36 results on '"Kiyomi Nishiyama"'
Search Results
2. Diagnostic utility of whole exome sequencing in patients showing cerebellar and/or vermis atrophy in childhood
- Author
-
Noriko Aida, Atsuko Tomita-Katsumoto, Hiroshi Doi, Chihiro Ohba, Sumimasa Yamashita, Kiyomi Nishiyama, Hirotomo Saitsu, Hitoshi Osaka, Yoshikatsu Eto, Ayumi Takamura, Nobuyuki Shimozawa, Yoshinori Tsurusaki, Mitsuko Nakashima, Mizue Iai, Fumiaki Tanaka, Yume Suzuki, Naomichi Matsumoto, and Noriko Miyake
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Ataxia ,Adolescent ,DNA Mutational Analysis ,Biology ,Compound heterozygosity ,Young Adult ,Cellular and Molecular Neuroscience ,Atrophy ,Cerebellum ,Genetics ,medicine ,Humans ,Exome ,Child ,Genetics (clinical) ,Exome sequencing ,Tripeptidyl-Peptidase 1 ,Genetic heterogeneity ,medicine.disease ,Hypoplasia ,Hypotonia ,Child, Preschool ,Mutation ,medicine.symptom - Abstract
Cerebellar and/or vermis atrophy is recognized in various types of childhood disorders with clinical and genetic heterogeneity. Although careful evaluation of clinical features and neuroimaging can lead to correct diagnosis of disorders, their diagnosis is sometimes difficult because clinical features can overlap with each other. In this study, we performed family-based whole exome sequencing of 23 families including 25 patients with cerebellar and/or vermis atrophy in childhood, who were unable to be diagnosed solely by clinical examination. Pathological mutations of seven genes were found in ten patients from nine families (9/23, 39.1 %): compound heterozygous mutations in FOLR1, C5orf42, POLG, TPP1, PEX16, and de novo mutations in CACNA1A, and ITPR1. Patient 1A with FOLR1 mutations showed extremely low concentration of 5-methyltetrahydrofolate in the cerebrospinal fluid and serum, and Patient 6 with TPP1 mutations demonstrated markedly lowered tripeptidyl peptidase 1 activity in leukocytes. Furthermore, Patient 8 with PEX16 mutations presented a mild increase of very long chain fatty acids in the serum as supportive data for genetic diagnosis. The main clinical features of these ten patients were nonspecific and mixed, and included developmental delay, intellectual disability, ataxia, hypotonia, and epilepsy. Brain MRI revealed both cerebellar and vermis atrophy in eight patients (8/10, 80 %), vermis atrophy/hypoplasia in two patients (2/10, 20 %), and brainstem atrophy in one patient (1/10, 10 %). Our data clearly demonstrate the utility of whole exome sequencing for genetic diagnosis of childhood cerebellar and/or vermis atrophy.
- Published
- 2013
3. De Novo Mutations in GNAO1, Encoding a Gαo Subunit of Heterotrimeric G Proteins, Cause Epileptic Encephalopathy
- Author
-
Kazuyuki Nakamura, Eriko Koshimizu, Hideki Hoshino, Hirofumi Kodera, Naomichi Matsumoto, Masaya Kubota, Takashi Shiihara, Hitoshi Osaka, Tenpei Akita, Hiroshi Terashima, Kiyoshi Hayasaka, Kazuhiro Ogata, Noriko Miyake, Mitsuhiro Kato, Tatsuro Kumada, Atsuo Fukuda, Masaaki Shiina, Jun Tohyama, Kiyomi Nishiyama, Satoko Miyatake, Satomi Iwata, Tomonori Furukawa, Yoshinori Tsurusaki, Mitsuko Nakashima, Shinichi Nakamura, and Hirotomo Saitsu
- Subjects
Models, Molecular ,GTP' ,Protein subunit ,Molecular Sequence Data ,Mutant ,GTP-Binding Protein alpha Subunits, Gi-Go ,Biology ,medicine.disease_cause ,GNAO1 ,Article ,Mice ,Heterotrimeric G protein ,Genetics ,medicine ,Animals ,Humans ,Exome ,Genetic Predisposition to Disease ,Genetics(clinical) ,Amino Acid Sequence ,Child ,Receptor ,Genetics (clinical) ,Mutation ,Epilepsy ,Infant ,Electroencephalography ,Sequence Analysis, DNA ,Magnetic Resonance Imaging ,Molecular biology ,Protein Transport ,G beta-gamma complex ,Phenotype ,Amino Acid Substitution ,Child, Preschool ,Calcium ,Female ,Mutant Proteins ,Signal Transduction - Abstract
