RESUMEN
Chromosome 15q11q13 is among the least stable regions in the genome due to its highly complex genomic architecture. Low copy repeat elements at 15q13.3 facilitate recurrent copy number variants (CNVs), with deletions established as pathogenic and CHRNA7 implicated as a candidate gene. However, the pathogenicity of duplications of CHRNA7 is unclear, as they are found in affected probands as well as in reportedly healthy parents and unaffected control individuals. We evaluated 18 children with microduplications involving CHRNA7, identified by clinical chromosome microarray analysis (CMA). Comprehensive phenotyping revealed high prevalence of developmental delay/intellectual disability, autism spectrum disorder, and attention deficit/hyperactivity disorder. As CHRNA7 duplications are the most common CNVs identified by clinical CMA, this study provides anticipatory guidance for those involved with care of affected individuals.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno del Espectro Autista/genética , Variaciones en el Número de Copia de ADN/genética , Discapacidades del Desarrollo/genética , Fenotipo , Receptor Nicotínico de Acetilcolina alfa 7/genética , Niño , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Análisis por Micromatrices , LinajeRESUMEN
The 22q13.3 deletion syndrome results from loss of terminal segments of varying sizes at 22qter. Few genotype-phenotype correlations have been found but all patients have mental retardation and severe delay, or absence of, expressive speech. We carried out clinical and molecular characterization of 13 patients. Developmental delay and speech abnormalities were common to all and comparable in frequency and severity to previously reported cases. Array-based comparative genomic hybridization showed the deletions to vary from 95 kb to 8.5 Mb. We also carried out high-resolution 244K array comparative genomic hybridization in 10 of 13 patients, that defined the proximal and distal breakpoints of each deletion and helped determine the size, extent, and gene content within the deletion. Two patients had a smaller 95 kb terminal deletion with breakpoints within the SHANK3 gene while three other patients had a similar 5.5 Mb deletion implying the recurrent nature of these deletions. The two largest deletions were found in patients with ring chromosome 22. No correlation could be made with deletion size and phenotype although complete/partial SHANK3 was deleted in all patients. There are very few reports on array comparative genomic hybridization analysis on patients with the 22q13.3 deletion syndrome, and we aim to accurately characterize these patients both clinically and at the molecular level, to pave the way for further genotype-phenotype correlations. (c) 2010 Wiley-Liss, Inc.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 22/genética , Anomalías Múltiples/genética , Adolescente , Trastorno Autístico/genética , Proteínas Portadoras/genética , Niño , Preescolar , Hibridación Genómica Comparativa , Discapacidades del Desarrollo/genética , Femenino , Estudios de Asociación Genética , Humanos , Trastornos del Desarrollo del Lenguaje/genética , Masculino , Proteínas del Tejido Nervioso , Fenotipo , Síndrome , Adulto JovenRESUMEN
Turner syndrome is hypothesized to result from haplo-insufficiency of a gene or perhaps multiple genes present on the sex chromosomes; however, the frequent association of mosaicism with deletions of the sex chromosomes prevents establishing useful genotype/phenotype correlations. In this clinical report, we present a male with a de novo, non-mosaic deletion of the Y-chromosome. The phenotype of this patient is unlike any similar cases previously reported in the literature. This patient exhibits many classical clinical features of Turner syndrome including short stature, characteristic facial anomalies, and webbed neck with low posterior hairline, aortic valve abnormality, and hearing impairment. Detailed molecular characterization of this deleted Y-chromosome could provide important information towards establishing genotype/phenotype correlations in Turner syndrome.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Y , Síndrome de Turner/fisiopatología , Niño , Análisis Citogenético , Humanos , Lactante , Masculino , Síndrome de Turner/genéticaRESUMEN
Only two isoforms of the adenine nucleotide translocase (Ant) protein have been identified in mouse, as opposed to the three in humans. To determine whether the homologous mouse and human proteins share similar patterns of expression, Northern and Western analyses were performed on several mouse tissues. Mouse Ant1 is expressed at high levels in skeletal muscle and heart, similar to human ANT1. Mouse Ant2 is strongly expressed in all tissues but muscle, in marked contrast to human ANT2. To investigate the molecular basis of these differences, we cloned and sequenced the genomic loci of mouse Ant1 and Ant2, and compared them to the three human ANT loci. The mouse and human ANT1 and ANT2 genes showed substantial homology starting about 300 base pairs (bp) 5' to the coding region and continuing through the 3' untranslated region (UTR). Repeats constituted 32% of 15kb of Ant1 sequence and 36% of the 27kb of Ant2 sequence and included SINEs, LINEs and LTR elements. The core promoters of the mouse and human ANT1 and ANT2 genes are very similar. However, the mouse Ant1 gene lacks the upstream OXBOX and REBOX elements found in human ANT1 genes, thought to be important for muscle-specific expression. The mouse Ant2 gene, like human ANT2, has an upstream GRBOX, yet this element is not associated with suppression of transcription, as hypothesized for human ANT2. These discrepancies indicate that additional studies will be required to fully understand the transcriptional regulation of both Ant1 and Ant2.
