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1.
Br J Cancer ; 110(5): 1244-9, 2014 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-24518592

RESUMO

BACKGROUND: Classification of lung carcinoids into typical and atypical is a diagnostic challenge since no immunohistochemical tools are available to support pathologists in distinguishing between the two subtypes. A differential diagnosis is essential for clinicians to correctly discuss therapy, prognosis and follow-up with patients. Indeed, the distinction between the two typical and atypical subtypes on biopsies/cytological specimens is still unfeasible and sometimes limited also after radical surgeries. By comparing the gene expression profile of typical (TC) and atypical carcinoids (AC), we intended to find genes specifically expressed in one of the two subtypes that could be used as diagnostic markers. METHODS: Expression profiling, with Affymetrix arrays, was performed on six typical and seven atypical samples. Data were validated on an independent cohort of 29 tumours, by means of quantitative PCR and immunohistochemistry (IHC). RESULTS: High-throughput gene expression profiling was successfully used to identify a gene signature specific for atypical lung carcinoids. Among the 273 upregulated genes in the atypical vs typical subtype, GC (vitamin D-binding protein) and CEACAM1 (carcinoembryonic antigen family member) emerged as potent diagnostic markers. Quantitative PCR and IHC on a validation set of 17 ACs and 12 TCs confirmed their reproducibility and feasibility. CONCLUSIONS: GC and CEACAM1 can distinguish between TC and AC, defining an IHC assay potentially useful for routine cytological and histochemical diagnostic procedures. The high sensitivity and reproducibility of this new diagnostic algorithm strongly support a further validation on a wider sample size.


Assuntos
Antígenos CD/genética , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/genética , Moléculas de Adesão Celular/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Proteína de Ligação a Vitamina D/genética , Idoso , Biomarcadores Tumorais/genética , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Transcriptoma
2.
Radiol Med ; 116(4): 564-74, 2011 Jun.
Artigo em Inglês, Italiano | MEDLINE | ID: mdl-21431301

RESUMO

PURPOSE: This study evaluated the methods, technical aspects and impact of preoperative radiological guidance in radioguided occult lesion localisation (ROLL) for single nonpalpable breast lesions. MATERIALS AND METHODS: A total of 288 patients underwent ROLL before surgery. Human serum albumin macroaggregates labelled with 3.7-7.4 MBq of technetium(99) were injected into the lesion. In the case of ultrasonographic guidance (221/288 patients), inoculum positioning resulted in a change of echogenicity at the lesion site. In the case of mammographic guidance (67/288 patients), iodinated contrast medium was injected following the radiotracer for subsequent mammographic evaluation. Patients underwent surgery within 24 h from ROLL. A gamma-detecting probe was used to locate the lesion during surgery and guide its removal. After excision, the specimen was examined by either ultrasonography or mammography to verify complete lesion removal before histological evaluation. RESULTS: The lesion was correctly localised in 281/288 patients (97.5%). One ROLL procedure failed because surgery could not be performed within 24 h and the radioactivity decayed. Of the six incorrect localisations, 2 were due to the radiological guidance and 4 to technetium(99) dispersion. CONCLUSIONS: Radiological guidance in ROLL ensured the outcome of the procedure of localisation and removal of single, nonpalpable breast lesions in the majority of cases.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Mama/diagnóstico por imagem , Radiografia Intervencionista , Compostos Radiofarmacêuticos , Agregado de Albumina Marcado com Tecnécio Tc 99m , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha , Mama/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/cirurgia , Meios de Contraste , Feminino , Humanos , Injeções Intradérmicas , Pessoa de Meia-Idade , Palpação , Cintilografia , Agregado de Albumina Marcado com Tecnécio Tc 99m/administração & dosagem , Ultrassonografia de Intervenção
4.
Oncogene ; 30(9): 1117-26, 2011 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-20972464