Heterotrimeric G proteins, composed of α, β, and γ subunits, can transduce a variety of signals from seven-transmembrane-type receptors to intracellular effectors. By whole-exome sequencing and subsequent mutation screening, we identified de novo heterozygous mutations in GNAO1, which encodes a Gαo subunit of heterotrimeric G proteins, in four individuals with epileptic encephalopathy. Two of the affected individuals also showed involuntary movements. Somatic mosaicism (approximately 35% to 50% of cells, distributed across multiple cell types, harbored the mutation) was shown in one individual. By mapping the mutation onto three-dimensional models of the Gα subunit in three different complexed states, we found that the three mutants (c.521A>G [p.Asp174Gly], c.836T>A [p.Ile279Asn], and c.572_592del [p.Thr191_Phe197del]) are predicted to destabilize the Gα subunit fold. A fourth mutant (c.607G>A), in which the Gly203 residue located within the highly conserved switch II region is substituted to Arg, is predicted to impair GTP binding and/or activation of downstream effectors, although the p.Gly203Arg substitution might not interfere with Gα binding to G-protein-coupled receptors. Transient-expression experiments suggested that localization to the plasma membrane was variably impaired in the three putatively destabilized mutants. Electrophysiological analysis showed that Gαo-mediated inhibition of calcium currents by norepinephrine tended to be lower in three of the four Gαo mutants. These data suggest that aberrant Gαo signaling can cause multiple neurodevelopmental phenotypes, including epileptic encephalopathy and involuntary movements.
- Published
- 2013
4. Targeted capture and sequencing for detection of mutations causing early onset epileptic encephalopathy
- Author
-
Eiji Nakagawa, Ming Lee, Yoshinori Tsurusaki, Mitsuko Nakashima, Mary Claire King, Hirotomo Saitsu, Mitsuhiro Kato, Masano Amamoto, Dorit Lev, Naomichi Matsumoto, Sayaka Ohta, Kazutoshi Ueda, Yutaka Nonoda, Kiyomi Nishiyama, Tom Walsh, Tally Lerman-Sagie, Kiyoshi Hayasaka, Jun Tohyama, Bruria Ben-Zeev, Alexander Nord, Rachel Straussberg, Noriko Miyake, Gaku Yamanaka, Tae Ikeda, Kazuyuki Nakamura, Hirofumi Kodera, and Saori Tanabe
- Subjects
Male ,DNA Copy Number Variations ,Biology ,medicine.disease_cause ,Frameshift mutation ,symbols.namesake ,Munc18 Proteins ,medicine ,Humans ,Genetic Testing ,Copy-number variation ,Gene ,Genetic testing ,COLD-PCR ,Sanger sequencing ,Genetics ,Mutation ,NAV1.2 Voltage-Gated Sodium Channel ,medicine.diagnostic_test ,Point mutation ,Microfilament Proteins ,Electroencephalography ,Sequence Analysis, DNA ,Microarray Analysis ,NAV1.1 Voltage-Gated Sodium Channel ,Neurology ,symbols ,Female ,Neurology (clinical) ,Carrier Proteins ,Spasms, Infantile - Abstract
Summary Purpose Early onset epileptic encephalopathies (EOEEs) are heterogeneous epileptic disorders caused by various abnormalities in causative genes including point mutations and copy number variations (CNVs). In this study, we performed targeted capture and sequencing of a subset of genes to detect point mutations and CNVs simultaneously. Methods We designed complementary RNA oligonucleotide probes against the coding exons of 35 known and potential candidate genes. We tested 68 unrelated patients, including 15 patients with previously detected mutations as positive controls. In addition to mutation detection by the Genome Analysis Toolkit, CNVs were detected by the relative depth of coverage ratio. All detected events were confirmed by Sanger sequencing or genomic microarray analysis. Key Findings We detected all positive control mutations. In addition, in 53 patients with EOEEs, we detected 12 pathogenic mutations, including 9 point mutations (2 nonsense, 3 splice-site, and 4 missense mutations), 2 frameshift mutations, and one 3.7-Mb microdeletion. Ten of the 12 mutations occurred de novo; the other two had been previously reported as pathogenic. The entire process of targeted capture, sequencing, and analysis required 1 week for the testing of up to 24 patients. Significance Targeted capture and sequencing enables the identification of mutations of all classes causing EOEEs, highlighting its usefulness for rapid and comprehensive genetic testing.
