RESUMEN
BACKGROUND: Insulin resistance and hyperglycaemia are common in severe sepsis. Mitochondrial uncoupling protein 2 (UCP2) plays a role in insulin release and sensitivity. OBJECTIVES: To determine if a common, functional polymorphism in the UCP2 gene promoter region (the -866 G/A polymorphism) contributes to the risk of hyperglycaemia in severe sepsis. RESULTS: In the prospective group 120 non-diabetic patients who were carriers of the G allele had significantly higher maximum blood glucose recordings than non-carriers (mean (SD) AA 8.5 (2.2) mmol/l; GA 8.5 (2.4) mmol/l; GG 10.1 (3.1) mmol/l; p = 0.0042) and required significantly more insulin to maintain target blood glucose (p = 0.0007). In the retrospective study 103 non-diabetic patients showed a similar relationship between maximum glucose and UCP genotype (AA 6.8 (2.3) mmol/l; GA 7.8 (2.2) mmol/l; GG 9.2 (2.9) mmol/l; p = 0.0078). CONCLUSIONS: A common, functional polymorphism in the promoter region of the UCP2 gene is associated with hyperglycaemia and insulin resistance in severe sepsis. This has implications for our understanding of the genetic pathophysiology of sepsis and is of use in the stratification of patients for more intensive management.
Asunto(s)
Hiperglucemia/genética , Canales Iónicos/genética , Proteínas Mitocondriales/genética , Sepsis/genética , Estrés Fisiológico/genética , Adulto , Anciano , Glucemia/genética , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Hiperglucemia/complicaciones , Hiperglucemia/epidemiología , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Regiones Promotoras Genéticas , Estudios Prospectivos , Estudios Retrospectivos , Sepsis/complicaciones , Proteína Desacopladora 2RESUMEN
The m.8993T-->C MTATP6 mutation of mitochondrial DNA (mtDNA) usually causes mitochondrial disease in childhood, but was recently described in a family with adult onset ataxia and polyneuropathy. Cytochrome c oxidase muscle histochemistry, which is the standard clinical investigation for mitochondrial disease in adults, is usually normal in patients with MTATP6 mutations. This raises the possibility that these cases have been missed in the past. We therefore studied 308 patients with unexplained ataxia and 96 patients with suspected Charcot-Marie-Tooth disease to determine whether the m.8993T-->C MTATP6 mutation is common in unexplained inherited ataxia and/or polyneuropathy. We identified a three-generation family with the m.8993T-->C mutation of mtDNA. One subject had episodic ataxia (EA) and transient hemipareses, broadening the phenotype. However, no further cases were identified in an additional cohort of 191 patients with suspected EA. In conclusion, m.8993T-->C MTATP6 should be considered in patients with unexplained ataxia, CMT or EA, but cases are uncommon.
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Neuropatía Hereditaria Motora y Sensorial/genética , Enfermedades Mitocondriales/genética , ATPasas de Translocación de Protón Mitocondriales/genética , Mutación Missense , Paresia/genética , Mutación Puntual , Degeneraciones Espinocerebelosas/genética , Adulto , Anciano , Enfermedad de Charcot-Marie-Tooth/genética , Estudios de Cohortes , ADN Mitocondrial/genética , Disartria/genética , Femenino , Heterogeneidad Genética , Neuropatía Hereditaria Motora y Sensorial/diagnóstico , Humanos , Persona de Mediana Edad , ATPasas de Translocación de Protón Mitocondriales/deficiencia , Trastornos de la Motilidad Ocular/genética , Linaje , PeriodicidadRESUMEN
Recent evidence suggests that polymorphic genetic variation in the non-coding region of mitochondrial DNA (the 16184-16193 polycytosine [poly-C] tract) contributes to the cause of type 2 diabetes, but previous studies only just reached significance. We aimed to investigate this association. We compared patients with type 2 diabetes (n=992) with two independent control groups (n=536, n=1029) from the UK, and saw no difference in the frequency of the 16184-16193 poly-C tract. This finding was confirmed by a meta-analysis of European studies of 1455 patients and 3132 controls (odds ratio 1.16, 95% CI 0.94-1.44). Genetic variation of the 16184-16193 poly-C tract is unlikely to have a major role in the cause of type 2 diabetes.
Asunto(s)
ADN Mitocondrial/genética , Diabetes Mellitus Tipo 2/genética , Poli C/genética , Humanos , Metaanálisis como AsuntoRESUMEN
The authors describe an infant with a severe spastic paraparesis caused by two codominant mutations of the spastin gene. This highlights the multiple molecular mechanisms that are likely to be involved in the molecular pathology of SPG4 and illustrates the importance of complete screening of the spastin gene in affected individuals, particularly if the index case has an unusual phenotype.
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Adenosina Trifosfatasas/genética , Sustitución de Aminoácidos , Mutación Missense , Mutación Puntual , Paraplejía Espástica Hereditaria/genética , Adenosina Trifosfatasas/química , Alelos , Análisis Mutacional de ADN , Exones/genética , Femenino , Genes Dominantes , Heterogeneidad Genética , Genotipo , Humanos , Lactante , Linaje , Penetrancia , Fenotipo , EspastinaRESUMEN
OBJECTIVE: Mutations in the skeletal muscle gene dysferlin cause two autosomal recessive forms of muscular dystrophy: Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). The purpose of this study was to define the genomic organization of the dysferlin gene and conduct mutational screening and a survey of clinical features in 21 patients with defined molecular defects in the dysferlin gene. METHODS: Genomic organization of the gene was determined by comparing the dysferlin cDNA and genomic sequence in P1-derived artificial chromosomes (PACs) containing the gene. Mutational screening entailed conformational analysis and sequencing of genomic DNA and cDNA. Clinical records of patients with defined dysferlin gene defects were reviewed retrospectively. RESULTS: The dysferlin gene encompasses 55 exons spanning over 150 kb of genomic DNA. Mutational screening revealed nine novel mutations associated with MM. The range of onset in this patient group was narrow with a mean of 19.0 +/- 3.9 years. CONCLUSION: This study confirms that the dysferlin gene is mutated in MM and LGMD2B and extends understanding of the timing of onset of the disease. Knowledge of the genomic organization of the gene will facilitate mutation detection and investigations of the molecular biologic properties of the dysferlin gene.