Publications by authors named "Kyoko Hoshino"

18 Publications

  • Page 1 of 1

Whole genome sequencing of 45 Japanese patients with intellectual disability.

Am J Med Genet A 2021 Feb 24. Epub 2021 Feb 24.

Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Intellectual disability (ID) is characterized by significant limitations in both intellectual functioning and adaptive behaviors, originating before the age of 18 years. However, the genetic etiologies of ID are still incompletely elucidated due to the wide range of clinical and genetic heterogeneity. Whole genome sequencing (WGS) has been applied as a single-step clinical diagnostic tool for ID because it detects genetic variations with a wide range of resolution from single nucleotide variants (SNVs) to structural variants (SVs). To explore the causative genes for ID, we employed WGS in 45 patients from 44 unrelated Japanese families and performed a stepwise screening approach focusing on the coding variants in the genes. Here, we report 12 pathogenic and likely pathogenic variants: seven heterozygous variants of ADNP, SATB2, ANKRD11, PTEN, TCF4, SPAST, and KCNA2, three hemizygous variants of SMS, SLC6A8, and IQSEC2, and one homozygous variant in AGTPBP1. Of these, four were considered novel. Furthermore, a novel 76 kb deletion containing exons 1 and 2 in DYRK1A was identified. We confirmed the clinical and genetic heterogeneity and high frequency of de novo causative variants (8/12, 66.7%). This is the first report of WGS analysis in Japanese patients with ID. Our results would provide insight into the correlation between novel variants and expanded phenotypes of the disease.
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http://dx.doi.org/10.1002/ajmg.a.62138DOI Listing
February 2021

An Interactive Smartphone App, Nenne Navi, for Improving Children's Sleep: Pilot Usability Study.

JMIR Pediatr Parent 2020 Dec 1;3(2):e22102. Epub 2020 Dec 1.

Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Osaka, Japan.

Background: Healthy sleep is important not only for physical health but also for brain development in children. Several reports have revealed that Japanese adults and children have later bedtimes and shorter sleep durations compared with those in other countries, possibly because of Japanese culture and lifestyles. Therefore, an intervention tool that is suitable to the Japanese sociocultural environment is urgently needed to improve children's sleep problems in their early years.

Objective: To provide appropriate sleep health literacy to caregivers and change their parenting behavior, we developed a smartphone app that allows reciprocal interaction between caregivers and pediatric sleep experts. This paper describes a preliminary study to examine the app's basic design and functions and to establish its acceptability and usability in a small sample.

Methods: A total of 10 caregivers and 10 infants (aged 18-28 months; 4/10, 40% boys) living in Japan participated in the study. At the start of the trial, the e-learning content regarding sleep health literacy was delivered via a smartphone. Thereafter, caregivers manually inputted recorded data about their own and their infant's sleep habits for 8 consecutive days per month for 2 months. After pediatric sleep experts retrieved this information from the Osaka University server, they specified the problems and provided multiple sleep habit improvement suggestions to caregivers. Caregivers then selected one of the feasible pieces of advice to practice and reported their child's sleep-related behaviors via the app. Actigraphy was used to monitor children's sleep behaviors objectively. The concordance between the information provided by caregivers and the actigraphy data was assessed. The acceptability and usability of the app were evaluated using self-report questionnaires completed by caregivers; qualitative feedback was obtained via semistructured interviews after the intervention.

Results: There was no significant difference between the information provided by the caregivers and the actigraphy data for bedtimes and wake-up times (P=.13 to P=.97). However, there was a difference between the actigraphy data and the caregivers' reports of nighttime sleep duration and nighttime awakenings (P<.001 each), similar to prior findings. User feedback showed that 6 and 5 of the 10 caregivers rated the app easy to understand and easy to continue to use, respectively. Additionally, 6 of the 10 caregivers rated the app's operativity as satisfactory. Although this was a short-term trial, children's sleep habits, caregivers' sleep health consciousness, and parenting behaviors improved to some extent.