- Published
- 2013
5. Clinical spectrum of early onset epileptic encephalopathies caused byKCNQ2mutation
- Author
-
Ayumi Matsumoto, Sumimasa Yamashita, Kenji Sugai, Kazuyuki Nakamura, Kayoko Saito, Mari Maeno, Taku Nakagawa, Kiyomi Nishiyama, Hiroshi Arai, Yoshinobu Oyazato, Ryosuke Kusano, Kaoru Imai, Naomichi Matsumoto, Takanori Yamagata, Shelly K. Weiss, Tami Uster, Hirofumi Kodera, Hirofumi Kashii, Kiyoshi Hayasaka, Noriko Miyake, Mitsuhiro Kato, Hirotomo Saitsu, Yoshinori Tsurusaki, Mitsuko Nakashima, Takanari FujII, David Chitayat, and Masaya Kubota
- Subjects
Male ,Phenytoin ,Pediatrics ,medicine.medical_specialty ,Ohtahara syndrome ,DNA Mutational Analysis ,Zonisamide ,Neonatal onset ,Epilepsy ,medicine ,Humans ,KCNQ2 Potassium Channel ,Genetic Predisposition to Disease ,Benign familial neonatal seizures ,Genetic Testing ,Valproic Acid ,business.industry ,Infant, Newborn ,Infant ,Electroencephalography ,Exons ,medicine.disease ,Magnetic Resonance Imaging ,Hypsarrhythmia ,Neurology ,Anesthesia ,Mutation ,Female ,Neurology (clinical) ,medicine.symptom ,Tomography, X-Ray Computed ,business ,medicine.drug - Abstract
Summary Purpose KCNQ2 mutations have been found in patients with benign familial neonatal seizures, myokymia, or early onset epileptic encephalopathy (EOEE). In this study, we aimed to delineate the clinical spectrum of EOEE associated with KCNQ2 mutation. Methods A total of 239 patients with EOEE, including 51 cases with Ohtahara syndrome and 104 cases with West syndrome, were analyzed by high-resolution melting (HRM) analysis or whole-exome sequencing. Detailed clinical information including electroencephalography (EEG) and brain magnetic resonance imaging (MRI) were collected from patients with KCNQ2 mutation. Key Findings A total of nine de novo and one inherited mutations were identified (two mutations occurred recurrently). The initial seizures, which were mainly tonic seizures, occurred in the early neonatal period in all 12 patients. A suppression-burst pattern on EEG was found in most. Only three patients showed hypsarrhythmia on EEG; eight patients became seizure free when treated with carbamazepine, zonisamide, phenytoin, topiramate, or valproic acid. Although the seizures were relatively well controlled, moderate-to-profound intellectual disability was found in all except one patient who died at 3 months. Significance De novo KCNQ2 mutations are involved in EOEE, most of which cases were diagnosed as Ohtahara syndrome. These cases showed distinct features with early neonatal onset, tonic seizures, a suppression-burst EEG pattern, infrequent evolution to West syndrome, and good response to sodium channel blockers, but poor developmental prognosis. Genetic testing for KCNQ2 should be considered for patients with EOEE.
- Published
- 2013
6. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood
- Author
-
Emi Kasai-Yoshida, Satoko Kumada, Hirokazu Arakawa, Noriko Miyake, Noboru Mizushima, Noriko Sawaura, Hirofumi Kodera, Taki Nishimura, Kiyomi Nishiyama, Kazuhiro Muramatsu, Hiroya Nishida, Naomichi Matsumoto, Yoshinori Tsurusaki, Mitsuhiro Kato, Ai Hoshino, Mitsuko Nakashima, Yukiko Kondo, Fukiko Ryujin, Kenji Sugai, Hirotomo Saitsu, and Seiichiro Yoshioka
- Subjects
Adult ,Protein family ,Neurodegeneration with brain iron accumulation ,Iron ,Biology ,WDR45 ,Intellectual Disability ,Mitophagy ,Autophagy ,Genetics ,medicine ,Humans ,Exome ,Child ,Gene ,De novo mutations ,Lennox Gastaut Syndrome ,Neurodegeneration ,High-Throughput Nucleotide Sequencing ,Neurodegenerative Diseases ,medicine.disease ,Magnetic Resonance Imaging ,Phenotype ,Mutation ,Female ,Carrier Proteins ,Spasms, Infantile - Abstract
Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is a recently established subtype of neurodegeneration with brain iron accumulation (NBIA). By exome sequencing, we found de novo heterozygous mutations in WDR45 at Xp11.23 in two individuals with SENDA, and three additional WDR45 mutations were identified in three other subjects by Sanger sequencing. Using lymphoblastoid cell lines (LCLs) derived from the subjects, aberrant splicing was confirmed in two, and protein expression was observed to be severely impaired in all five. WDR45 encodes WD-repeat domain 45 (WDR45). WDR45 (also known as WIPI4) is one of the four mammalian homologs of yeast Atg18, which has an important role in autophagy. Lower autophagic activity and accumulation of aberrant early autophagic structures were demonstrated in the LCLs of the affected subjects. These findings provide direct evidence that an autophagy defect is indeed associated with a neurodegenerative disorder in humans.
