RESUMEN

CMT2B1, an axonal subtype (MIM 605588) of the Charcot-Marie-Tooth disease, is an autosomal recessive motor and sensory neuropathy characterized by progressive muscular and sensory loss in the distal extremities with chronic distal weakness. The genetic defect associated with the disease is, to date, a unique homozygous missense mutation, p.Arg298Cys (c.892C>T), in the LMNA gene. So far, this mutation has only been found in affected individuals originating from a restricted region of North Western Africa (northwest of Algeria and east of Morocco), strongly suggesting a founder effect. In order to address this hypothesis, genotyping of both STRs and intragenic SNPs was performed at the LMNA locus, at chromosome 1q21.2-q21.3, in 42 individuals affected with CMT2B1 from 25 Algerian families. Our results indicate that the affected individuals share a common ancestral haplotype in a region of about 1.0 Mb (1 cM) and that the most recent common ancestor would have lived about 800-900 years ago (95% confidence interval: 550 to 1300 years).

Asunto(s)

Enfermedad de Charcot-Marie-Tooth/genética , Efecto Fundador , Lamina Tipo A/genética , Mutación Missense , Argelia , Sustitución de Aminoácidos , Femenino , Homocigoto , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Secuencias Repetidas en Tándem , Factores de Tiempo

Asunto(s)

Blefaroptosis/genética , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 2/genética , Predisposición Genética a la Enfermedad , Oftalmoplejía/genética , Translocación Genética , Niño , Mapeo Cromosómico , Segregación Cromosómica , Femenino , Fibrosis , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Persona de Mediana Edad , Músculos Oculomotores/patología , Oftalmoplejía/congénito , Oftalmoplejía/patología , Linaje

Asunto(s)

Enfermedad de Charcot-Marie-Tooth/genética , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 13/genética , Enfermedades Desmielinizantes/genética , Homocigoto , Adulto , Argelia/etnología , Enfermedad de Charcot-Marie-Tooth/etnología , Enfermedad de Charcot-Marie-Tooth/patología , Mapeo Cromosómico , Enfermedades Desmielinizantes/etnología , Enfermedades Desmielinizantes/patología , Femenino , Genes Recesivos , Pruebas Genéticas , Humanos , Líbano/etnología , Masculino , Linaje , Nervio Sural/patología

Asunto(s)

Enfermedades Desmielinizantes/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Enfermedades del Sistema Nervioso Periférico/genética , Empalme Alternativo/genética , Axones/fisiología , Secuencia de Bases , Niño , Codón sin Sentido , Consanguinidad , ADN/química , ADN/genética , Análisis Mutacional de ADN , ADN Complementario/química , ADN Complementario/genética , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/fisiopatología , Electrofisiología , Salud de la Familia , Femenino , Genotipo , Humanos , Masculino , Microscopía Electrónica , Linaje , Enfermedades del Sistema Nervioso Periférico/patología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Nervio Peroneo/patología , Nervio Peroneo/ultraestructura , Fenotipo

RESUMEN

In Plasmodium falciparum, the causative agent of human malaria, the catalytic subunit gene of cAMP-dependent protein kinase (Pfpka-c) exists as a single copy. Interestingly, its expression appears developmentally regulated, being at higher levels in the pathogenic asexual stages than in the sexual forms of parasite that are responsible for transmission to the mosquito vector. Within asexual parasites, PfPKA activity can be readily detected in schizonts. Similar to endogenous PKA activity of noninfected red blood cells, the parasite enzyme can be stimulated by cAMP and inhibited by protein kinase inhibitor.Importantly, ex vivo treatment of infected erythrocytes with the classical PKA-C inhibitor H89 leads to a block in parasite growth. This suggests that the PKA activities of infected red blood cells are essential for parasite multiplication. Finally, structural considerations suggest that drugs targeting the parasite, rather than the erythrocyte enzyme, might be developed that could help in the fight against malaria.