Conclusions: The present findings suggest that the app can easily be used and is acceptable by Japanese caregivers. Given the user feedback, the app has the potential to improve children's sleep habits by sending individualized advice that fits families' backgrounds and home lives. Further studies are needed to confirm the efficacy of the app and facilitate social implementation.
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http://dx.doi.org/10.2196/22102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738258PMC
December 2020

Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing.

J Med Genet 2019 06 6;56(6):396-407. Epub 2019 Mar 6.

Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.

Background: Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (). Our objective to investigate the genetic landscape of -negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES).

Methods: We performed WES on 77 -negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria.

Results: Pathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including ) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes: a de novo variant in each of ATPase H transporting V0 subunit A1 (), ubiquitin-specific peptidase 8 () and microtubule-associated serine/threonine kinase 3 (), as well as biallelic variants in nuclear receptor corepressor 2 ().

Conclusions: Our study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.
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http://dx.doi.org/10.1136/jmedgenet-2018-105775DOI Listing
June 2019

Correction: PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia.

J Hum Genet 2019 01;64(1):61-63

Department of Neurology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.

The originally published version of this article contained an error in Fig. 1 and Table 2. The correct figure and table of this article should have read as below. This has now been corrected in the PDF and HTML versions of the article. The authors apologize for any inconvenience caused.
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http://dx.doi.org/10.1038/s10038-018-0533-9DOI Listing
January 2019

PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia.

J Hum Genet 2019 Jan 9;64(1):55-59. Epub 2018 Oct 9.

Department of Neurology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.

PLA2G6-associated neurodegeneration (PLAN) comprises heterogeneous neurodegenerative disorders, including infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation 2B, and Parkinson disease 14 (PARK14). In addition, very recently, PLA2G6 mutations have been reported to represent a phenotype of hereditary spastic paraplegia (HSP). In this study, we screened 383 HSP families to clarify the frequency of PLA2G6 mutations in the Japan Spastic Paraplegia Research Consortium, and revealed the clinical characteristics of HSP with PLA2G6 mutations. We found three families with compound heterozygous mutations of the PLA2G6 gene, c.517 C > T/c.1634A > G, c.662 T > C/c.991 G > T, and c.1187-2 A > G/c.1933C > T, and one family with a homozygous mutation of the PLA2G6 gene, c.1904G > A/c.1904G > A. All three families with compound heterozygous mutations presented a uniform phenotype of a complicated form of HSP with infantile/child-onset spastic paraplegia, cerebellar ataxia, and mental retardation. On the other hand, the family with a homozygous mutation presented a late-onset complicated form of HSP with parkinsonism. This study may extend the clinical and genetic findings for PLAN.
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http://dx.doi.org/10.1038/s10038-018-0519-7DOI Listing
January 2019

GRIN2D variants in three cases of developmental and epileptic encephalopathy.

Clin Genet 2018 12;94(6):538-547

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

N-methyl-d-aspartate (NMDA) receptors are glutamate-activated ion channels that are widely distributed in the central nervous system and essential for brain development and function. Dysfunction of NMDA receptors has been associated with various neurodevelopmental disorders. Recently, a de novo recurrent GRIN2D missense variant was found in two unrelated patients with developmental and epileptic encephalopathy. In this study, we identified by whole exome sequencing novel heterozygous GRIN2D missense variants in three unrelated patients with severe developmental delay and intractable epilepsy. All altered residues were highly conserved across vertebrates and among the four GluN2 subunits. Structural consideration indicated that all three variants are probably to impair GluN2D function, either by affecting intersubunit interaction or altering channel gating activity. We assessed the clinical features of our three cases and compared them to those of the two previously reported GRIN2D variant cases, and found that they all show similar clinical features. This study provides further evidence of GRIN2D variants being causal for epilepsy. Genetic diagnosis for GluN2-related disorders may be clinically useful when considering drug therapy targeting NMDA receptors.
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http://dx.doi.org/10.1111/cge.13454DOI Listing
December 2018

Abnormal myocardial scintigraphy in a GTP cyclohydrolase 1 mutation carrier with Parkinson's disease.

Mov Disord 2016 Mar 10;31(3):422-3. Epub 2016 Feb 10.