- Published
- 2013
7. CASK aberrations in male patients with Ohtahara syndrome and cerebellar hypoplasia
- Author
-
Hitoshi Osaka, Noriko Miyake, Kiyomi Nishiyama, Hideki Horita, Yuriko Yoneda, Mitsuhiro Kato, Kiyoshi Hayasaka, Naomichi Matsumoto, Yukiko Kondo, Hiroshi Doi, Hirotomo Saitsu, Nobuko Moriyama, and Yoshinori Tsurusaki
- Subjects
Genetics ,Microcephaly ,medicine.diagnostic_test ,FG syndrome ,Pontocerebellar hypoplasia ,Copy number analysis ,Biology ,medicine.disease ,Molecular biology ,Neurology ,medicine ,Neurology (clinical) ,Cerebellar hypoplasia (non-human) ,CASK ,Exome sequencing ,Fluorescence in situ hybridization - Abstract
Summary Purpose: Ohtahara syndrome (OS) is one of the most severe and earliest forms of epilepsy. STXBP1 and ARX mutations have been reported in patients with OS. In this study, we aimed to identify new genes involved in OS by copy number analysis and whole exome sequencing. Methods: Copy number analysis and whole exome sequencing were performed in 34 and 12 patients with OS, respectively. Fluorescence in situ hybridization, quantitative polymerase chain reaction (PCR), and breakpoint-specific and reverse-transcriptase PCR analyses were performed to characterize a deletion. Immunoblotting using lymphoblastoid cells was done to examine expression of CASK protein. Key Findings: Genomic microarray analysis revealed a 111-kb deletion involving exon 2 of CASK at Xp11.4 in a male patient. The deletion was inherited from his mother, who was somatic mosaic for the deletion. Sequencing of the mutant transcript expressed in lymphoblastoid cell lines derived from the patient confirmed the deletion of exon 2 in the mutant transcript with a premature stop codon. Whole exome sequencing identified another male patient who was harboring a c.1A>G mutation in CASK, which occurred de novo. Both patients showed severe cerebellar hypoplasia along with other congenital anomalies such as micrognathia, a high arched palate, and finger anomalies. No CASK protein was detected by immunoblotting in lymphoblastoid cells derived from two patients. Significance: The detected mutations are highly likely to cause the loss of function of the CASK protein in male individuals. CASK mutations have been reported in patients with intellectual disability with microcephaly and pontocerebellar hypoplasia or congenital nystagmus, and those with FG syndrome. Our data expand the clinical spectrum of CASK mutations to include OS with cerebellar hypoplasia and congenital anomalies at the most severe end.
