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Yoshiko Nomura

Publications and source records attributed to Yoshiko Nomura.

18 recordsLinked to original sources
PubMed2005

An alanine in segment 3 of domain III (IIIS3) of the cockroach sodium channel contributes to the low pyrethroid sensitivity of an alternative splice variant.

In a previous study, we showed that two alternative exons (G1 and G2 encoding IIIS3-S4) were involved in the differential sensitivity of two cockroach sodium channel splice variants, BgNa(v)1-1 and BgNa(v)2-1 (previously called KD1 and KD2), to deltamethrin, a pyrethroid insecticide (Tan, et al., 2002b. Alternative splicing of an insect sodium channel gene generates pharmacologically distinct sodium channels. J. Neurosci. 22, 5300-5309.). Here, we report the identification of an amino acid residue in exon G2 that contributes to the low deltamethrin sensitivity of BgNa(v)2-1. Replacement of A1356 in BgNa(v)2-1 with the corresponding V1356 in BgNa(v)1-1 enhanced the sensitivity of the BgNa(v)2-1 channel to deltamethrin by six-fold. Conversely, substitution of V1356 with A1356 in BgNa(v)1-1 produced a recombinant BgNa(v)1-1 channel that was 5-fold more resistant to deltamethrin. These results demonstrate that A1356 contributes to the low sensitivity of BgNa(v)2-1 to deltamethrin. A1356V substitution also shifted the voltage-dependence of activation by 10 mV in the hyperpolarizing direction. Possible mechanisms by which this amino acid change affects the action of pyrethroids on the sodium channel are discussed.

Alanine↗
PubMed2005

Early behavior characteristics and sleep disturbance in Rett syndrome.

This paper reviews the early features of Rett syndrome (RTT). The behavioral characteristics of RTT were analyzed retrospectively by taking history and asking about early infancy behaviors. The earliest behavioral characteristics are thought to be autistic features and hypotonia of trunkal muscles. Analysis of sleep-wake rhythm and all-night polysomnography suggested that the initial lesion is serotonergic and noradrenargic hypofunction at brainstem level. Dopaminergic (DA) hypofunction associated with DA receptor supersensitivity follows as the brain matures. Characteristic symptoms developing at specific age ranges are based on the neuronal connections of the brainstem aminergic neurons and DA neurons with the pedunculo-pontine nuclei, projecting to specific cortical areas.

Child↗
PubMed2005

Preface.

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Humans↗
PubMed2005

A missense mutation in SCN1A in brothers with severe myoclonic epilepsy in infancy (SMEI) inherited from a father with febrile seizures.

Severe myoclonic epilepsy in infancy (SMEI) is an age-dependent epileptic encephalopathy occurring in the first year of life and is one of the intractable epilepsies. Heterozygous mutations in the voltage-gated sodium channel alpha subunit type1 gene (SCN1A) are frequently identified in patients with SMEI; two-thirds of these mutations are truncation mutations (non-sense and frameshift), and one-third are missense mutations. Although most reported SMEI cases arise as sporadic mutations, close relatives of SMEI patients have also been shown to manifest other types of epilepsies at a higher rate than that in the general population. Here, we report a familial case of SMEI, in which two brothers were affected with SMEI while their father had previously experienced simple febrile seizures. A gene-based analysis identified a novel missense mutation in the SCN1A gene (c.5138G>A, S1713N) in both brothers and in their father. Clinically, both siblings showed failure in locomotion, an impairment of the sleep-wake cycle after late infancy, and the subsequent appearance of frontal foci. The similarity in clinical manifestations in both brothers suggests that the impairment of elements of the brainstem, particularly aminergic neurons, develops after late infancy in SMEI. However, the siblings differed in age at onset of SMEI and of myoclonic seizures, as well as in the severity of speech delay. Our molecular and clinical findings suggest that different genetic backgrounds and/or environmental factors may critically affect the clinical features of patients with SCN1A mutations, consistent with the heterogeneity prevalent in this disorder.

Adult↗
PubMed2005

Rett syndrome.