RESUMO

Computed tomography (CT) screening of lung cancer allows the detection of early tumors. The objective of our study was to verify whether initial asymptomatic lung cancers, identified by high-resolution low-dose CT (LD-CT) on a high-risk population, show genetic abnormalities that could be indicative of the early events of lung carcinogenesis. We analyzed 78 tumor samples: 21 (pilot population) from heavy smokers with asymptomatic non-screening detected early-stage lung cancers and 57 from 5203 asymptomatic heavy smoker volunteers, who underwent a LD-CT screening study. During surgical resection of the detected tumors, tissue samples were collected and short-term cultures were started for karyotype evaluation. Samples were classified according to the normal (NK) or aneuploid (AK) karyotype. The NK samples were further analyzed by the Affymetrix single-nucleotide polymorphisms (SNPs) technology. Metaphase spreads were obtained in 73.0% of the selected samples: 80.7% showed an AK. A statistically significant correlation was found between presence of vascular invasion and abnormal karyotype. A total of 10 NK samples were suitable for SNPs analysis. Subtle genomic alterations were found in eight tumors, the remaining two showing no evidence to date of chromosomal aberrations anywhere in the genome. Two common regions of amplification were identified at 5p and 8p11. Mutation analysis by direct sequencing was conducted for the K-RAS, TP53 and EGFR genes, confirming data already described for heavy smokers. We show that: (i) the majority of screening-detected tumors are aneuploid; (ii) early-stage tumors tend to harbor a less abnormal karyotype; (iii) whole genome analysis of NK tumors allows for the detection of common regions of copy number variation (such as amplifications at 5p and 8p11), highlighting genes that might be considered candidate markers of early events in lung carcinogenesis.


Assuntos
Aneuploidia , Doenças Assintomáticas , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Idoso , Variações do Número de Cópias de DNA , Detecção Precoce de Câncer , Genes erbB-1 , Genes p53 , Genes ras , Humanos , Cariotipagem , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Programas de Rastreamento , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Fumar , Tomografia Computadorizada por Raios X
7.
Diabet Med ; 26(9): 847-54, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19719704

RESUMO

AIMS: Studies have pointed to insulin resistance as a pathogenic factor in fatty liver. Although pancreatic B-cell function is believed to be involved, its role is unclear. This study was undertaken to test whether fasting C-peptide, an index of fasting B-cell function, was related to intra-hepatic fat (IHF) content in non-diabetic humans. METHODS: We assessed, retrospectively, fasting plasma C-peptide concentration in 31 patients with fatty liver and 62 individuals without fatty liver. The IHF content was measured by proton magnetic resonance spectroscopy ((1)H-MRS), while insulin sensitivity was estimated based on fasting plasma glucose and insulin with the homestasis model assessment (HOMA) 2 method. RESULTS: Age, sex and body mass index (BMI) were not different between groups. Patients with fatty liver had higher fasting insulin (P < 0.01), C-peptide (P < 0.005) and lower insulin sensitivity (HOMA2-%S). Fasting insulin alone explained 14% of the IHF content variability (P < 0.001); inclusion of fasting C-peptide in multivariate regression explained up to 32% (P < 0.001). A subgroup analysis was performed by matching 1 : 1 for HOMA2-%S. These data were analysed by conditional logistic regression which showed that, when HOMA2-%S was matched between groups, fasting C-peptide remained the only significant predictor of fatty liver. CONCLUSIONS: Non-diabetic individuals with fatty liver are characterized by increased fasting plasma C-peptide concentration, irrespective of their insulin resistant state.


Assuntos
Linfócitos B/fisiologia , Glicemia/metabolismo , Peptídeo C/metabolismo , Fígado Gorduroso/metabolismo , Resistência à Insulina/fisiologia , Adulto , Jejum/fisiologia , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Valores de Referência , Estudos Retrospectivos
8.
Heart ; 95(8): 630-5, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19008274

RESUMO

OBJECTIVE: Ageing of the human heart is characterised by morphological, functional and metabolic changes. Short-term interventions and cross-sectional studies in older individuals questioned the possibility that physical exercise may reverse these alterations. In this study we aimed to assess whether in middle-aged men involved in regular and long lasting physical activity these alterations were attenuated. DESIGN: Left ventricular (LV) magnetic resonance imaging (MRI) and three-dimensional image selected in-vivo spectroscopy (3D-ISIS) (31)P magnetic resonance spectroscopy (MRS) were performed using a 1.5T scanner in 20 healthy, young and 25 healthy middle-aged non-obese men with a sedentary lifestyle (11 young and 14 middle-aged) or undergoing regular aerobic oxidative training (9 young and 11 middle-aged). Insulin sensitivity was estimated by the homeostatic model assessment 2 (HOMA-2) model. RESULTS: Sedentary young and middle-aged men were not different with respect to LV morphological parameters and systolic function. The phosphocreatine/ATP (PCr/ATP) ratio (marker of high energy phosphates metabolism) and the LV E-peak filling rate/A-peak filling rate ratio (E/A ratio) were lower in sedentary middle-aged than physically active subjects. Parameters of LV systolic function and the PCr/ATP ratio were not different in the middle-aged compared with the young trained men; the E/A peak flow ratio was higher in the middle-aged trained men than in the middle-aged sedentary men. Within the entire population, the PCr/ATP ratio and the E/A peak flow ratio were associated with insulin sensitivity. CONCLUSIONS: Trained middle-aged subjects showed a better pattern of LV energy metabolism and of diastolic function than their sedentary counterparts. At this age the exercise-related cardiac benefits were detectable when physical exercise was performed regularly and for a long period of time.