- Published
- 2012
8. A girl with early-onset epileptic encephalopathy associated with microdeletion involving CDKL5
- Author
-
Naomichi Matsumoto, Hirotomo Saitsu, Hitoshi Osaka, Kiyomi Nishiyama, Hiroshi Doi, Yoshinori Tsurusaki, and Noriko Miyake
- Subjects
Pathology ,medicine.medical_specialty ,CDKL5 ,Copy number analysis ,Protein Serine-Threonine Kinases ,Biology ,Developmental Neuroscience ,Rett Syndrome ,medicine ,Humans ,Genetic Testing ,Child ,Generalized tonic seizures ,Sequence Deletion ,Cerebral atrophy ,Genetics ,Epilepsy ,Breakpoint ,General Medicine ,medicine.disease ,Hypotonia ,Pediatrics, Perinatology and Child Health ,Encephalitis ,Female ,Neurology (clinical) ,medicine.symptom ,Myoclonus ,Developmental regression - Abstract
Recent studies have shown that aberrations of CDKL5 in female patients cause early-onset intractable seizures, severe developmental delay or regression, and Rett syndrome-like features. We report on a Japanese girl with early-onset epileptic encephalopathy, hypotonia, developmental regression, and Rett syndrome-like features. The patient showed generalized tonic seizures, and later, massive myoclonus induced by phone and light stimuli. Brain magnetic resonance imaging showed no structural brain anomalies but cerebral atrophy. Electroencephalogram showed frontal dominant diffuse poly spikes and waves. Through copy number analysis by genomic microarray, we found a microdeletion at Xp22.13. A de novo 137-kb deletion, involving exons 5-21 of CDKL5, RS1, and part of PPEF1 gene, was confirmed by quantitative PCR and breakpoint specific PCR analyses. Our report suggests that the clinical features associated with CDKL5 deletions could be implicated in Japanese patients, and that genetic testing of CDKL5, including both sequencing and deletion analyses, should be considered in girls with early-onset epileptic encephalopathy and RTT-like features.
- Published
- 2012
9. Early onset West syndrome with severe hypomyelination and coloboma-like optic discs in a girl with SPTAN1 mutation
- Author
-
Zvonka Rener Primec, Karin Writzl, Hirotomo Saitsu, Damjan Osredkar, Kiyomi Nishiyama, Naomichi Matsumoto, Branka Stirn Kranjc, Nuška Pečarič-Meglič, and Barbara Gnidovec Stražišar
- Subjects
medicine.medical_specialty ,Coloboma ,Pathology ,medicine.diagnostic_test ,business.industry ,Myoclonic Jerk ,West Syndrome ,Electroencephalography ,Audiology ,SPTAN1 ,medicine.disease ,Hypsarrhythmia ,Hypotonia ,Atrophy ,Neurology ,medicine ,Neurology (clinical) ,medicine.symptom ,business - Abstract
Recent study has shown that mutations in the alpha-II-spectrin (SPTAN1) gene cause early onset intractable seizures, severe developmental delay, diffuse hypomyelination, and widespread brain atrophy. We report a Slovene girl with hypotonia, lack of visual attention, early onset epileptic encephalopathy, and severe developmental delay. The patient presented with segmental myoclonic jerks at the age of 6 weeks, and infantile spasms at the age of 3.5 months. Her seizures were resistant to treatment. Multiple electroencephalography recordings showed deterioration of the background activity, followed by multifocal abnormalities before progressing to hypsarrhythmia. Ophthalmologic examination revealed bilateral dysplastic, coloboma-like optic discs. Brain magnetic resonance imaging showed diffusely reduced white matter and brainstem volumes with hypomyelination. A de novo heterozygous in-frame deletion was detected in SPTAN1: c.6619_6621delGAG (p.E2270del). This report supports the causative relationship between SPTAN1 mutations and early onset intractable seizures with severe hypomyelination and widespread brain volume reduction. Coloboma-like optic discs might be an additional feature observed in patients with SPTAN1 mutations.
- Published
- 2012
10. Identification of a novel in-frame de novo mutation in SPTAN1 in intellectual disability and pontocerebellar atrophy
- Author
-
Kiyomi Nishiyama, Jacques L. Michaud, Fadi F. Hamdan, Naomichi Matsumoto, Jean-Claude Lacaille, Sylvia Dobrzeniecka, Dan Spiegelman, Guy A. Rouleau, Hirotomo Saitsu, Julie Gauthier, and Jean-Claude Décarie
- Subjects
Male ,Pontocerebellar atrophy ,Heterozygote ,DNA Mutational Analysis ,Mutation, Missense ,Short Report ,Fluorescent Antibody Technique ,Biology ,Transfection ,medicine.disease_cause ,Mice ,Olivopontocerebellar atrophy ,Atrophy ,Cell Line, Tumor ,Intellectual Disability ,Genetics ,medicine ,Animals ,Humans ,Missense mutation ,Spectrin ,Genetic Testing ,Genetics (clinical) ,Sequence Deletion ,Mutation ,Epilepsy ,Genome, Human ,Genetic Carrier Screening ,Microfilament Proteins ,Brain ,medicine.disease ,SPTAN1 ,Magnetic Resonance Imaging ,Phenotype ,Protein Structure, Tertiary ,Radiography ,Case-Control Studies ,Olivopontocerebellar Atrophies ,Female ,Carrier Proteins - Abstract
Heterozygous in-frame mutations (p.E2207del and p.R2308_M2309dup) in the α-II subunit of spectrin (SPTAN1) were recently identified in two patients with intellectual disability (ID), infantile spasms (IS), hypomyelination, and brain atrophy. These mutations affected the C-terminal domain of the protein, which contains the nucleation site of the α/β spectrin heterodimer. By screening SPTAN1 in 95 patients with idiopathic ID, we found a de novo in-frame mutation (p.Q2202del) in the same C-terminal domain in a patient with mild generalized epilepsy and pontocerebellar atrophy, but without IS, hypomyelination, or other brain structural defects, allowing us to define the core phenotype associated with these C-terminal SPTAN1 mutations. We also found a de novo missense variant (p.R566P) of unclear clinical significance in a patient with non-syndromic ID. These two mutations induced different patterns of aggregation between spectrin subunits in transfected neuronal cell lines, providing a paradigm for the classification of candidate variants.