Department of Neurology, School of Medicine, Kitasato University, Sagamihara, Kanagawa, Japan.

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http://dx.doi.org/10.1002/mds.26523DOI Listing
March 2016

A case of acute encephalopathy with biphasic seizures and late reduced diffusion associated with Streptococcus pneumoniae meningoencephalitis.

Brain Dev 2012 Jun 19;34(6):529-32. Epub 2011 Sep 19.

Department of Pediatrics, Saitama Medical University, Saitama, Japan.

Acute encephalopathy with biphasic seizures and reduced diffusion (AESD) encompasses a group of encephalopathy characterized by biphasic seizures and disturbance of consciousness in the acute stage followed in the subacute stage by reduced diffusion in the subcortical white matter on magnetic resonance imaging. The etiology of AESD is viral infection and associated pathological changes. Here we report the first case of AESD caused by bacterial infection (Streptococcus pneumoniae meningitis) in a 1-year-old boy.
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http://dx.doi.org/10.1016/j.braindev.2011.08.010DOI Listing
June 2012

Neocortical layer formation of human developing brains and lissencephalies: consideration of layer-specific marker expression.

Cereb Cortex 2011 Mar 12;21(3):588-96. Epub 2010 Jul 12.

Department of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry, Kodaira, 187-8502, Japan.

To investigate layer-specific molecule expression in human developing neocortices, we performed immunohistochemistry of the layer-specific markers (TBR1, FOXP1, SATB2, OTX1, CUTL1, and CTIP2), using frontal neocortices of the dorsolateral precentral gyri of 16 normal controls, aged 19 gestational weeks to 1 year old, lissencephalies of 3 Miller-Dieker syndrome (MDS) cases, 2 X-linked lissencephaly with abnormal genitalia (XLAG) cases, and 4 Fukuyama-type congenital muscular dystrophy (FCMD) cases. In the fetal period, we observed SATB2+ cells in layers II-IV, CUTL1+ cells in layers II-V, FOXP1+ cells in layer V, OTX1+ cells in layers II or V, and CTIP2+ and TBR1+ cells in layers V and VI. SATB2+ and CUTL1+ cells appeared until 3 months of age, but the other markers disappeared after birth. Neocortices of MDS and XLAG infants revealed SATB2+, CUTL1+, FOXP1+, and TBR1+ cells diffusely located in the upper layers. In fetal FCMD neocortex, neurons labeled with the layer-specific markers located over the glia limitans. The present study provided new knowledge indicating that the expression pattern of these markers in the developing human neocortex was similar to those in mice. Various lissencephalies revealed abnormal layer formation by random migration.
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http://dx.doi.org/10.1093/cercor/bhq125DOI Listing
March 2011

Non-convulsive status epilepticus and audiogenic seizures complicating a patient with asymmetrical epileptic spasms.

Brain Dev 2010 Aug 6;32(7):583-7. Epub 2009 Sep 6.

Department of Child Neurology, National Center Hospital of Neurology and Psychiatry, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

A female infant suffered from epilepsy since the neonatal period, which evolved into West syndrome at the age of 2 months. Spasms in series and hypsarrhythmia disappeared after treatment with high-dose phenobarbital; however, single spasms persisted with right-sided predominance, and polyspike activity in the left parieto-temporal areas preceded or coincided with these spasms. Magnetic resonance imaging revealed a small calcification in the right occipital area, and positron emission tomography showed hypometabolism over the right hemisphere. Widespread epileptic discharges gradually increased on electroencephalography (EEG) during sleep thereafter. The patient presented with daytime unresponsiveness at 1 year and 6 months, when diffuse, irregular spike and wave activity characterized the waking EEG. Spasms or brief tonic seizures with right-sided predominance were provoked by auditory stimuli during this period, particularly by her mother's voice, with ictal EEG of right posterior predominant fast activity and subsequent desynchronization. The administration of clobazam resulted in the marked improvement of EEG findings and transient disappearance of spasms. Presumably, certain patients with asymmetrical epileptic spasms may be regarded as a unique type of localization-related epilepsy, and can show an unusual course of evolution in comparison to other cases of epilepsy that evolve after West syndrome.
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http://dx.doi.org/10.1016/j.braindev.2009.08.001DOI Listing
August 2010

Circadian Clock mutation in dams disrupts nursing behavior and growth of pups.