PURPOSE OF REVIEW: Nearly 70 reports on Rett syndrome were published in 2004. We have selected 51 articles, including clinical reports, on pathophysiology, genotype-phenotype correlation, and clinical and basic molecular biology studies. These articles explain how mutation of the gene (MECP2) for methyl-CpG-binding protein 2 causes the particular disorders of Rett syndrome, and also induces other neurodevelopmental disorders, clarifying the situation for future studies. RECENT FINDINGS: The role of X-chromosome inactivation has been clarified in animal experiments. New isoforms of MeCP2 have been discovered and its functional characteristics are under research. Understanding of the influence of the MECP2 mutation on other neurodevelopmental disorders has increased. However, there is no apparent progress in neurophysiological studies. SUMMARY: Clinical studies included the pathophysiology of stereotyped movement, and cardiac and respiratory disturbances, and there were four therapeutic trials including one for epilepsy. For genotype-phenotype correlation the role of X-chromosome inactivation was looked at and its basic mechanisms were studied extensively in animals. Characteristics of mutations in the C-terminus and the biological function of the new isoform, exon 1, were introduced. In studies on related neurodevelopmental disorders, a relationship is suggested between the MECP2 gene and autism-related gene, with overlapping pathways, but this is not common to other neurodevelopmental disorders. Developmental studies suggest an important role for MeCP2 in the formation and/or maintenance of synapses, and clarify the molecular biological aspects of Rett syndrome. However, early involvement of the aminergic neurons, suggested as the basic, pathognomonic lesion of Rett syndrome, has unfortunately not been investigated with the MECP2 mutation.

Animals↗
PubMed2005

Natural history of Rett syndrome.

Rett syndrome is a unique neurodevelopmental disorder, with onset of hypotonia, autistic tendency, and abnormalities of fine finger movements and gross movements of the arms in early infancy. Clinical features include specific age-dependent symptoms. Studies of early and late signs correlated locomotive dysfunction to language disability and stereotypy to regression of higher cortical functions. Studies of sleep parameters revealed early hypofunction of brainstem aminergic neurons and late occurrence of hypofunction of dopaminergic neurons, followed by receptor supersensitivity. The syndrome's pathophysiology suggests that early hypofunction of aminergic neurons interferes with the development of higher neuronal systems. Particular symptoms surface at different ages throughout the natural course of Rett syndrome, with regressional and static periods.

Age Factors↗
PubMed2005

[Today and tomorrow in child neurology at a neurological clinic for children--the importance of child neurology as the life-long neurology].

Segawa Neurological Clinic for Children was founded in 1973, and specializes in neurological disorders that start in childhood. In thirty-one years since the foundation, about 16,000 patients visited this clinic. The ages of the first visit to this clinic of the patients are mostly below 15 years. The main diseases are epilepsy, autism, mental retardation with various etiologies, Tourette syndrome, and other neurological disorders. Most of the diseases follow a chronic course and require long term follow-up. In this clinic those patients who need the continuous follow-up are seen even after reaching to adulthood. The average age of patients who were seen in the clinic during 2003 was about 21 years of age (20.77 +/- 14.28), suggesting that many of the patients are followed in this clinic for 20-30 years. The etiologies and pathophysiologies of most of these diseases are not fully understood. Therefore, the treatments based on the causes are difficult. The pathophysiologies of these diseases are modified by the ages. For example, some patients with epilepsy develop psychiatric symptoms in adulthood, and require the consultation by psychiatrists. The long-term follow up of certain disorders and evaluations of the disorders at different ages up to the adulthood have lead to new scientific discoveries. Examples include age-dependent symptoms observed in Segawa disease, psychiatric symptoms developing in frontal lobe epilepsy cases, alterations of behaviors in autism and Tourette syndrome. This knowledge suggests insights for the early prevention of later adverse outcomes. Social awareness and understanding of these neurological problems occurring in childhood are essential. The medical economic base for child neurology is another challenging and urgent issue to be solved. The importance of child neurology in the life-long neurology is stressed.