Asunto(s)
Translocasas Mitocondriales de ADP y ATP/genética , Animales , Secuencia de Bases , Northern Blotting , Western Blotting , ADN/química , ADN/genética , Femenino , Expresión Génica , Genes/genética , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Ratones , Ratones Endogámicos , Translocasas Mitocondriales de ADP y ATP/metabolismo , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Secuencias Repetitivas de Ácidos Nucleicos , Alineación de Secuencia , Análisis de Secuencia de ADN , Homología de Secuencia de Ácido Nucleico , Distribución TisularRESUMEN
In an attempt to create an animal model of tissue-specific mitochondrial disease, we generated 'knockout' mice deficient in the heart/muscle isoform of the adenine nucleotide translocator (Ant1). Histological and ultrastructural examination of skeletal muscle from Ant1 null mutants revealed ragged-red muscle fibers and a dramatic proliferation of mitochondria, while examination of the heart revealed cardiac hypertrophy with mitochondrial proliferation. Mitochondria isolated from mutant skeletal muscle exhibited a severe defect in coupled respiration. Ant1 mutant adults also had a resting serum lactate level fourfold higher than that of controls, indicative of metabolic acidosis. Significantly, mutant adults manifested severe exercise intolerance. Therefore, Ant1 mutant mice have the biochemical, histological, metabolic and physiological characteristics of mitochondrial myopathy and cardiomyopathy.
Asunto(s)
Cardiomiopatías/genética , Modelos Animales de Enfermedad , Mitocondrias Musculares/metabolismo , Translocasas Mitocondriales de ADP y ATP/genética , Miopatías Mitocondriales/genética , Secuencia de Aminoácidos , Animales , Cardiomegalia/genética , Cardiomegalia/patología , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Respiración de la Célula , Clonación Molecular , Ratones , Ratones Noqueados , Mitocondrias Musculares/genética , Mitocondrias Musculares/ultraestructura , Translocasas Mitocondriales de ADP y ATP/deficiencia , Translocasas Mitocondriales de ADP y ATP/metabolismo , Miopatías Mitocondriales/metabolismo , Miopatías Mitocondriales/patología , Datos de Secuencia Molecular , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Miocardio/metabolismo , Miocardio/patología , Fosforilación Oxidativa , Esfuerzo Físico , ARN Mensajero/análisis , ARN Mensajero/genética , Células Madre/patologíaRESUMEN
The mitochondrial DNA (mtDNA) sequence was determined on 3 patients with Alzheimer's disease (AD) exhibiting AD plus Parkinson's disease (PD) neuropathologic changes and one patient with PD. Patient mtDNA sequences were compared to the standard Cambridge sequence to identify base changes. In the first AD+PD patient, 2 of the 15 nucleotide substitutions may contribute to the neuropathology, a nucleotide pair (np) 4336 transition in the tRNA(Gln) gene found 7.4 times more frequently in patients than in controls, and a unique np 721 transition in the 12S rRNA gene which was not found in 70 other patients or 905 controls. In the second AD+PD patient, 27 nucleotide substitutions were detected, including an np 3397 transition in the ND1 gene which converts a conserved methionine to a valine. In the third AD+PD patient, 2 polymorphic base substitutions frequently found at increased frequency in Leber's hereditary optic neuropathy patients were observed, an np 4216 transition in ND1 and an np 13708 transition in the ND5 gene. For the PD patient, 2 novel variants were observed among 25 base substitutions, an np 1709 substitution in the 16S rRNA gene and an np 15851 missense mutation in the cytb gene. Further studies will be required to demonstrate a causal role for these base substitutions in neurodegenerative disease.
