , FisiognomiaRESUMO
Phenotypic abnormalities of the renin-angiotensin system have been associated with the predisposition to high blood pressure. The angiotensin I converting enzyme (ACE) gene has been implicated as a candidate gene. We examined the distribution of common alleles of the ACE gene and measured circulating components of the renin-angiotensin system and urinary sodium excretion in 170 young Caucasian adults with contrasting genetic predisposition to high blood pressure. Predisposition was defined on the basis of personal and parental blood pressure levels by using the four corners sampling method. Young adults with greatest predisposition who had high blood pressure and two parents with high blood pressure did not show any significant difference in the distribution of the markers of the ACE gene, either as genotype or allele frequencies, when compared with young adults with least predisposition who had low blood pressure and two parents with low blood pressure. Offspring with urinary sodium excretion above the median (143.4 mmol per day) also showed no significant differences in the distribution of ACE alleles or genotype between groups. Different genotypes were associated with different average serum ACE concentrations (p < 0.0001), but plasma angiotensin II and aldosterone showed no significant variation with ACE genotype. These results suggest that in a group of Caucasians selected from the general population, the ACE gene is not associated with genetic predisposition to high blood pressure. In this population common ACE gene allelic markers would not be useful indexes of susceptibility to hypertension.
Assuntos
Pressão Sanguínea , Hipertensão/genética , Peptidil Dipeptidase A/genética , Adulto , Aldosterona/sangue , Alelos , Angiotensina II/sangue , Diástole , Família , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Hipertensão/enzimologia , Masculino , Pessoa de Meia-Idade , Pais , Peptidil Dipeptidase A/sangue , Renina/sangue , SístoleRESUMO
AIM: To assess the feasibility and utility of a new method to identify factors associated with increased predisposition to high blood pressure in young people. SUBJECTS: Eight hundred and sixty-four people aged 16-24 years and their parents. SETTING: Ladywell Medical Centre, Edinburgh, Scotland, UK. METHOD: Blood pressure was measured in 864 young adults and in both of their parents. Four groups of approximately 50 offspring were selected from the corners of a scatter diagram, with offspring blood pressure scores on one axis and combined parental blood pressure scores on the other. Blood and urine samples were taken for biochemical and genetic analyses. RESULTS: Two groups of offspring had parents with high blood pressure and two groups had parents with low blood pressure. When parental blood pressure was low, comparison of offspring with high and low blood pressure revealed significantly higher mean body mass index in offspring with high blood pressure, but no significant elevation of biochemical or hormonal variables. When parental blood pressure was high, comparison of offspring with high and low blood pressure also revealed a significant difference in body mass index, but in addition, offspring with high blood pressure and high parental blood pressure had higher levels of angiotensinogen, cortisol and 18-OH corticosterone. Restriction fragment length polymorphism analysis revealed that 27% of offspring at the greatest genetic risk (high personal and parental blood pressure) were homozygous for the larger allele of the glucocorticoid receptor gene compared with only 9% of those at lowest genetic risk (low personal and parental blood pressure). CONCLUSION: The combined biochemical and genetic findings suggest that abnormalities of glucocorticoid metabolism and the renin-angiotensin system may help to explain genetic predisposition to high blood pressure. The new sampling method is practicable and could be applied to the investigation of other continuously distributed variables which show familial aggregation.
Assuntos
Pressão Sanguínea/genética , Glucocorticoides/metabolismo , Hipertensão/genética , Sistema Renina-Angiotensina/genética , Adolescente , Adulto , Métodos Epidemiológicos , Estudos de Viabilidade , Feminino , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Receptores de Glucocorticoides/genética , Fatores de Risco , Estudos de AmostragemRESUMO
The new Colorant Mixture Computer (COMIC II) has been designed as a tool for use in matching and controlling color production. It does not replace a trained colorist, but frees him of routine color matching problems. Some of the theory and practice of COMIC II applications in the automotive industry are described.