Adolescent↗
PubMed2004

RNA editing generates tissue-specific sodium channels with distinct gating properties.

Sodium channels play an essential role in generating the action potential in eukaryotic cells, and their transcripts, especially those in insects, undergo extensive A-to-I RNA editing. The functional consequences of RNA editing of sodium channel transcripts, however, have yet to be determined. We characterized 20 splice variants of the German cockroach sodium channel gene BgNa(v). Functional analysis revealed that these variants exhibited a broad range of voltage-dependent activation and inactivation. Further analysis of two variants, BgNa(v)1-1 and BgNa(v)1-2, which activate at more depolarizing membrane potentials than other variants, showed that RNA editing events were responsible for variant-specific gating properties. Two U-to-C editing sites identified in BgNa(v)1-1 resulted in a Leu to Pro change in segment 1 of domain III (IIIS1) and a Val to Ala change in IVS4. The Leu to Pro change shifted both the voltage dependence of activation and steady-state inactivation in the depolarizing direction. Two A-to-I editing events in BgNa(v)1-2 resulted in a Lys to Arg change in IS2 and an Ile to Met change in IVS3. The Lys to Arg change shifted the voltage dependence of activation in the depolarizing direction. Moreover, these RNA editing events occurred in a tissue-specific and development-specific manner. Our findings provide direct evidence that RNA editing is an important mechanism generating tissue-/cell type-specific functional variants of sodium channels.

Alternative Splicing↗
PubMed2004

A variant of childhood-onset myasthenia gravis: HLA typing and clinical characteristics in Japan.

To investigate the correlation between clinical features and HLA DR/DQ genetic variability in myasthenia gravis (MG), we evaluated HLA DR/DQ allele frequencies in 87 Japanese patients with childhood-onset disease. HLA genotypes DRB1*1302/DQA1*0102/DQB1*0604 and DRB1*0901/DQA1*0301/DQB1*0303 were significantly higher in patients than in healthy controls (P(c) < 0.0001, RR = 5.5; P(c) < 0.0001, RR = 8.5, for two genotypes, respectively). Patients who had a significantly higher likelihood of the HLA types DRB1*1302/DQA1*0102/DQB1*0604 or DRB1*0901/DQA1*0301/DQB1*0303 belonged to the latent general type (LG) of MG; this is clinically ocular type, but shows myasthenic electromyographic findings in extremity muscles. The LG type of MG was observed in 78% of patients exhibiting the clinically ocular type; this group comprised approximately 75% of patients with childhood-onset MG. These date suggest that LG type of MG may present a particular subset of childhood-onset MG, which is associated with the specific HLA subtypes DRB1*1302/DQA1*0102/DQB1*0604 and DRB1*0901/DQA1*0301/DQB1*0303.

Adolescent↗
PubMed2004

[Inherited dystonia update].

Among idiopathic dystonia, inherited dystonia whose causative gene or linkage has been clarified are named as DYT1 to DYT15. The causative genes of DYT1, 5 and 11 were identified as genes of Torsin A, GTP cyclohydrolase I, and epsilon-sarcoglycan, respectively. All three are inherited dominantly. DYT1, and DYT5 which is known as Segawa disease, are dystonia with onset in childhood. After identification of the causative gene, each disorder was found to show the various phenotypes. In both DYT1 and Segawa disease, early onset develops generalized dystonia, and later onset focal or segmental dystonia. Deep brain stimulation of globus pallidus internal segment shows remarkable effect on DYT1. Segawa disease responds markedly to L-dopa without any side effect lifelong. The pathophysiology of Segawa disease is that partial deficiency of BH4 resulted from GCH I deficiency, rate limiting enzyme of synthesis of BH4, affects the TH activity at terminal of nigrostriatal dopamine neuron. The role of Torsin A in the pathogenesis of DYT1 is unknown. For a certain neuron or neuronal system to manifest a clinical symptom, it should reach to a certain maturational level. The symptoms of inherited dystonia are influenced by the developmental level of responsible neuron or neuronal circuit.

Dystonia↗
PubMed2003

Complete sequencing and characterization of 21,243 full-length human cDNAs.