- Published
- 2012
11. Early infantile epileptic encephalopathy associated with the disrupted gene encoding Slit-Robo Rho GTPase activating protein 2 (SRGAP2)
- Author
-
Hiroshi Doi, Hitoshi Osaka, Naoki Harada, Takeshi Mizuguchi, Naomichi Matsumoto, Mitsuhiro Kato, Kiyomi Nishiyama, Yoshinori Tsurusaki, Noriko Miyake, Kenji Kurosawa, Shirou Sugiyama, Hirotomo Saitsu, and Akira Nishimura
- Subjects
medicine.medical_specialty ,Neurite ,Chromosomal translocation ,In situ hybridization ,Biology ,Segmental Duplications, Genomic ,Seizures ,Internal medicine ,Genetics ,medicine ,Humans ,Cloning, Molecular ,In Situ Hybridization, Fluorescence ,Genetics (clinical) ,SLIT-ROBO Rho GTPase-Activating Protein 2 ,Base Sequence ,GTPase-Activating Proteins ,Breakpoint ,Infant, Newborn ,Brain ,Chromosome Mapping ,Infant ,Electroencephalography ,Human brain ,Magnetic Resonance Imaging ,SRGAP2 ,Hypsarrhythmia ,Endocrinology ,medicine.anatomical_structure ,Child, Preschool ,Female ,medicine.symptom ,Spasms, Infantile - Abstract
We report on a female patient with early infantile epileptic encephalopathy and severe psychomotor disability possessing a de novo balanced translocation t(1;9)(q32;q13). The patient showed clonic convulsions of extremities 2 days after birth. Electroencephalogram (EEG) transiently showed atypical suppression-burst pattern. The seizures evolved to brief tonic spasms, and hypsarrhythmia on EEG was noticed at age of 5 months, indicating the transition to West syndrome. By using fluorescent in situ hybridization (FISH), southern hybridization, and inverse PCR, the translocation breakpoints were successfully determined at the nucleotide level. The 1q32.1 breakpoint was located within a segmental duplication and disrupted the gene encoding Slit-Robo Rho GTPase activating protein 2 (SRGAP2). The 9q13 breakpoint was suggested to reside in the heterochromatin region. Srgap2 has been shown to be specifically expressed in developing brain of rodents, negatively regulate neuronal migration and induce neurite outgrowth and branching. Thus, SRGAP2 is very likely to play a role in the developing human brain. This is a first report of the SRGAP2 abnormality associated with early infantile epileptic encephalopathy.