Asunto(s)
Enfermedad de Alzheimer/genética , ADN Mitocondrial/química , Enfermedad de Parkinson/genética , Secuencia de Aminoácidos , Humanos , Datos de Secuencia Molecular , Mutación , Análisis de Secuencia de ADNRESUMEN
To determine if somatic mtDNA mutations might contribute to the neurodegeneration observed in Huntington's disease (HD), we quantitated the amount of the common mitochondrial 4977 nucleotide pair deletion (mtDNA4977) in cortex and putamen of HD patients and age-matched controls by the serial dilution-polymerase chain reaction method. Cortical deletion levels were analyzed in the temporal, frontal, and occipital lobes. HD temporal lobes had an 11-fold greater mean mtDNA4977 deletion level than age-matched controls, and HD frontal lobes had fivefold greater levels. HD occipital lobe and putamen deletion levels were comparable with control levels. These results support the hypothesis that HD is associated with elevated cortical mtDNA damage.
Asunto(s)
Corteza Cerebral/química , ADN Mitocondrial/análisis , Enfermedad de Huntington/genética , Adulto , Secuencia de Bases , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
Levels of the common 4977 nucleotide pair (np) mitochondrial DNA (mtDNA) deletion (mtDNA4977) were quantitated in the cortex, putamen, and cerebellum of patients with Alzheimer disease (AD) and compared to age-matched controls. Although cerebellum deletion levels were comparably low in AD patients and controls of all ages, cortical deletion levels were clearly different. The levels of mtDNA deletions in control brains started low, but rose markedly after age 75, while those of AD patients started high and declined to low levels by age 80. Choosing age 75 to arbitrarily delineate between younger and older subjects, younger patients had 15 times more mtDNA deletions than younger controls, while older patients had one-fifth the deletion level of older controls. Younger AD patients also had fourfold more deletions than older AD patients. These results support the hypothesis that OXPHOS defects resulting from somatic mtDNA mutations may play a role in AD pathophysiology.
Asunto(s)
Enfermedad de Alzheimer/genética , ADN Mitocondrial/genética , Eliminación de Secuencia , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Cerebelo/metabolismo , Corteza Cerebral/metabolismo , Daño del ADN , ADN Mitocondrial/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fosforilación Oxidativa , Putamen/metabolismo , Distribución TisularRESUMEN
The effects of buspirone in treating cocaine and phencyclidine (PCP) withdrawal were studied. Withdrawal symptoms of these two street-drugs are thought to be due to norepinephrine, dopamine and possibly serotonin depletion. Buspirone acts by enhancing dopaminergic and noradrenergic firing as well by suppressing serotonergic activity. Thirty-two cocaine abusers and 24 PCP abusers were withdrawn over a 30-day period. Half of each group received buspirone 10 mg t.i.d. and the other half 10 mg placebo t.i.d. In the cocaine group, buspirone was significantly more effective from the fifth day onward. In the PCP group, significant improvement was seen on the thirtieth day. Delayed effectiveness in PCP is thought due to its actions at other neurotransmitter sites.