As a base for human transcriptome and functional genomics, we created the "full-length long Japan" (FLJ) collection of sequenced human cDNAs. We determined the entire sequence of 21,243 selected clones and found that 14,490 cDNAs (10,897 clusters) were unique to the FLJ collection. About half of them (5,416) seemed to be protein-coding. Of those, 1,999 clusters had not been predicted by computational methods. The distribution of GC content of nonpredicted cDNAs had a peak at approximately 58% compared with a peak at approximately 42%for predicted cDNAs. Thus, there seems to be a slight bias against GC-rich transcripts in current gene prediction procedures. The rest of the cDNAs unique to the FLJ collection (5,481) contained no obvious open reading frames (ORFs) and thus are candidate noncoding RNAs. About one-fourth of them (1,378) showed a clear pattern of splicing. The distribution of GC content of noncoding cDNAs was narrow and had a peak at approximately 42%, relatively low compared with that of protein-coding cDNAs.

Chromosomes, Human, 21-22 and Y↗
PubMed2003

Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease).

Autosomal dominant guanosine triphosphate cyclohydrolase I (GCH-I) deficiency (Segawa disease) is a dopa-responsive dystonia caused by mutation of the GCH-I gene located on 14q22.1-q22.2. Neurohistochemical examination revealed a decrease of the tyrosine hydroxylase protein as well as its activity in the striatum and decrease of dopamine content, particularly in its ventral portion rich in D1 receptors (striatal direct pathways). Neuroimaging, clinical neurophysiological, and biochemical studies showed preservation of the structure and function of the terminal of the nigrostriatal DA neuron. Clinical neurophysiological studies showed no progressive decrement of DA activities. As the enzymatic activity of pteridine metabolism is highest in the early developmental course, it may modulate dopamine receptors maturing early in the developmental course. Its product, tetrahydrobiopterin, has higher affinity to tyrosine hydroxylase among hydroxylases. Thus, partial deficiency of tetrahydrobiopterin caused by heterozygous mutation of the GCH-I gene decreases dopamine activity rather selectively. This affects the DA receptors that mature early and demonstrates characteristic symptoms age-dependently along with the developmental decrement of the tyrosine hydroxylase activities at the terminals and the maturational processes of the projecting neurons of the basal ganglia. A difference in the ratio of mutant/wild-type GCH-I mRNA that depends on the locus of mutation may explain intrafamilial and interfamilial variation of phenotype.

Age of Onset↗
PubMed2003

Neurology of Tourette's syndrome (TS) TS as a developmental dopamine disorder: a hypothesis.

The favorable effect of dopamine (DA) depletors or DA receptor blockers suggested the state of increased transmission of DA system as the pathophysiology of Tourette's syndrome (TS). We have analysed the neurological signs of TS and evaluated the role of levodopa on the symptoms of TS. The data were compared with age-matched patients with Hereditary Progressive Dystonia (HPD) with marked diurnal fluctuation. Neurological examination of 81 drug naive TS patients revealed the clumsiness of rapid alternating pronation-supination movements of the arms and induced rigidity in the contralateral arm, which responded to the oral levodopa, and suggested hypofunction of the nigrostriatal (NS)-DA system. Postural asymmetry or scoliosis and abnormal tilting response suggested the asymmetric involvement of DA. The rotation to the side of less affected DA neuron on stepping with closed eyes suggested DA receptor supersensitivity. The favourable effects of a small dose of levodopa on these signs suggest the existence of DA receptor supersensitivity, because a small dose of levodopa is considered to alleviate the supersensitized DA receptors.

Adolescent↗
PubMed2003

Abnormalities of voluntary saccades in Gilles de la Tourette's syndrome: pathophysiological consideration.

