RESUMEN
PURPOSE: Schwannomatosis, a subtype of neurofibromatosis, is characterized by multiple benign, nonvestibular, nonintradermal schwannomas. Although the tumor suppressor SMARCB1 gene has been frequently identified as the underlying genetic cause of half of familial and ~10% of sporadic schwannomatosis, for most other cases, further causative genes remain to be discovered. Herein, we characterize the genome of a schwannomatosis family without constitutional inactivation of the SMARCB1 gene to explore novel genomic alterations predisposing individuals to the familial disease. METHODS: We performed whole-genome/exome sequencing on genomic DNA of both schwannomatosis-affected and normal members of the family. RESULTS: We identified a novel missense mutation (p.Asp208His; c.622G>C) in the coenzyme Q10 (CoQ10) biosynthesis monooxygenase 6 gene (COQ6) in schwannomatosis-affected members. The deleterious effects of the COQ6 mutations were validated by their lack of complementation in a coq6-deficient yeast mutant. Our study further indicated that the resultant haploinsufficiency of COQ6 might lead to CoQ10 deficiency and chronic overproduction of reactive oxygen species in Schwann cells. CONCLUSION: Although the exact oncogenetic mechanisms in this schwannomatosis family remain to be elucidated, our data strongly indicate a probable role of COQ6 mutation and CoQ10 deficiency in the development of familial schwannomatosis.Genet Med 16 10, 787-792.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Mutación de Línea Germinal , Mutación Missense , Neurilemoma/genética , Neurofibromatosis/genética , Neoplasias Cutáneas/genética , Ubiquinona/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Western Blotting , Línea Celular , Células Cultivadas , Proteínas Cromosómicas no Histona/genética , Análisis Mutacional de ADN/métodos , Proteínas de Unión al ADN/genética , Salud de la Familia , Técnicas de Silenciamiento del Gen , Prueba de Complementación Genética , Humanos , Hibridación Fluorescente in Situ , Datos de Secuencia Molecular , Linaje , Ratas , Especies Reactivas de Oxígeno/metabolismo , Proteína SMARCB1 , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crecimiento & desarrollo , Homología de Secuencia de Aminoácido , Factores de Transcripción/genética , Ubiquinona/análogos & derivados , Ubiquinona/metabolismoRESUMEN
BACKGROUND: The association between obesity and type 2 diabetes has been well documented in epidemiological studies. Patients with type 2 diabetes have a higher body weight than control populations. Relatively few studies, however, have examined the prevalence of obesity in a cohort of hospitalized type 2 diabetes mellitus patients using an electronic health records database. This study measured the prevalence of obesity in hospitalized type 2 diabetes patients and described demographic and clinical characteristics using electronic health records from Convergence CT sites located in the southwestern United States. MATERIAL AND METHODS: Hospitalized patients with type 2 diabetes mellitus were identified in electronic health records from the Convergence Global Research Network. Demographic and clinical characteristics were examined for hospitalized patients with type 2 diabetes. Comparisons were made between males and females across different clinical characteristics as well as between obese patients (BMI ≥30 kg/m2) and patients with BMI <30 kg/m2. RESULTS: Approximately 26.8% of hospitalized type 2 diabetes patients were overweight (BMI=25-29.9 kg/m2) and 57.7% were obese (BMI ≥30 kg/m2). A higher percentage of females (61.3%) were obese compared to males (54.6%) (p=0.002). Obese patients with type 2 diabetes were younger, appeared to have inadequate glycemic control, exhibited higher blood pressure, and had worse lipid profiles compared to type 2 diabetes patients with BMI <30 kg/m2. CONCLUSIONS: Approximately 84.5% of the hospitalized type 2 diabetes patients identified in this study were overweight or obese (BMI ≥25 kg/m2), suggesting the need for effective weight loss intervention in this population.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Hospitalización/estadística & datos numéricos , Obesidad/complicaciones , Obesidad/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sudoeste de Estados Unidos/epidemiología , Adulto JovenRESUMEN
Chemical biotinylation of protein complexes followed by binding to two-dimensional (monolayer) crystals of streptavidin is shown to be an effective way to prepare cryo-EM specimens from samples at low protein concentration. Three different multiprotein complexes are used to demonstrate the generality of this method. In addition, native thermosomes, purified from Sulfolobus solfataricus P2, are used to demonstrate that a uniform distribution of Euler angles is produced, even though this particle is known to adopt a preferred orientation when other methods of cryo-EM specimen preparation are used.