Asunto(s)

Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Eritrocitos/parasitología , Isoquinolinas/farmacología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/crecimiento & desarrollo , Sulfonamidas , Secuencia de Aminoácidos , Animales , Antimaláricos/farmacología , Western Blotting , Dominio Catalítico , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Diseño de Fármacos , Eritrocitos/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Datos de Secuencia Molecular , Plasmodium falciparum/enzimología , Plasmodium falciparum/genética , Conformación Proteica , Subunidades de Proteína , ARN Mensajero/genética , ARN Mensajero/metabolismo , Alineación de Secuencia

RESUMEN

Prader-Willi syndrome (PWS) is a complex neurogenetic disorder with considerable clinical variability that is thought in large part to be the result of a hypothalamic defect. PWS results from the absence of paternal expression of imprinted genes localized in the 15q11-q13 region; however, none of the characterized genes has so far been shown to be involved in the etiology of PWS. Here, we provide a detailed investigation of a mouse model deficient for NECDIN: Linked to the mutation, a neonatal lethality of variable penetrance is observed. Viable NECDIN: mutants show a reduction in both oxytocin-producing and luteinizing hormone-releasing hormone (LHRH)-producing neurons in hypothalamus. This represents the first evidence of a hypothalamic deficiency in a mouse model of PWS. NECDIN:-deficient mice also display increased skin scraping activity in the open field test and improved spatial learning and memory in the Morris water maze. The latter features are reminiscent of the skin picking and improved spatial memory that are characteristics of the PWS phenotype. These striking parallels in hypothalamic structure, emotional and cognitive-related behaviors strongly suggest that NECDIN is responsible for at least a subset of the multiple clinical manifestations of PWS.

Asunto(s)

Proteínas del Tejido Nervioso/genética , Neuronas/fisiología , Proteínas Nucleares/genética , Síndrome de Prader-Willi/genética , Animales , Cognición/fisiología , Trastornos del Conocimiento/genética , Modelos Animales de Enfermedad , Hormona Liberadora de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Hipotálamo/fisiología , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/fisiología , Proteínas Nucleares/deficiencia , Proteínas Nucleares/fisiología , Oxitocina/metabolismo , Síndrome de Prader-Willi/psicología , Desempeño Psicomotor/fisiología

RESUMEN

Prader-Willi syndrome (PWS) is a complex neurogenetic disorder. The phenotype is likely to be a contiguous gene syndrome involving genes which are paternally expressed only, located in the human 15q11-q13 region. Four mouse models of PWS have been reported but these do not definitively allow the delineation of the critical region and the associated genes involved in the aetiology of PWS. Moreover, targeted mutagenesis of mouse homologues of the human candidate PWS genes does not appear to result in any of the features of PWS. Therefore, the isolation of new genes in this region remains crucial for a better understanding of the molecular basis of PWS. In this manuscript, we report the characterization of MAGEL2 and its mouse homologue Magel2. These are located in the human 15q11-q13 and mouse 7C regions, in close proximity to NDN / Ndn. By northern blot analysis we did not detect any expression of MAGEL2 / Magel2 but by RT-PCR analysis, specific expression was detected in fetal and adult brain and in placenta. Both genes are intronless with tandem direct repeat sequences contained within a CpG island in the 5'-untranscribed region. The transcripts encode putative proteins that are homologous to the MAGE proteins and NDN. Moreover, MAGEL2 / Magel2 are expressed only from the paternal allele in brain, suggesting a potential role in the aetiology of PWS and its mouse model, respectively.

Asunto(s)

Mapeo Cromosómico , Síndrome de Prader-Willi/genética , Proteínas/genética , Regiones no Traducidas 5' , Secuencia de Aminoácidos , Animales , Antígenos de Neoplasias , Secuencia de Bases , Encéfalo/metabolismo , Cromosomas Humanos Par 15 , Islas de CpG , Expresión Génica , Impresión Genómica , Humanos , Ratones , Ratones Endogámicos , Datos de Secuencia Molecular , Linaje , Proteínas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alineación de Secuencia , Secuencias Repetidas en Tándem