Gilles de la Tourette's syndrome (TS) is a neurobehavioral disorder. Although the etiology and the pathophysiology of TS are still unknown, the involvement of the basal ganglia has long been postulated. On the other hand, saccadic eye movement was shown to be a useful measure to assess order and disorder of the function of the basal ganglia. To investigate the dysfunction of the basal ganglia of TS, we examined voluntary saccades in children with TS in comparison with the saccades in age-matched control children. Two kinds of saccades, visually-guided saccades (VGS) and memory-guided (MGS) saccades were evaluated. During the MGS, distracted saccades (DS), which indicate the distractibility, were examined. The results revealed the abnormalities in the parameters of the MGS, i.e. longer latencies and hypometric amplitudes, and decrease in the frequency of MGS. Whereas, the frequency of DS, the saccade to the predicted cue was significantly lower in younger patients (6-<9-years) than normal, but it was higher in the older TS children (9-<12-years). In addition, some of the patients showed large involuntary saccades, usually associated with eye blinks, during the task performance. These results suggest that in TS the basal ganglia fails to disinhibit the saccade neuron in the superior colliculus with the input of the frontal eye field to the striatum, and later allow the neurons to evoke non-goal directed saccades. In reference to abnormal saccades in other basal ganglia disorders with dopamine deficiency and to animal experiments with MPTP monkeys, these findings postulate primary hypodopaminergic state followed by upward regulation of dopamine receptors later in TS.

Age Factors↗
PubMed2002

Alternative splicing of an insect sodium channel gene generates pharmacologically distinct sodium channels.

Alternative splicing is a major mechanism by which potassium and calcium channels increase functional diversity in animals. Extensive alternative splicing of the para sodium channel gene and developmental regulation of alternative splicing have been reported in Drosophila species. Alternative splicing has also been observed for several mammalian voltage-gated sodium channel genes. However, the functional significance of alternative splicing of sodium channels has not been demonstrated. In this study, we identified three mutually exclusive alternative exons encoding part of segments 3 and 4 of domain III in the German cockroach sodium channel gene, para(CSMA). The splice site is conserved in the mouse, fish, and human Na(v)1.6 sodium channel genes, suggesting an ancient origin. One of the alternative exons possesses a stop codon, which would generate a truncated protein with only the first two domains. The splicing variant containing the stop codon is detected only in the PNS, whereas the other two full-size variants were detected in both the PNS and CNS. When expressed in Xenopus oocytes, the two splicing variants produced robust sodium currents, but with different gating properties, whereas the splicing variant with the stop codon did not produce any detectable sodium current. Furthermore, these two functional splicing variants exhibited a striking difference in sensitivity to a pyrethroid insecticide, deltamethrin. Exon swapping partially reversed the channel sensitivity to deltamethrin. Our results therefore provide the first evidence that alternative splicing of a sodium channel gene produces pharmacologically distinct channels.

Alternative Splicing↗
PubMed2002

[Pathophysiology of Rett syndrome from the standpoints of clinical characteristics and clinical neurophysiological findings].

The pathophysiology of Rett syndrome (RTT) was discussed by reviewing the characteristic clinical features and neurophysiological studies. The electroencephalography (EEG), sensory evoked potentials (SEP), sleep-wake rhythm (SWR) study and polysomnographical (PSG) study showed age dependent characteristics. The findings in EEG and SEP studies suggested the specific subcortical and cortical involvements taking place during the development. PSG suggested the early dysfunction of the brainstem and midbrain monoaminergic systems; hypoactive serotonin and noradrenaline systems and dopaminergic system associated with receptor supersensitivity. The monoaminergic systems are known to influence the maturation of the higher neuronal systems at specific areas and at the critical developmental stages. Particularly the synaptogenesis of the cerebral cortex are modulated by region or layer specifically from early stage of the development. The age dependent appearance of characteristic clinical features of RTT, and the variation of the clinical severities; e.g. classical, variant, form fruste etc. can be explained by the specific features of these monoaminergic systems. The analysis of the components of rapid eye movement sleep (REM) suggested the onset of RTT lies between 36 gestational weeks to 3-4 months postnatally. The roles of the causative gene, methyl-CpG-binding protein 2 gene (MECP2) are thought to modulate the transcription of the specific target genes which act these area at specific developmental stages.

Chromosomal Proteins, Non-Histone↗