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At least 37 records · Page 2Linked to original sources
PubMed2002

A nonsense mutation in the fibrillin-1 gene of a Marfan syndrome patient induces NMD and disrupts an exonic splicing enhancer.

A nonsense mutation in the fibrillin-1 (FBN1) gene of a Marfan syndrome (MFS) patient induces in-frame exon skipping of FBN1 exon 51. We present evidence, based on both in vivo and in vitro experiments, that the skipping of this exon is due to the disruption of an SC35-dependent splicing enhancer within exon 51. In addition, this nonsense mutation induces nonsense-mediated decay (NMD), which degrades the normally spliced mRNA in the patient's cells. In contrast to NMD, skipping of FBN1 exon 51 does not require translation.

Alternative Splicing↗
PubMed2004

Stop codon-mediated suppression of splicing is a novel nuclear scanning mechanism not affected by elements of protein synthesis and NMD.

The pre-mRNA splicing machine must frequently discriminate between normal and many potential 5'splice sites that match the consensus sequence but remain latent. Suppression of splicing (SOS) at such latent 5'splice sites is required for the maintenance of an open reading frame, and to ensure that only RNAs that encode for functional proteins will be formed. In this study we show that SOS is a novel mechanism distinct from the known RNA surveillance mechanisms. First, SOS is distinct from nonsense-mediated mRNA decay (NMD) because it is not dependent on translation and is not affected by RNAi-mediated down-regulation of hUpf1 and hUpf2--two key components of the NMD pathway. Second, SOS is distinct from nonsense-associated alternative splicing (NAS), because a mutant of hUpf1, which was shown to abrogate NAS, does not activate latent splicing. Elucidating the mechanism of SOS is pertinent to human disease in view of the large number of human genes that harbor latent splice sites.

5' Untranslated Regions↗
PubMed2005

Suppression of termination mutations caused by defects of the NMD machinery in Saccharomyces cerevisiae.

Among a large collection of nonsense (termination) suppressors of Saccharomyces cerevisiae, a few remained obscure for their molecular nature. Of those, a group of weak and recessive suppressors, sup111, sup112 and sup113, is of particular interest because of their dependency on [PSI+], a yeast prion. From the facts that these suppressors map at positions quite similar to the UPF2, UPF3 and UPF1 genes, respectively, and that some mutations in the UPF genes confer termination suppressor activity, we suspected that sup111, sup112 and sup113 would very well be mutant alleles of the UPF genes. We tested our speculation and found that sup113, sup111 and sup112 were in fact complemented with the wild-type alleles of UPF1, UPF2 and UPF3, respectively. We further obtained evidence that the UPF1, UPF2 and UPF3 loci of the strains carrying sup113, sup111 and sup112, respectively, had point mutations. From these results, we conclude that sup111, sup112 and sup113 are mutant alleles of UPF2, UPF3 and UPF1, respectively, and thus attribute suppressor activity of these mutations to defects in the NMD (nonsense-mediated mRNA decay) machinery.

Gene Expression Regulation, Fungal↗
PubMed1988

Retardation of amygdala kindling by antagonism of NMD-aspartate and muscarinic cholinergic receptors: evidence for the summation of excitatory mechanisms in kindling.

DL-2-amino-5-phosphonovaleric acid (APV), a specific antagonist of N-methyl-D-aspartate (NMDA) receptors, was administered alone and in combination with scopolamine (SCO), an antagonist of muscarinic cholinergic receptors, to different groups of rats undergoing electrical kindling of the amygdala. Both groups were significantly retarded in their rate of kindling during 15 drug sessions compared to controls, and the group receiving APV and SCO kindled significantly slower than the group receiving APV alone. These results indicate that both NMDA and muscarinic cholinergic receptors are involved in kindling of the amygdala, and implicate a mechanism involving the summation of excitatory neurotransmission in kindling of the amygdala.

2-Amino-5-phosphonovalerate↗
PubMed2006

Conventional 3' end formation is not required for NMD substrate recognition in Saccharomyces cerevisiae.

The recognition and rapid degradation of mRNAs with premature translation termination codons by the nonsense-mediated pathway of mRNA decay is an important RNA quality control system in eukaryotes. In mammals, the efficient recognition of these mRNAs is dependent upon exon junction complex proteins deposited on the RNA during pre-mRNA splicing. In yeast, splicing does not play a role in recognition of mRNAs that terminate translation prematurely, raising the possibility that proteins deposited during alternative pre-mRNA processing events such as 3' end formation might contribute to the distinction between normal and premature translation termination. We have utilized mRNAs with a 3' poly(A) tail generated by ribozyme cleavage to demonstrate that the normal process of 3' end cleavage and polyadenylation is not required for mRNA stability or the detection of a premature stop codon. Thus, in yeast, the distinction between normal and premature translation termination events is independent of both splicing and conventional 3' end formation.

3' Untranslated Regions↗
PubMed1998

Transplacentally induced neuronal migration disorders: an animal model for the study of the epilepsies.

