Asunto(s)
Colágeno Tipo VI/genética , Miositis/diagnóstico , Niño , Femenino , Humanos , Imagen por Resonancia Magnética , Mutación , Miositis/genéticaAsunto(s)
Complejo I de Transporte de Electrón/deficiencia , Enfermedad de Leigh/genética , Enfermedades Mitocondriales/genética , NADH Deshidrogenasa/genética , Eliminación de Secuencia/genética , Compuestos Azo , Encéfalo/patología , Niño , Complejo I de Transporte de Electrón/genética , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Enfermedad de Leigh/patología , Imagen por Resonancia Magnética , Masculino , Músculo Esquelético/patologíaRESUMEN
Hypomyelination and congenital cataract (HCC, OMIM #610532) is a rare autosomal recessive disorder due to FAM126A mutations characterized by congenital cataract, progressive neurologic impairment, and myelin deficiency in the central and peripheral nervous system. We have identified two novel mutations in three affected members of two unrelated families. Two sibs harbouring a microdeletion causing a premature stop in the protein showed the classical clinical and neuroradiologic HCC picture. The third patient carrying a missense mutation showed a relatively mild clinical picture without peripheral neuropathy. A residual amount of hyccin protein in primary fibroblasts was demonstrated by functional studies indicating that missense mutations are likely to have less detrimental effects if compared with splice-site mutations or deletions that cause the full-blown HCC phenotype, including peripheral nervous system involvement.
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Catarata/congénito , Catarata/genética , Enfermedad de Charcot-Marie-Tooth/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/genética , Mutación , Secuencia de Aminoácidos , Encéfalo/metabolismo , Encéfalo/patología , Catarata/patología , Enfermedad de Charcot-Marie-Tooth/patología , Niño , Femenino , Humanos , Lactante , Péptidos y Proteínas de Señalización Intracelular/química , Proteínas de la Membrana/química , Datos de Secuencia Molecular , Linaje , Alineación de SecuenciaAsunto(s)
Caveolina 3/genética , Aberraciones Cromosómicas , Deleción Cromosómica , Análisis Mutacional de ADN , Genes Recesivos/genética , Calambre Muscular/genética , Debilidad Muscular/genética , Enfermedades Musculares/genética , Adulto , Biopsia , Creatina Quinasa/sangre , Electromiografía , Exones/genética , Femenino , Tamización de Portadores Genéticos , Genotipo , Humanos , Contracción Muscular/genética , Calambre Muscular/diagnóstico , Debilidad Muscular/diagnóstico , Músculo Esquelético/patología , Enfermedades Musculares/diagnóstico , Examen Neurológico , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple/genética , Receptores de Oxitocina/genéticaRESUMEN
Deficiency of glycogen branching enzyme is causative of Glycogen Storage Disease type IV (GSD-IV), a rare autosomal recessive disorder of the glycogen synthesis, characterized by the accumulation of amylopectin-like polysaccharide, also known as polyglucosan, in almost all tissues. Its clinical presentation is variable and involves the liver or the neuromuscular system and different mutations in the GBE1 gene, located on chromosome 3, have been identified in both phenotypes. This review will addresses the neuromuscular clinical variants, focusing on the molecular genetics aspects of this disorder.
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Enzima Ramificadora de 1,4-alfa-Glucano/deficiencia , Enfermedad del Almacenamiento de Glucógeno Tipo IV/enzimología , Enfermedades Neuromusculares/enzimología , Polimorfismo de Nucleótido Simple , Sustitución de Aminoácidos , Animales , Cromosomas Humanos Par 3 , Modelos Animales de Enfermedad , Genotipo , Enfermedad del Almacenamiento de Glucógeno Tipo IV/genética , Humanos , Mutación , Enfermedades Neuromusculares/genéticaRESUMEN
Lysosomal free sialic acid storage diseases are recessively inherited allelic neurodegenerative disorders that include Salla disease (SD) and infantile sialic acid storage disease (ISSD) caused by mutations in the SLC17A5 gene encoding for a lysosomal membrane protein, sialin, transporting sialic acid from lysosomes. The classical form of SD, enriched in the Finnish population, is related to the p.R39C designed Salla(FIN) founder mutation. A more severe phenotype is due both to compound heterozygosity for the p.R39C mutation and to different mutations. The p.R39C has not been reported in ISSD. We identified the first case of SD caused by the homozygosity for p.K136E (c.406A>G) mutation, showing a severe clinical picture, as demonstrated by the early age at onset, the degree of motor retardation, the occurrence of peripheral nerve involvement, as well as cerebral hypomyelination. Recently, in vitro functional studies have shown that the p.K136E mutant produces a mislocalization and a reduced activity of the intracellular sialin. We discuss the in vivo phenotypic consequence of the p.K136E in relation to the results obtained by the in vitro functional characterization of the p.K136E mutant. The severity of the clinical picture, in comparison with the classical SD, may be explained by the fact that the p.K136E mutation mislocalizes the protein to a greater degree than p.R39C. On the other hand, the presence of a residual transport activity may account for the absence of hepatosplenomegaly, dysostosis multiplex, and early lethality typical of ISSD and related to the abolished transport activity found in this latter form.