Assuntos
Metabolismo Energético/fisiologia , Exercício Físico/fisiologia , Função Ventricular Esquerda/fisiologia , Trifosfato de Adenosina/metabolismo , Adulto , Envelhecimento/fisiologia , Antropometria/métodos , Humanos , Resistência à Insulina/fisiologia , Estilo de Vida , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Atividade Motora/fisiologia , Contração Miocárdica , Fosfocreatina/metabolismo , Adulto Jovem
9.
Heart ; 95(3): 228-33, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18708417

RESUMO

OBJECTIVE: Areas of intramyocardial late enhancement (LE) at delayed enhanced magnetic resonance imaging (DE-MRI) and reduction of myocardial phosphocreatine (PCr)/ATP-ratio at phosphorus magnetic resonance spectroscopy ((31)P-MRS) are both reported in hypertrophic cardiomyopathy (HCM) and indicate areas of increased interstitial myocardial space with fibrosis and impairment of myocardial energy metabolism, respectively. We sought to ascertain whether in HCM patients the abnormal features of left ventricular (LV) interstitial space revealed by DE-MRI correlated with impaired LV energy metabolism shown at (31)P-MRS. METHODS: 19 patients with HCM proved by histological analysis of multiple endomyocardial biopsies and with normal coronary arteries, underwent cardiac MRI including DE-MRI and (31)P-MRS. DE-MRI for detection and quantification of late enhancement (LE) and (31)P-MRS to assess the myocardial PCr/ATP-ratio were performed by means of a 1.5-T magnet. 19 healthy subjects, matched for gender and age were studied by (31)P-MRS as control group. RESULTS: LE areas in the LV wall were found in 17 out of 19 patients with an extension ranging from 0.8% to 19.5% of the LV-mass (mean value 7.6% (SD 5.6%). The PCr/ATP-ratio was lower in HCM patients than in control subjects (2.18 (0.41) vs 2.41 (0.30); p<0.05). LE% and PCr/ATP-ratio were inversely related (R = -0.57; p<0.05) and LE% was the stronger predictor of PCr/ATP-ratio by multivariate analysis. CONCLUSIONS: This study demonstrated that the known alteration of the PCr/ATP-ratio observed in HCM patients is correlated with the presence of fibrotic areas in the myocardium of the left ventricle.


Assuntos
Trifosfato de Adenosina/metabolismo , Cardiomiopatia Hipertrófica/metabolismo , Fibrose Endomiocárdica/metabolismo , Miocárdio/patologia , Fosfocreatina/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Meios de Contraste , Diagnóstico Precoce , Fibrose Endomiocárdica/patologia , Metabolismo Energético , Feminino , Fibrose , Gadolínio , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Humanos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Volume Sistólico
11.
J Pediatr Surg ; 39(9): 1305-11, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15359381