Recent clinical and laboratory data suggest that there is a link between neuronal migration disorders (NMD) and increased seizure threshold. To characterize an animal model with features similar to human NMD and to assess seizure susceptibility, NMD were induced in the rat at the time of neuroblastic division (PG15) and three other gestational ages (PG 13, PG14, PG16) by transplacental exposure to methylaxozymethanol (MAM, 25 mg/kg). Offspring pups were monitored for spontaneous and electrographic seizures. At postnatal day 14, randomly selected rat pups were sacrificed for histological examination. In other MAM-exposed pups and controls, status epilepticus was induced by intraperitoneal administration of kainic acid. On histology, NMD were found in all PG 15 MAM-exposed rats, in comparison to 63% of PG 13, 70% of PG 14, 80% of PG16. Histological features included cortical laminar disorganization, ectopic neurons in the subcortical white matter and in cortical layer I, persistent granular layer, marginal glioneuronal heterotopia, and discrete areas of neuronal ectopia in the CA1 subfield of the hippocampus. Based on the severity of the neuronal migration abnormalities, rats were divided into three categories: severe, moderate, and mild. Severe and moderate NMD were only found in the PG 15 MAM-exposed rats. EEG recording in rats with NMD did not disclose spontaneous seizures; however, rats with severe NMD had higher slow wave activity compared to controls (P < .05). MAM-exposed rats with severe NMD were more susceptible to kainic-induced seizures compared to controls (P < .05). In rats with severe NMD, kainic acid-induced status epilepticus produced hippocampal damage in the CA3/4 region. These results demonstrate that MAM-induced NMD have histological and electrographic characteristics similar to human NMD. The severity of neuronal abnormality depends on the time of transplacental exposure as the most severe NMD were found after exposure to MAM at the time of neuroblastic division. The degree of NMD positively correlates with seizure susceptibility, since only rats with severe NMD have decreased seizure threshold. The occurrence of status epilepticus-induced hippocampal damage in pups with severe NMD suggests that the severely compromised hippocampus is less resistant to seizure-induced injury than the normal developing brain.

Animals↗
PubMedDate not supplied

Different effect of erythromycin on absorption kinetics of nimodipine in male and female rats.

Effect of erythromycin (ERY) on oral absorption of nimodipine (NMD) in female and male rat was investigated in vivo and in vitro. In vivo, at 15 min following oral dose of 50 mg/kg ERY, an oral dose 20 mg/kg NMD was given to rats, plasma concentrations of NMD were determined. In vitro, everted jejunum sac and ileum sac were used, NMD transport from mucosal side to serol side was measured, in absences of ERY and cyclosprin A (CSA) or in presence of ERY and CSA. Large gender difference was found after oral dose NDM. Male rats had lower plasma concentration than female rat did. AUC180 and Cmax in male rats were less than 5-folds and 3-folds than those in female rats, respectively. Co-administrating ERY may increase plasma concentrations of NMD in rats. AUC180 in male rats and female rats were 2.2-folds and 1.9-folds of those NMD alone, respectively. Cmax was about 3-folds of that NMD alone. The NMD transport in intestine showed a regional variation and gender differences. In female rat, transport rate in the jejunum was about 1.3 higher than ileum. Both ERY and CSA significant increases transport of NMD. Contrast to female, NMD transport in jejunum was lower that that in ileum. Bothe ERY and CSA had little effect on NMD transport in intestine. These results indicated that there existed gender difference in oral absorption of NMD and effect of ERY on oral absorption kinetics of NMD in female rats was different from that in male rat.

Animals↗
PubMedDate not supplied

Effects of manometrically discovered nonspecific motility disorders of the esophagus on the outcomes of antireflux surgery.

Nonspecific motility disorders (NMDs) of the esophagus are common manometric findings in patients evaluated for gastroesophageal reflux disease (GERD). However, it is unclear how these disorders affect the outcomes of antireflux surgery. The purpose of this study was to assess symptomatic outcomes of patients with and without NMDs undergoing surgical treatment for GERD. A prospectively gathered database of all patients undergoing antireflux surgery was retrospectively reviewed for preoperative symptoms, symptom severity using the GERD-HRQL (best score 0, worst score 50), esophageal manometry measurements, presence of NMD, type of operation, any transient or permanent postoperative dysphagia, severity of postoperative dysphagia (best score 0, worst score 5), and postoperative symptom severity. A total of 239 patients were studied; 24% had a NMD identified by preoperative esophageal manometry, and 17% of this +NMD group had preoperative dysphagia or atypical chest/epigastric pain compared to 28% of those without a NMD (-NMD group) (P=NS). Preoperative symptom scores were +NMD 33 vs. -NMD 27 (P=0.01). Postoperative symptom scores were +NMD 5 vs. -NMD 3 (P=NS). There were no differences in preoperative or postoperative dysphagia scores. Transient postoperative dysphagia was 15.8% in the +NMD group vs. 16.4% in the -NMD group (P=NS). Postoperative dilation was 0% in the +NMD group vs. 2% in the -NMD group (P=NS). Manometrically discovered NMDs do not appear to affect preoperative symptoms or symptomatic outcomes of patients surgically treated for GERD. These findings my reflect the severity of GERD and may improve with antireflux surgery.