Endocrinology 2006 Apr 26;147(4):1916-23. Epub 2006 Jan 26.

Department of Physiology and Pharmacology, Waseda University School of Science and Engineering, Nishitokyo, Japan.

To understand the role of the circadian molecular clock in mouse reproduction, we investigated the daily rhythms associated with nursing and pup growth in Clock-mutant mice maintained under light-dark housing conditions. The daily rhythm associated with the maternal behavior of crouching had a strong diurnal peak and two weak nocturnal peaks in wild-type dams, whereas homozygotes (Clock/Clock) exhibited no significant peaks in activity. Wild-type, but not Clock-mutant, dams showed high, rhythmic levels of prolactin content in serum that corresponded with crouching. Pup body weight increased at a significantly slower rate in Clock-mutant dams compared with wild-type dams under all experimental conditions when the pups ranged from 10-15 in number. Heterozygote dams equally bred wild-type, heterozygote, or homozygote pups. The amount of milk secreted from dams, as calculated by the increase in pup body weight through suckling, was lower in Clock-mutant mothers vs. wild-type mice. When Clock-mutant dams gave birth to more than 10 pups, survival was poor for offspring until the time of weaning. The present results demonstrate that Clock mutation disrupts daily maternal behavior and the growth and survival rate of pups, especially with the breeding of more than 10 pups.
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http://dx.doi.org/10.1210/en.2005-1343DOI Listing
April 2006

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

Brain Dev 2005 Sep 12;27(6):424-30. Epub 2005 Jan 12.

Segawa Neurological Clinic for Children, 2-8 Surugadai Kanda, Chiyoda-ku, Tokyo 101-0062, Japan.

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.
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http://dx.doi.org/10.1016/j.braindev.2004.11.005DOI Listing
September 2005

How many dimensions are required to approximate the potential energy landscape of a model protein?

J Chem Phys 2005 Feb;122(8):84714

Nonlinear Science Laboratory, Department of Earth and Planetary Sciences, Faculty of Science, Kobe University, Nada, Kobe 657-8501, Japan.

A scheme to approximate the multidimensional potential energy landscape in terms of a minimal number of degrees of freedom is proposed using a linear transformation of the original atomic Cartesian coordinates. For one particular off-lattice model protein the inherent frustration can only be reproduced satisfactorily when a relatively large number of coordinates are employed. However, when this frustration is removed in a Go-type model, the number of coordinates required is significantly lower, especially around the global potential energy minimum. To aid our interpretation of the results we consider modified disconnectivity graphs where a measure of the structural diversity and a metric relation between the stationary points are incorporated.
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http://dx.doi.org/10.1063/1.1854123DOI Listing
February 2005

Production of brain-derived neurotrophic factor in Escherichia coli by coexpression of Dsb proteins.

Biosci Biotechnol Biochem 2002 Feb;66(2):344-50

Faculty of Life Sciences, Toyo University, Ora-gun, Gunma, Japan.

When brain-derived neurotrophic factor (BDNF) is produced in the Escherichia coli periplasm, insoluble BDNF proteins with low biological activity and having mismatched disulfide linkages are formed. The coexpression of cysteine oxidoreductases (DsbA and DsbC) and membrane-bound enzymes (DsbB and DsbD), which play an important role in the formation of disulfide bonds in the periplasm, was investigated to improve the production of soluble and biologically active BDNF. The expression levels of Dsb proteins changed when the growth medium and the Dsb expression plasmids were changed, and the production rate of soluble BDNF was almost proportional to the expression level of DsbC protein with disulfide isomerase activity in the case of a low expression level of BDNF. The rate of soluble BDNF production with coexpression of DsbABCD was as high as 35%. These results show that coexpression of BDNF and Dsb proteins can effectively increase the production of soluble and biologically active BDNF.
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http://dx.doi.org/10.1271/bbb.66.344DOI Listing
February 2002