RESUMO

BACKGROUND/PURPOSE: The Currarino syndrome (CS) is a peculiar form of caudal regression syndrome (CRS) characterized by the association of hemisacrum, anorectal malformation (ARM), and presacral mass. The authors analyzed retrospectively their series, and they propose a multidisciplinary diagnostic and therapuetic protocol that until now has not been introduced. METHODS: A series of 6 patients with CS is presented. Five of them were treated initially in other centers. None of them had an early diagnosis. All presented associated anomalies; in 50%, Hirschsprung's disease (HD) and other dysganglionoses were present. One patient died of a presacral ectopic nephroblastoma. RESULTS: Depending on the expressivity, 3 types of CS can be identified, complete, mild, and minimal. Dysganglionoses and HD can be considered part of CS. A multidisciplinary diagnostic and therapeutic protocol is presented. Main points are sacrum x-Ray, molecular genetic diagnosis, radiologic evaluation of every member of CS families, magnetic resonance (MR) evaluation of patient spine and pelvis, suction rectal biopsies, and search for associated anomalies. CONCLUSIONS: This protocol could give a valid contribution to the treatment of CS, allowing an early diagnosis and proposing a rational timing of multidisciplinary surgical procedures. Early diagnosis and treatment are essential to avoid morbidity and mortality from an undiagnosed presacral mass.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/cirurgia , Canal Anal/anormalidades , Meningocele/diagnóstico , Meningocele/cirurgia , Reto/anormalidades , Sacro/anormalidades , Anormalidades Múltiplas/genética , Cromossomos Humanos Par 7/genética , Cóccix/anormalidades , Colostomia , Constipação Intestinal/etiologia , Diagnóstico Precoce , Evolução Fatal , Feminino , Genes Dominantes , Doença de Hirschsprung/complicações , Proteínas de Homeodomínio/genética , Humanos , Recém-Nascido , Lipoma/genética , Vértebras Lombares/anormalidades , Masculino , Meningocele/complicações , Defeitos do Tubo Neural/etiologia , Neoplasias Pélvicas/genética , Fenótipo , Fístula Retal/congênito , Estudos Retrospectivos , Síndrome , Teratoma/genética , Fatores de Transcrição/genética , Vagina/anormalidades , Tumor de Wilms/complicações , Tumor de Wilms/genética
12.
Clin Genet ; 57(5): 388-93, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10852374

RESUMO

We report an infant with holoprosencephaly (HPE), sacral anomalies, and situs ambiguus with a 46,XY,der(7)t(2;7)(p23.2;q36.1) karyotype as a result of an adjacent-1 segregation of a t(2;7)pat. The chromosomal abnormality was diagnosed prenatally after sonographic detection of HPE in the fetus. The baby was born at 37 weeks gestation, and died in the newborn period; he had dysmorphic features consistent with HPE sequence. Postmortem internal evaluation showed semilobar HPE, abdominal situs ambiguus, multiple segments of bowel atresia, dilatation of the ureters, and bony sacral anomalies. Molecular analysis confirmed hemizygosity for the SHH and HLXB9 genes, which are likely to be responsible for the HPE and sacral phenotypes, respectively. Immunohistochemical studies showed intact dopaminergic pathways in the mesencephalon, suggesting that midbrain dopamine neuron induction appears to require only one functioning SHH allele.


Assuntos
Abdome/anormalidades , Cromossomos Humanos Par 2 , Cromossomos Humanos Par 7 , Genes Homeobox/genética , Holoprosencefalia/genética , Monossomia/genética , Proteínas/genética , Região Sacrococcígea/anormalidades , Transativadores , Trissomia/genética , Abdome/patologia , Anormalidades Múltiplas/genética , Proteínas Hedgehog , Holoprosencefalia/diagnóstico por imagem , Holoprosencefalia/patologia , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Recém-Nascido , Masculino , Radiografia Abdominal , Região Sacrococcígea/diagnóstico por imagem , Região Sacrococcígea/patologia
14.
Nat Genet ; 20(4): 358-61, 1998 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9843207

RESUMO

Partial absence of the sacrum is a rare congenital defect which also occurs as an autosomal dominant trait; association with anterior meningocoele, presacral teratoma and anorectal abnormalities constitutes the Currarino triad (MIM 176450). Malformation at the caudal end of the developing notochord at approximately Carnegie stage 7 (16 post-ovulatory days), which results in aberrant secondary neurulation, can explain the observed pattern of anomalies. We previously reported linkage to 7q36 markers in two dominantly inherited sacral agenesis families. We now present data refining the initial subchromosomal localization in several additional hereditary sacral agenesis (HSA) families. We excluded several candidate genes before identifying patient-specific mutations in a homeobox gene, HLXB9, which was previously reported to map to 1q41-q42.1 and to be expressed in lymphoid and pancreatic tissues.