Case-Control Studies↗
PubMedDate not supplied

Long term follow-up of ventilated patients with thoracic restrictive or neuromuscular disease.

OBJECTIVE: To evaluate the long term effects of home mechanical ventilation (HMV) on pulmonary function, nighttime gas exchange, daytime arterial blood gases, sleep architecture and functional exercise capacity (6 min walk). Patients with respiratory failure attributable to thoracic restrictive disease (TRD) (kyphoscoliosis) or neuromuscular disease (NMD) were assessed, ventilated, trained and followed in a dedicated unit for the care of patients requiring long term ventilation. DESIGN: All patients admitted for home ventilation training since 1988 were reviewed. Measurements of lung function, gas exchange during wakefulness and sleep, as well as functional exercise capacity, were recorded before and immediately after the establishment of HMV. Measurements were repeated one to two years, five years and eight to 10 years later. PATIENTS: Seventy-four individuals with TRD or NMD who completed the home ventilation training program and continued with HMV during all or part of the day for at least one year were studied. RESULTS: Forty patients had TRD. The characteristics of these patients were (mean SE) as follows: age 58 2.4 years; vital capacity (VC) 27% 1.6% predicted, forced expiratory volume in 1 s (FEV1) 25% 1.5% predicted; FEV1/forced VC (FVC) 78% 1.8%. Thirty-four patients had NMD. The characteristics of these patients were as follows: age 44 3.1 years; VC 41% 4.9% predicted, FEV1 44 5.3% predicted; FEV1/FVC 83% 4.2%. There was a significant improvement in distance walked in 6 min (maximum change 51.2 m in patients with NMD and 93.0 m in patients with TRD), daytime partial pressure of arterial carbon dioxide (maximum change 12.9 mmHg in patients with NMD and 10.4 mmHg in patients with TRD) and nighttime partial pressure of arterial carbon dioxide (maximum change 11.7 mmHg in patients with NMD and 18.0 mmHg in patients with TRD) over time (P 0.004). Ventilation resulted in an improvement in partial pressure of arterial oxygen in patients with TRD (68.1 2.8 mmHg to 80.1 3.5 mmHg) and in patients with NMD (52.9 1.7 mmHg to 65.3 2.1 mmHg), although the change was not statistically significant in patients with NMD (P=0.001 in patients with TRD; P=0.105 in patients with NMD). The improvement after ventilation was maintained over several years. Sleep efficiency (75% 18%, 79% 2.2%), the arousal index (13.4 13 events/h, 28.2 17 events/h) and the apnea-hypopnea index (10.1 11.3 events/h, 13.9 9.5 events/h) did not change with time in either patients with TRD or patients with NMD, respectively (P 0.5). CONCLUSIONS: HMV was associated with sustained, long term improvements in nighttime and daytime gas exchange in patients with TRD and NMD. Function exercise capacity increased in patients with TRD and in a subgroup of ambulatory patients with NMD. In patients with TRD, these improvements were maintained for up to 10 years after HMV was established.

Analysis of Variance↗
PubMed2006

Impact of nonsense-mediated mRNA decay on the global expression profile of budding yeast.

Nonsense-mediated mRNA decay (NMD) is a eukaryotic mechanism of RNA surveillance that selectively eliminates aberrant transcripts coding for potentially deleterious proteins. NMD also functions in the normal repertoire of gene expression. In Saccharomyces cerevisiae, hundreds of endogenous RNA Polymerase II transcripts achieve steady-state levels that depend on NMD. For some, the decay rate is directly influenced by NMD (direct targets). For others, abundance is NMD-sensitive but without any effect on the decay rate (indirect targets). To distinguish between direct and indirect targets, total RNA from wild-type (Nmd(+)) and mutant (Nmd(-)) strains was probed with high-density arrays across a 1-h time window following transcription inhibition. Statistical models were developed to describe the kinetics of RNA decay. 45% +/- 5% of RNAs targeted by NMD were predicted to be direct targets with altered decay rates in Nmd(-) strains. Parallel experiments using conventional methods were conducted to empirically test predictions from the global experiment. The results show that the global assay reliably distinguished direct versus indirect targets. Different types of targets were investigated, including transcripts containing adjacent, disabled open reading frames, upstream open reading frames, and those prone to out-of-frame initiation of translation. Known targeting mechanisms fail to account for all of the direct targets of NMD, suggesting that additional targeting mechanisms remain to be elucidated. 30% of the protein-coding targets of NMD fell into two broadly defined functional themes: those affecting chromosome structure and behavior and those affecting cell surface dynamics. Overall, the results provide a preview for how expression profiles in multi-cellular eukaryotes might be impacted by NMD. Furthermore, the methods for analyzing decay rates on a global scale offer a blueprint for new ways to study mRNA decay pathways in any organism where cultured cell lines are available.

Codon, Initiator↗