RESUMEN

The cDNA encoding Pfmap-2, an enzyme of the human malaria parasite Plasmodium falciparum, was cloned, sequenced, and expressed in Escherichia coli. The open reading frame carried by the Pfmap-2 cDNA encodes a 508-amino acid polypeptide of 59.2 kDa with maximal homology to mitogen-activated protein kinases (MAPKs) from various organisms. The purified recombinant enzyme displayed functional characteristics of MAPKs such as (i) ability to undergo autophosphorylation, (ii) ability to phosphorylate myelin basic protein, a classical MAPK substrate, (iii) regulation of kinase activity by a MAPK-specific phosphatase, and (iv) ability to be activated by component(s) present in cell extracts. Mutational analysis of the recombinant protein allowed the identification of residues that are important for enzymatic activity. Northern blot analysis and immunofluorescence assays indicated that Pfmap-2 is expressed specifically in gametocytes, the form that is responsible for transmission of the parasite to the mosquito vector. Gametocyte extracts activated recombinant Pfmap-2 more efficiently than extracts from asexual parasites, which is consistent with this stage specificity. Despite its overall high level of homology to MAPKs, Pfmap-2 presents the peculiarity of not possessing the conserved threonine-X-tyrosine activation motif usually found in enzymes of this family; instead, it has a threonine-serine-histidine at the same location. This atypical feature formed the basis for a detailed analysis of the primary structure of MAPKs, allowing us to define an operational MAPK signature, which is shared by Pfmap-2. The fact that no MAPK from vertebrates diverge in the activation motif suggests that the fine mechanisms of Pfmap-2 regulation may offer an opportunity for antimalarial drug targeting.

Asunto(s)

Células Germinativas/enzimología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Plasmodium falciparum/enzimología , Proteínas Protozoarias , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Dominio Catalítico , ADN Complementario , Activación Enzimática , Regulación Enzimológica de la Expresión Génica , Humanos , Proteínas Quinasas Activadas por Mitógenos/genética , Datos de Secuencia Molecular , Sistemas de Lectura Abierta , Plasmodium falciparum/crecimiento & desarrollo , Homología de Secuencia de Aminoácido

RESUMEN

The fragile X syndrome is the most frequent cause of inherited mental retardation. CGG repeat alleles are usually classified as normal, premutation, or full mutation based on the length of this triplet in the 5' untranslated region of the FMR1 gene. The pattern of inheritance follows a two-stage intergenerational process in which the premutation evolves into the full mutation. Some reverse mutations have been described, but they appear to be very rare. We describe a family in which a mother of two affected males herself carried a full mutation. Surprisingly, her clinically normal daughter, initially considered to be a carrier by linkage analysis, carried a very short premutation. Findings from our family study corroborate the hypothesis that the expansion during female transmission could be a postzygotic event and raise the problem of mosaicism.

Asunto(s)

Síndrome del Cromosoma X Frágil/genética , Repeticiones de Trinucleótidos/genética , Southern Blotting , Sondas de ADN , Femenino , Síndrome del Cromosoma X Frágil/diagnóstico , Ligamiento Genético , Humanos , Masculino , Mutación , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Diagnóstico Prenatal , Cromosoma X/genética

RESUMEN

We report on a large family (4 generations), with 77 studied individuals, 9 mentally retarded males, and one affected female with fragile X syndrome [fra(X)]. The analysis of 6 flanking polymorphic DNA markers showed that the affection is transmitted, through the carrier daughters to the grandsons and the greatgrandsons and that the great-grandfather is a transmitting male. This observation led us to question the importance of these clinically normal males, who are nonexpressing carriers and termed transmitting males. One propositus, described as a mentally retarded young man, had inherited identical restriction polymorphisms from his mother. Chromosome analysis showed a Klinefelter syndrome, with a fragile site in 18% of the cells leading to the conclusion that the nondisjunction occurred at the first stage of the maternal meiosis.

Asunto(s)

Síndrome del Cromosoma X Frágil/genética , Síndrome de Klinefelter/complicaciones , Sondas de ADN , Femenino , Síndrome del Cromosoma X Frágil/complicaciones , Marcadores Genéticos , Humanos , Síndrome de Klinefelter/genética , Masculino , No Disyunción Genética , Linaje , Polimorfismo de Longitud del Fragmento de Restricción