Assuntos
Doenças Ósseas/genética , Genes Dominantes , Genes Homeobox , Sacro/anormalidades , Sequência de Bases , Doenças Ósseas/congênito , Cromossomos Humanos Par 1 , Feminino , Haplótipos , Humanos , Masculino , Linhagem , Fenótipo , Mapeamento Físico do Cromossomo
15.
Hum Genet ; 102(4): 387-92, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9600232

RESUMO

The human Sonic Hedgehog gene (SHH) is one of the vertebrate homologs related to the Drosophila segment polarity gene hedgehog. The entire coding and promoter region of the SHH gene, including 2 kb 5' of the transcriptional start site has been screened for mutations in families with autosomal dominant sacral agenesis and autosomal dominant triphalangeal thumb, two conditions previously known to be linked to 7q36. We have also studied the SHH gene in five families with mirror polydactyly associated with tibial hemimelia and in 51 unrelated patients with neural tube defects. Except for two sequence variants in exon 3, no mutations were found in these disease categories. OFF


Assuntos
Anormalidades Múltiplas/genética , Polidactilia/genética , Regiões Promotoras Genéticas , Proteínas/análise , Proteínas/genética , Região Sacrococcígea/anormalidades , Polegar/anormalidades , Transativadores , Sequência de Bases , Cromossomos Humanos Par 7 , Clonagem Molecular , Éxons , Proteínas Hedgehog , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Análise de Sequência de DNA
16.
Hum Mol Genet ; 6(11): 1847-53, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9302262

RESUMO

Holoprosencephaly (HPE) is the most common brain anomaly in humans, involving abnormal formation and septation of the developing central nervous system. Among the heterogeneous causes of HPE, mutations in the Sonic Hedgehog (SHH) gene have been shown to result in an autosomal dominant form of the disorder. Here we describe a total of five different mutations in the processing domain encoded by exon 3 of SHH in familial and sporadic HPE. This is the first instance in humans where SHH mutations in the domain responsible for autocatalytic cleavage and cholesterol modification of the N-terminal signaling domain of the protein have been observed.


Assuntos
Holoprosencefalia/genética , Mutação Puntual , Proteínas/genética , Transativadores , Alanina/genética , Sequência de Aminoácidos , Animais , Linhagem Celular Transformada , Análise Mutacional de DNA , Éxons , Feminino , Genes Dominantes , Ácido Glutâmico/genética , Glicina/genética , Proteínas Hedgehog , Holoprosencefalia/etiologia , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Deleção de Sequência , Homologia de Sequência de Aminoácidos , Serina/genética , Treonina/genética , Valina/genética
17.
Hum Genet ; 100(2): 172-81, 1997 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9254845

RESUMO

Holoprosencephaly (HPE) is a genetically heterogeneous disorder that affects the midline development of the forebrain and midface in humans. As a step toward identifying one of the HPE genes, we have set out to refine the HPE3 critical region on human chromosome 7q36 by analyzing 34 cell lines from families with cytogenetic abnormalities involving 7q, 24 of which are associated with HPE. Genomic clones surrounding the DNA marker D7S104, which has previously been shown to be in the HPE3 critical region, have been examined by fluorescent in situ hybridization and microsatellite analysis of our panel of patient cell lines. We report the analysis of a cluster of four translocation breakpoints within a 300-kb region of 7q36 that serves to define the minimal critical region for HPE3 and that has directed the search for candidate genes. The human Sonic Hedgehog (hSHH) gene maps to this region and has been shown to be HPE3 on the basis of mutations within the coding region of the gene. We present evidence that cytogenetic deletions and/or rearrangements of this region of chromosome 7q containing Sonic Hedgehog, and translocations that may suppress Sonic Hedgehog gene expression through a position effect are common mechanisms leading to HPE.


Assuntos
Cromossomos Humanos Par 7/genética , Deleção de Genes , Holoprosencefalia/genética , Proteínas/genética , Transativadores , Translocação Genética , Padronização Corporal/genética , Quebra Cromossômica , Fragilidade Cromossômica , Mapeamento Cromossômico , Indução Embrionária/genética , Proteínas Hedgehog , Heterozigoto , Holoprosencefalia/etiologia , Humanos , Microcefalia/genética
18.
Nat Genet ; 14(3): 357-60, 1996 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8896572

RESUMO

Holoprosencephaly (HPE) is a common developmental defect of the forebrain and frequently the midface in humans, with both genetic and environmental causes. HPE has a prevalence of 1:250 during embryogenesis and 1:16,000 newborn infants, and involves incomplete development and septation of midline structures in the central nervous system (CNS) with a broad spectrum of clinical severity. Alobar HPE, the most severe form which is usually incompatible with postnatal life, involves complete failure of division of the forebrain into right and left hemispheres and is characteristically associated with facial anomalies including cyclopia, a primitive nasal structure (proboscis) and/or midfacial clefting. At the mild end of the spectrum, findings may include microcephaly, mild hypotelorism, single maxillary central incisor and other defects (Fig. 1). This phenotypic variability also occurs between affected members of the same family. The molecular basis underlying HPE is not known, although teratogens, non-random chromosomal anomalies and familial forms with autosomal dominant and recessive inheritance have been described. HPE3 on chromosome 7q36 is one of at least four different loci implicated in HPE. Here, we report the identification of human Sonic Hedgehog (SHH) as HPE3-the first known gene to cause HPE. Analyzing 30 autosomal dominant HPE (ADHPE) families, we found five families that segregate different heterozygous SHH mutations. Two of these mutations predict premature termination of the SHH protein, whereas the others alter highly conserved residues in the vicinity of the alpha-helix-1 motif or signal cleavage site.