- Published
- 2011
12. Mutations in POLR3A and POLR3B Encoding RNA Polymerase III Subunits Cause an Autosomal-Recessive Hypomyelinating Leukoencephalopathy
- Author
-
Masaaki Shiina, Kiyomi Nishiyama, Masayuki Sasaki, Yukiko Kondo, Hitoshi Osaka, Ken Inoue, Hidehiro Shibayama, Kazuhiro Ogata, Hiroshi Doi, Yoshinori Tsurusaki, Akio Yamashita, Jun-ichi Takanashi, Hirotomo Saitsu, Naomichi Matsumoto, Keisuke Hamada, and Noriko Miyake
- Subjects
Adult ,Male ,Models, Molecular ,Adolescent ,Molecular Sequence Data ,Nonsense mutation ,Mutation, Missense ,Genes, Recessive ,Compound heterozygosity ,RNA polymerase III ,Corpus Callosum ,Exon ,Transcription (biology) ,Report ,Genetics ,Humans ,Missense mutation ,Exome ,Genetic Predisposition to Disease ,Genetics(clinical) ,Genetics (clinical) ,Polymerase ,Base Sequence ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,RNA Polymerase III ,Sequence Analysis, DNA ,Molecular biology ,Nonsense Mediated mRNA Decay ,Pedigree ,Hereditary Central Nervous System Demyelinating Diseases ,Codon, Nonsense ,Transfer RNA ,biology.protein ,Female ,RNA Splice Sites - Abstract
Congenital hypomyelinating disorders are a heterogeneous group of inherited leukoencephalopathies characterized by abnormal myelin formation. We have recently reported a hypomyelinating syndrome characterized by diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). We performed whole-exome sequencing of three unrelated individuals with HCAHC and identified compound heterozygous mutations in POLR3B in two individuals. The mutations include a nonsense mutation, a splice-site mutation, and two missense mutations at evolutionally conserved amino acids. Using reverse transcription-PCR and sequencing, we demonstrated that the splice-site mutation caused deletion of exon 18 from POLR3B mRNA and that the transcript harboring the nonsense mutation underwent nonsense-mediated mRNA decay. We also identified compound heterozygous missense mutations in POLR3A in the remaining individual. POLR3A and POLR3B encode the largest and second largest subunits of RNA Polymerase III (Pol III), RPC1 and RPC2, respectively. RPC1 and RPC2 together form the active center of the polymerase and contribute to the catalytic activity of the polymerase. Pol III is involved in the transcription of small noncoding RNAs, such as 5S ribosomal RNA and all transfer RNAs (tRNA). We hypothesize that perturbation of Pol III target transcription, especially of tRNAs, could be a common pathological mechanism underlying POLR3A and POLR3B mutations.
- Published
- 2011
13. SMOC1 Is Essential for Ocular and Limb Development in Humans and Mice
- Author
-
Akira Nishimura, Yoshinori Tsurusaki, Koh-ichiro Yoshiura, Kyoji Horie, Takaya Tohma, Norio Niikawa, Takeshi Mizuguchi, Ferda Ozkinay, Kiyomi Nishiyama, Eliane Chouery, Ozgur Cogulu, Fumiki Hirahara, Naomichi Matsumoto, Tadashi Kaname, Ippei Okada, Takahisa Furukawa, Hiroshi Doi, Tatsuya Furuichi, Haruka Hamanoue, Shiro Ikegawa, Satoko Miyatake, Koji Terada, Junji Takeda, Noriko Miyake, André Mégarbané, Joelle Abou-Ghoch, Hirotomo Saitsu, Nadine Jalkh, and Ege Üniversitesi
- Subjects
genetic structures ,RNA Splicing ,Molecular Sequence Data ,Limb Deformities, Congenital ,Genes, Recessive ,Biology ,Eye ,Microphthalmia ,Article ,Mice ,Genetics ,medicine ,Animals ,Humans ,Microphthalmos ,Limb development ,Osteonectin ,Waardenburg Syndrome ,Genetics(clinical) ,Optic stalk ,Syndactyly ,Genetics (clinical) ,Chromosomes, Human, Pair 14 ,Mice, Inbred ICR ,Anophthalmia ,Base Sequence ,ComputerSystemsOrganization_COMPUTER-COMMUNICATIONNETWORKS ,Chromosome Mapping ,Extremities ,Optic Nerve ,Aplasia ,Anatomy ,medicine.disease ,eye diseases ,Hypoplasia ,Mice, Inbred C57BL ,ComputingMilieux_MANAGEMENTOFCOMPUTINGANDINFORMATIONSYSTEMS ,ComputingMethodologies_PATTERNRECOGNITION ,Codon, Nonsense ,Genetic Loci ,Optic nerve ,sense organs ,InformationSystems_MISCELLANEOUS - Abstract