Asunto(s)
Buspirona/uso terapéutico , Cocaína/efectos adversos , Abuso de Fenciclidina/rehabilitación , Fenciclidina/efectos adversos , Síndrome de Abstinencia a Sustancias/rehabilitación , Trastornos Relacionados con Sustancias/rehabilitación , Nivel de Alerta/efectos de los fármacos , Buspirona/efectos adversos , Terapia Combinada , Consejo , Impulso (Psicología) , Femenino , Humanos , Masculino , Abuso de Fenciclidina/psicología , Detección de Abuso de Sustancias , Síndrome de Abstinencia a Sustancias/psicología , Trastornos Relacionados con Sustancias/psicología , Resultado del TratamientoRESUMEN
Postoperative monitoring of vascular perfusion was performed in 72 revascularized/replanted digits in 40 patients. Sodium fluorescein (1.0 to 1.5 mg/kg) was administered intravenously every 2 hours for 36 to 48 hours beginning immediately after surgery. Quantitative fluorescence readings of each injured digit were obtained 10 minutes after fluorescein injection and were compared with readings from an uninjured (control) digit. A ratio between the fluorescence of the injured digit and that of the control digit was used for analysis. Viable digits had a fluorescein perfusion ratio of 86.4 +/- 16. Digits that did not survive had fluorescein perfusion ratios of 5.2 +/- 10 (p less than 0.001). The results of this study indicate that quantitative surface fluorescence assessment of revascularized/replanted digits is a minimally invasive, and reliable tool for monitoring vascular perfusion.
Asunto(s)
Dedos/irrigación sanguínea , Monitoreo Fisiológico , Piel/irrigación sanguínea , Niño , Fluoresceína , Fluoresceínas , Fluorescencia , Humanos , Masculino , Persona de Mediana Edad , Perfusión , Periodo Posoperatorio , Estudios Prospectivos , Pulgar/irrigación sanguínea , Factores de TiempoRESUMEN
In a laboratory model, quantitative skin-surface fluorescence has been used to reliably measure skin perfusion in ischemic random flaps and to predict viability. The method is reproducible and allows investigators to sequentially monitor soft-tissue perfusion using a fluorescent indicator. It is superior to the conventional fluorescein test (Wood's lamp method), which allows only a single subjective assessment within a 24-hour period.
Asunto(s)
Fluoresceínas/análisis , Piel/irrigación sanguínea , Colgajos Quirúrgicos , Animales , Fluorescencia/instrumentación , Supervivencia de Injerto , Ratas , Ratas Endogámicas , Flujo Sanguíneo Regional , Distribución TisularRESUMEN
Changes in oxyhemoglobin dissociation compensate partially for decreased O2 transport caused by high altitude, anemia, and cardiac disease. This investigation determined whether similar changes occurred in patients undergoing myocardial revascularization and the possible significance of such changes. In 15 patients scheduled for coronary vein bypass surgery the following were inserted: a #7 French catheter into the coronary sinus or great cardiac vein, a pulmonary arterial catheter (Swan-Ganz), and a radial arterial catheter. Patients were anesthetized with either halothane-N2O 50% or morphine (2 mg/kg IV) with N2O 50%. Hemodynamic status was measured and blood samples were taken from the catheters in the preoperative period and after endotracheal intubation, sternotomy, bypass, and chest closure. Blood samples were analyzed for pH, blood gas tensions, and O2 saturation. Values for P50 for mixed venous and coronary sinus blood were calculated from O2 tension and saturation. Patients were divided into two groups on the basis of peroperative mixed venous P50 values: group I had normal P50 levels of 26.1 +/- 2.0 torr (mean +/- SD); group II had elevated values for mixed venous blood P50 of 32.5 +/- 1.6 (mean +/- SD). Unlike group I, group II had depressed ventricular function and higher P50 values for coronary sinus blood than for mixed venous blood. Induction of anesthesia increased P50 values in group I but not in group II and removed the significant differences between group I and group II mixed venous P50 values. In group II patients, cardiopulmonary bypass lowered the elevated P50 of coronary sinus blood so that it equaled P50 for mixed venous blood. It is concluded that induction of anesthesia may elevate P50 in patients who have normal preoperative P50 values. The already elevated P50 values of patients with ventricular dysfunction did not change. Cardiopulmonary bypass decreased coronary sinus P50 in group II patients, and this change might be deleterious if the original elevation represents a compensatory response to a reduction in O2 transport.