Assuntos
Proteínas de Drosophila , Holoprosencefalia/genética , Mutação , Proteínas/genética , Alelos , Sequência de Aminoácidos , Sequência Conservada , Primers do DNA , Feminino , Proteínas Hedgehog , Heterozigoto , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Linhagem , Polimorfismo Conformacional de Fita Simples
19.
Nat Genet ; 14(3): 353-6, 1996 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8896571

RESUMO

Holoprosencephaly (HPE) is a genetically and phenotypically heterogenous disorder involving the development of forebrain and midface, with an incidence of 1:16,000 live born and 1:250 induced abortions. This disorder is associated with several distinct facies and phenotypic variability: in the most extreme cases, anophthalmia or cyclopia is evident along with a congenital absence of the mature nose. The less severe form features facial dysmorphia characterized by ocular hypertelorism, defects of the upper lip and/or nose, and absence of the olfactory nerves or corpus callosum. Several intermediate phenotypes involving both the brain and face have been described. One of the gene loci, HPE3, maps to the terminal band of chromosome 7. We have performed extensive physical mapping studies and established a critical interval for HPE3, and subsequently identified the sonic hedgehog (SHH) gene as the prime candidate for the disorder. SHH lies within 15-250 kilobases (kb) of chromosomal rearrangements associated with HPE, suggesting that a 'position effect' has an important role in the aetiology of HPE. As detailed in the accompanying report, this role for SHH is confirmed by the detection of point mutations in hereditary HPE patients.


Assuntos
Mapeamento Cromossômico , Holoprosencefalia/genética , Proteínas/genética , Transativadores , Sequência de Aminoácidos , Sequência de Bases , Criança , Cromossomos Humanos Par 7 , Clonagem Molecular , Feminino , Deleção de Genes , Rearranjo Gênico , Proteínas Hedgehog , Humanos , Hibridização in Situ Fluorescente , Dados de Sequência Molecular , Fenótipo , Mapeamento por Restrição , Homologia de Sequência do Ácido Nucleico , Translocação Genética
20.
Genomics ; 37(3): 345-53, 1996 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-8938447

RESUMO

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) have been shown to act on a wide range of tissue and cell types, both in the central nervous system and in the periphery. Two distinct receptors for VIP, the VIP receptor type 1 (VIPR1) and the VIP receptor type 2 (VIPR2), have recently been cloned, each of which binds PACAP and VIP with equal affinity. We report here the chromosomal mapping of the human and mouse VIPR2 genes by fluorescence in situ hybridization. The VIPR2 gene maps to the human chromosomal region 7q36.3 and to the F2 region of mouse chromosome 12. Our localization of the human gene places it in the region where the locus for the craniofacial defect holoprosencephaly type 3 (HPE3) maps. Further mapping experiments, carried out on cell lines derived from patients with HPE or HPE microforms and associated 7q deletions, have led us to redefine the distal extent of the HPE3 minimal critical region, originally characterized by Gurrieri et al. (1993, Nature Genet. 3: 247-251.) The VIPR2 gene lies within this new HPE3 minimal critical region. Our results suggest that deletion of the VIPR2 gene is not the sole factor responsible for the HPE3 phenotype. However, it is possible that monosomy at the VIPR2 locus may contribute to the phenotype observed in many cases of HPE3.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 7/genética , Holoprosencefalia/genética , Camundongos/genética , Receptores de Peptídeo Intestinal Vasoativo/genética , Animais , Linhagem Celular , Cromossomos Artificiais de Levedura/genética , Cricetinae , Genes , Holoprosencefalia/classificação , Holoprosencefalia/patologia , Humanos , Células Híbridas , Hibridização in Situ Fluorescente , Receptores Tipo II de Peptídeo Intestinal Vasoativo , Especificidade da Espécie
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