RESUMEN
We have performed association studies between a novel coding single nucleotide polymorphism (D104N) in endostatin, one of the most potent inhibitors of angiogenesis, and prostate cancer. We observed that heterozygous N104 individuals have a 2.5 times increased chance of developing prostate cancer as compared with homozygous D104 subjects (odds ratio, 2.4; 95% confidence interval, 1.4-4.16). Modeling of the endostatin mutant showed that the N104 protein is stable. These results together with the observation that residue 104 is evolutionary conserved lead us to propose that: (a) the DNA segment containing this residue might contain a novel interaction site to a yet unknown receptor; and (b) the presence of N104 impairs the function of endostatin.
Asunto(s)
Adenocarcinoma/genética , Inhibidores de la Angiogénesis/genética , Colágeno/genética , Fragmentos de Péptidos/genética , Polimorfismo Genético , Neoplasias de la Próstata/genética , Anciano , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/fisiología , Colágeno/química , Colágeno/fisiología , Endostatinas , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Modelos Moleculares , Fragmentos de Péptidos/química , Fragmentos de Péptidos/fisiología , Electricidad Estática , Propiedades de SuperficieRESUMEN
OBJECTIVE: To compare the clinical features of a familial prion disease with those of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). BACKGROUND: Prion diseases are not usually considered in the differential diagnosis of FTDP-17, since familial Creutzfeldt-Jakob disease (CJD), the most common inherited prion disease, often manifests as a rapidly progressive dementia. Conversely, FTDP-17 usually has an insidious onset in the fifth decade, with abnormal behavior and parkinsonian features. METHOD: We present the clinical features of 12 patients from a family with CJD associated with a point mutation at codon 183 of the prion protein gene. RESULTS: The mean age at onset was 44.0 +/- 3.7; the duration of the symptoms until death ranged from two to nine years. Behavioral disturbances were the predominant presenting symptoms. Nine patients were first seen by psychiatrists. Eight patients manifested parkinsonian signs. CONCLUSION: These clinical features bear a considerable resemblance to those described in FTDP-17.
Asunto(s)
Cromosomas Humanos Par 17/genética , Síndrome de Creutzfeldt-Jakob/genética , Trastornos Parkinsonianos/genética , Adulto , Síndrome de Creutzfeldt-Jakob/diagnóstico , Demencia/diagnóstico , Demencia/genética , Diagnóstico Diferencial , Femenino , Ligamiento Genético , Humanos , Masculino , Persona de Mediana Edad , Trastornos Parkinsonianos/diagnóstico , LinajeRESUMEN
We report on a four-generation inbred family including 10 individuals affected with a form of craniotubular dysplasia (CTD). All affected patients were born to consanguineous healthy parents; this finding, together with the equal sex ratio among affected individuals and the occurrence of only normal individuals among their offspring, indicates that the disease in this family is an autosomal recessive (AR) trait. Taking into account the segregation pattern of the disease in the family and the radiological characteristics of two young CTD patients, the most likely diagnosis for the defect is AR craniometaphyseal dysplasia (CMD). CMD is a CTD, with both autosomal dominant (AD) and recessive forms. The description of the present genealogy confirms the AR pattern of inheritance of some cases of CMD and contributes to a better delineation of the clinical spectrum of AR CMD, suggesting a more pronounced diaphyseal involvement in the AR compared with the AD CMD. Through genomewide scanning, we mapped the AR CMD to a 7 cM interval, between D6S302 and D6S1639, at 6q21-22 region. We have also excluded the positional candidate COL10A1 gene as being the responsible for this disorder. Curiously, a form of AR spondylocostal dysplasia (SD) also segregates in the family, including one affected individual with both conditions. The gene DLL3, mapped to 19q13 region, was recently found to be responsible for one form of AR SD; however, we did not find evidence of linkage between this 19q region and the SD segregating in our family, thus implying in genetic heterogeneity for AR SD.
Asunto(s)
Huesos/anomalías , Cromosomas Humanos Par 6/genética , Colágeno Tipo I , Colágeno/genética , Anomalías Craneofaciales/genética , Genes Recesivos , Osteocondrodisplasias/genética , Adulto , Anciano , Huesos/diagnóstico por imagen , Preescolar , Mapeo Cromosómico , Cromosomas Humanos Par 19/genética , Cadena alfa 1 del Colágeno Tipo I , Anomalías Craneofaciales/diagnóstico por imagen , ADN/análisis , Femenino , Heterogeneidad Genética , Ligamiento Genético , Humanos , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Osteocondrodisplasias/diagnóstico por imagen , Linaje , Fenotipo , RadiografíaRESUMEN
Human prion diseases include Creutzfeldt-Jakob disease, Gerstmann-Stráussler-Scheinker disease, fatal familial insomnia, and kuru. Each of these diseases has a specific clinical presentation while spongiform encephalopathy, neuronal loss, and gliosis are their neuropathological hallmarks. We studied a Brazilian family with an autosomal dominant form of dementia. Nine members of the family were affected by a dementia with frontotemporal clinical features, with a mean age at onset of 44.8 +/- 3.8 years and a mean duration of symptoms of 4.2 +/- 2.4 years. Neuropathological examination of 3 patients showed severe spongiform change and neuronal loss in the deep cortical layers and in the putamen, but minimal gliosis in the most severely affected areas. The putamen and cerebellum, but not other areas of the affected brain, displayed prion protein immunoreactivity. A novel prion protein gene mutation causing a nonconservative substitution at codon 183 was identified in 2 neuropathologically confirmed affected individuals (mother and son). The mutation was transmitted in a mendelian fashion to 12 members of the family. Therefore, we identified a novel prion disease variant characterized by an early onset and long duration of the symptoms, severe spongiform change with minimal gliosis, associated with a prion protein gene mutation at codon 183.