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Homocigoto , Mutación , Transportadores de Anión Orgánico/genética , Enfermedad por Almacenamiento de Ácido Siálico/genética , Simportadores/genética , Encéfalo/patología , Preescolar , Genotipo , Humanos , Italia , Lisosomas/metabolismo , Imagen por Resonancia Magnética , Masculino , Ácido N-Acetilneuramínico/metabolismo , FenotipoRESUMEN
BACKGROUND: Glycogen storage disease type IV (GSD-IV) is a clinically heterogeneous autosomal recessive disorder due to glycogen branching enzyme (GBE) deficiency and resulting in the accumulation of an amylopectin-like polysaccharide. The typical presentation is liver disease of childhood, progressing to lethal cirrhosis. The neuromuscular form of GSD-IV varies in onset (perinatal, congenital, juvenile, or adult) and severity. OBJECTIVE: To identify the molecular bases of different neuromuscular forms of GSD-IV and to establish possible genotype/phenotype correlations. METHODS: Eight patients with GBE deficiency had different neuromuscular presentations: three had fetal akinesia deformation sequence (FADS), three had congenital myopathy, one had juvenile myopathy, and one had combined myopathic and hepatic features. In all patients, the promoter and the entire coding region of the GBE gene at the RNA and genomic level were sequenced. RESULTS: Nine novel mutations were identified, including nonsense, missense, deletion, insertion, and splice-junction mutations. The three cases with FADS were homozygous, whereas all other cases were compound heterozygotes. CONCLUSIONS: This study expands the spectrum of mutations in the GBE gene and confirms that the neuromuscular presentation of GSD-IV is clinically and genetically heterogeneous.
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Enzima Ramificadora de 1,4-alfa-Glucano/genética , Heterogeneidad Genética , Enfermedad del Almacenamiento de Glucógeno Tipo IV/genética , Mutación , Enzima Ramificadora de 1,4-alfa-Glucano/química , Enzima Ramificadora de 1,4-alfa-Glucano/deficiencia , Adulto , Edad de Inicio , Sustitución de Aminoácidos , Células Cultivadas/enzimología , Niño , Preescolar , Consanguinidad , ADN/genética , Análisis Mutacional de ADN , Eritrocitos/enzimología , Resultado Fatal , Fibroblastos/enzimología , Genotipo , Enfermedad del Almacenamiento de Glucógeno Tipo IV/enzimología , Enfermedad del Almacenamiento de Glucógeno Tipo IV/epidemiología , Enfermedad del Almacenamiento de Glucógeno Tipo IV/patología , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Lactante , Recién Nacido , Hígado/patología , Modelos Moleculares , Músculos/enzimología , Músculos/patología , Fenotipo , Conformación Proteica , Sitios de Empalme de ARN/genética , Eliminación de SecuenciaRESUMEN
4-Hydroxynonenal (HNE) in the concentration range detectable in many pathophysiologic conditions is able to modulate signal transduction cascades and gene expression. Here, we report the stimulating effect of 1 microM HNE on the release of the monocyte chemotactic protein-1 (MCP-1) by murine macrophages. MCP-1-increased export following 1-h cell treatment with HNE proved to be comparable to that exerted by standard amounts of bacterial lipopolysaccharide (LPS). However, the key molecular event in HNE-induced secretion of MCP-1 appeared to be the increased activity of beta-PKC isoforms, which are recognized as playing a role in the regulation of cell protein transport and secretion. On the other hand, in LPS-stimulated cells, the delta isoform was seen to be involved and was probably related to LPS-mediated effects on MCP-1 expression and synthesis. In conclusion, HNE might interact with other pro-inflammatory stimuli, like LPS, in a concerted amplification of MCP-1 production and secretion.