Use of next-generation sequencing as a diagnostic tool for congenital myasthenic syndrome.
congenital myasthenic syndrome; Congenital/*genetics/therapy; Continuous Positive Airway Pressure/methods; Humans; Infant; Male; Muscle Proteins/*genetics; Mutation/*genetics; Myasthenic Syndromes; next-generation sequencing; pyridostigmine; rapsyn
BACKGROUND: The clinical presentation of congenital myasthenic syndromes is similar to many other neuromuscular disorders of infancy, and with 12 known discrete genetic forms of congenital myasthenic syndromes, both the diagnosis and treatment decisions present clinical challenges. PATIENT DESCRIPTION: We report a
Das Alvin S; Agamanolis Dimitri P; Cohen Bruce H
Pediatric neurology
2014
2014-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.pediatrneurol.2014.07.032" target="_blank" rel="noreferrer noopener">10.1016/j.pediatrneurol.2014.07.032</a>
Sex differences in striatal dopaminergic function within heterozygous mutant dopamine transporter knock-out mice.
*Sex Characteristics; 3; 4-Dihydroxyphenylacetic Acid/metabolism; Animals; Brain/drug effects/*metabolism; Corpus Striatum/drug effects/*metabolism; Dopamine Plasma Membrane Transport Proteins/*genetics; Dopamine Uptake Inhibitors/pharmacology; Dopamine/*metabolism; Down-Regulation/drug effects/genetics; Female; Gene Expression Regulation/drug effects/genetics; Heterozygote; Knockout; Male; Methamphetamine/pharmacology; Mice; Mutation/*genetics; Neural Pathways/drug effects/metabolism; Potassium Chloride/metabolism/pharmacology; Substantia Nigra/drug effects/metabolism; Synaptic Transmission/drug effects/genetics; Up-Regulation/drug effects/genetics
The issue of whether a deletion of the dopamine transporter (DAT) allele (+/- DAT) would differentially alter striatal dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) concentrations and DA release upon potassium and methamphetamine (MA) stimulation between male and female mice was examined. Striatal DA and DOPAC concentrations of female +/- DAT mice were significantly decreased as compared with wild type (+/+) controls and male +/- DAT mice. No such changes were obtained from the olfactory tubercle suggesting that these effects might be specific for the striatum. Potassium-stimulated DA was increased in male and female +/- DAT mice and maximally stimulated DA was obtained from +/- DAT females, although these mice showed the lowest DA concentrations. MA-evoked DA was increased in male and female +/- mice. While MA-evoked DA was significantly increased in +/+ males versus +/+ females, the +/- females showed the highest DA responses, thereby showing a reversal in the results seen in wild-type conditions. These findings indicate: (1) that a deficiency in the DAT interacts with the sex of the subject, (2)+/- DAT females show more extreme changes in dopaminergic responses, and (3) the importance for considering such variables such as sex when examining differences among knock-out conditions.
Ji Jing; Dluzen Dean E
Journal of neural transmission (Vienna, Austria : 1996)
2008
2008-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s00702-007-0017-0" target="_blank" rel="noreferrer noopener">10.1007/s00702-007-0017-0</a>
Aberrant induction of Par-4 is involved in apoptosis of hippocampal neurons in presenilin-1 M146V mutant knock-in mice.
*Intracellular Signaling Peptides and Proteins; Alzheimer Disease/*genetics/metabolism/physiopathology; Animals; Apoptosis Regulatory Proteins; Apoptosis/*genetics; Carrier Proteins/*genetics/metabolism; Caspases/metabolism; Gene Expression Regulation/physiology; Glucose/deficiency; Hippocampus/*metabolism/physiopathology; Membrane Proteins/*genetics; Mice; Mitochondria/metabolism/pathology; Mutation/*genetics; Neurons/*metabolism/pathology; Presenilin-1; Signal Transduction/genetics; Transgenic/genetics/metabolism
Mutations in presenilin-1 (PS-1) have been shown to increase neuronal vulnerability to apoptosis in Alzheimer's disease (AD). Par-4 is a novel cell-death-promoting protein associated with neuronal degeneration in AD. We previously reported that, in transfected PC12 cells, Par-4 seems to be involved in the neurodegenerative mechanisms of PS-1 mutations. However, direct evidence for a necessary role of Par-4 in the pathogenic mechanisms of PS-1 mutations in neurons is lacking. We recently generated and characterized presenilin-1 mutant M146V knock-in (PS-1 M146V KI) mice. We now report that expression of the mutant presenilin-1 in these mice induces early and exaggerated increase in Par-4 expression in hippocampal neurons following glucose deprivation (an insult relevant to the pathogenesis of AD). Importantly, inhibition of Par-4 expression by antisense par-4 oligonucleotide treatment counteracts neuronal apoptosis promoted by M146V mutation of PS-1. Mitochondrial dysfunction and caspase-3 activity induced by glucose deprivation was significantly exacerbated in hippocampal neurons expressing the mutant PS-1. Antisense par-4 treatment largely suppressed the adverse effect of the mutant PS-1 on mitochondrial dysfunction and caspase activation. These results provide evidence in hippocampal neurons that Par-4 is involved in the neurodegenerative cascades associated with PS-1 M146V mutation by acting relatively early in the apoptotic process before mitochondrial dysfunction and caspase-3 activation. Since levels of Par-4 are significantly increased in the hippocampus in human AD brain, the results of this study may provide a significant link between aberrant induction of Par-4 and the neurodegenerative cascades promoted by PS-1 mutations in AD.
Xie J; Chang X; Zhang X; Guo Q
Brain research
2001
2001-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0006-8993(01)02803-7" target="_blank" rel="noreferrer noopener">10.1016/s0006-8993(01)02803-7</a>