Asunto(s)
Encéfalo/patología , Mutación , Enfermedades por Prión/genética , Priones/genética , Adulto , Edad de Inicio , Secuencia de Aminoácidos , Secuencia de Bases , Brasil , Cartilla de ADN , Exones , Femenino , Genes Dominantes , Enfermedad de Gerstmann-Straussler-Scheinker/genética , Humanos , Masculino , Persona de Mediana Edad , Linaje , Reacción en Cadena de la Polimerasa , Enfermedades por Prión/fisiopatología , Enfermedades por Prión/psicologíaRESUMEN
Autosomal recessive limb-girdle muscular dystrophies (AR LGMD) represent a group of muscle diseases with a wide spectrum of clinical signs, varying from very severe to mild. Four different loci that when mutated cause the AR LGMD phenotype have been mapped or cloned or both: in two of them the linked families seem to have a relatively mild phenotype (LGMD2a and LGMD2b), in the third one the reported linked families show a more severe clinical course (LGMD2c), while mutations in the fourth locus may cause severe or mild phenotypes (LGMD2d). The relative proportion of each of these genetic forms among the LGMD families and whether there are other genes that when mutated cause this phenotype is unknown. The closest available informative markers for each of the mapped AR LGMD genes have been tested in 13 Brazilian families with at least three affected patients. The findings from the present report confirm non-allelic heterogeneity for LGMD and suggest that in our population about 33% of the LGMD families are caused by mutations in the 15q gene, 33% in the 2p gene, 17% by mutations in the adhalin gene, and less than 10% may be by mutations at the 13q locus. They also suggest that there is at least one other gene responsible for this phenotype. In addition, the main clinical features of the different forms are discussed.
Asunto(s)
Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 15/genética , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 2/genética , Genes Recesivos , Heterogeneidad Genética , Distrofias Musculares/genética , Adolescente , Adulto , Brasil/epidemiología , Calpaína/deficiencia , Calpaína/genética , Niño , Preescolar , Consanguinidad , Proteínas del Citoesqueleto/genética , Femenino , Marcadores Genéticos , Genotipo , Humanos , Escala de Lod , Masculino , Glicoproteínas de Membrana/genética , Distrofias Musculares/clasificación , Distrofias Musculares/epidemiología , Distrofias Musculares/patología , Linaje , Fenotipo , SarcoglicanosRESUMEN
We describe a method for the purification of ferritin from Musca domestica larval hemolymph. Musca ferritin occurs in hemolymph predominantly as a native protein with molecular weight equal to 550,000 and subunits of 26,000. The average iron content of purified ferritin was determined to be 3,000 +/ 600 iron atoms per molecule. The iron contents of ferritin was heterogeneous; both fully iron loaded molecules and apoferritin are probably present in the Musca hemolymph. The anti-ferritin serum raised in rabbit was able to recognize native ferritin but was not reactive with the protein subunits isolated by SDS-PAGE. The ferritin concentration in hemolymph attains a maximum of 0.28 mg/ml in the wandering stage larvae decreasing to 0.13 mg/ml at the middle of pupal stadium. The ferritin contents of midgut and fat bodies were also determined. Fat body ferritin content is greatly reduced when the feeding larva passes into wandering stage.
Asunto(s)
Ferritinas/sangre , Moscas Domésticas/metabolismo , Animales , Ferritinas/aislamiento & purificación , Hemolinfa , Larva , Pupa , ConejosRESUMEN
The mild autosomal recessive limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of muscle diseases. The first gene to be mapped and associated with this phenotype was a locus on 15q based on linkage analysis in families from a French geographic isolate. These results have been confirmed in other populations, but it was shown that there is genetic heterogeneity for this form of LGMD. Recently, a second locus has been mapped to chromosome 2p. The confirmation of the mapping of this second locus in LGMD families from different populations is of utmost importance for the positional cloning of this gene (HGMW-approved symbol LGMD2B). In this publication, haplotypes generated from five chromosome 2 markers from all of the known large families linked to chromosome 2p are reported together with the recombinants that show the current most likely location of the LGMD 2B gene.