WOS: 000286501500003, PubMed ID: 21194678, Microphthalmia with limb anomalies (MLA) is a rare autosomal-recessive disorder, presenting with anophthalmia or microphthalmia and hand and/or foot malformation. We mapped the MLA locus to 14q24 and successfully identified three homozygous (one nonsense and two splice site) mutations in the SPARC (secreted protein acidic and rich in cysteine)-related modular calcium binding 1 (SMOC1) in three families. Smoc1 is expressed in the developing optic stalk, ventral optic cup, and limbs of mouse embryos. Smoc1 null mice recapitulated MLA phenotypes, including aplasia or hypoplasia of optic nerves, hypoplastic fibula and bowed tibia, and syndactyly in limbs. A thinned and irregular ganglion cell layer and atrophy of the anteroventral part of the retina were also observed. Soft tissue syndactyly, resulting from inhibited apoptosis, was related to disturbed expression of genes involved in BMP signaling in the interdigital mesenchyme. Our findings indicate that SMOC1/Smoc1 is essential for ocular and limb development in both humans and mice., Ministry of Health, Labour and WelfareMinistry of Health, Labour and Welfare, Japan; Japan Science and Technology AgencyJapan Science & Technology Agency (JST); Japan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science, We would like to thank the patients and their families for their participation in this study. We thank Yoshiko Takahashi (Nara Institute of Science and Technology) and Atsushi Yamada (Showa University) for providing the Bmp2 and Sox9 probes; Elizabeth J. Robertson (University of Oxford) and Makoto Ishibashi (Kyoto University) for the Bmp7 probe; Robert E. Maxson, Jr. (University of Southern California Keck School of Medicine) for the Msx2 probe; Tomonori Hirose, Kazunori Akimoto, and Kazunori Sasaki (Yokohama City University) for providing useful information about mouse breeding, taking photos on a stereo microscope, and mRNA quantification; and Kohei Shiota and Sumiko Kimura (Kyoto University) for helpful comments about NB staining and limb anomalies. This work was supported by research grants from the Ministry of Health, Labour and Welfare (T. Furuichi, N. Miyake, N. Matsumoto, and H.S.) and the Japan Science and Technology Agency (N. Matsumoto), a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (T. Furuichi and N. Matsumoto), and a Grant-in-Aid for Young Scientist from the Japan Society for the Promotion of Science (K.N., H.D., N. Miyake, and H.S.). This work has been carried out at the Advanced Medical Research Center of Yokohama City University.
- Published
- 2011
14. Paternal mosaicism of an STXBP1 mutation in OS
- Author
-
Hiroshi Doi, Yoshinori Tsurusaki, Kiyomi Nishiyama, Ippei Okada, Masaya Kubota, Hirotomo Saitsu, Yuriko Yoneda, Kiyoshi Hayasaka, Noriko Miyake, Mitsuhiro Kato, Hideki Hoshino, and Naomichi Matsumoto
- Subjects
Male ,Genetics ,Epilepsy ,Mosaicism ,Somatic cell ,Buccal swab ,Mutant ,Infant, Newborn ,Intron ,Infant ,Biology ,Molecular biology ,Fathers ,Exon ,Munc18 Proteins ,RNA splicing ,Mutation (genetic algorithm) ,Humans ,Female ,Allele ,Spasms, Infantile ,Genetics (clinical) - Abstract
Saitsu H, Hoshino H, Kato M, Nishiyama K, Okada I, Yoneda Y, Tsurusaki Y, Doi H, Miyake N, Kubota M, Hayasaka K, Matsumoto N. Paternal mosaicism of an STXBP1 mutation in OS. Ohtahara syndrome (OS) is one of the most severe and earliest forms of epilepsy. We have recently identified that the de novo mutations of STXBP1 are important causes for OS. Here we report a paternal somatic mosaicism of an STXBP1 mutation. The affected daughter had onset of spasms at 1 month of age, and interictal electroencephalogram showed suppression-burst pattern, leading to the diagnosis of OS. She had a heterozygous c.902+5G>A mutation of STXBP1, which affects donor splicing of exon 10, resulting in 138-bp insertion of intron 10 sequences in the transcript. The mutant transcript had a premature stop codon, and was degraded by nonsense-mediated mRNA decay in lymphoblastoid cells derived from the patient. High-resolution melting analysis of clinically unaffected parental DNAs suggested that the father was somatic mosaic for the mutation, which was also suggested by sequencing. Cloning of PCR products amplified with the paternal DNA samples extracted from blood, saliva, buccal cells, and nails suggested that 5.3%, 8.7%, 11.9%, and 16.9% of alleles harbored the mutation, respectively. This is a first report of somatic mosaicism of an STXBP1 mutation, which has implications in genetic counseling of OS.
- Published
- 2010
15. STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern
- Author
-
Ippei Okada, Kenji E. Orii, Hitoshi Osaka, Hirotomo Saitsu, Yuichi Takami, Naomichi Matsumoto, Kiyomi Nishiyama, Toshihide Watanabe, Tsukasa Higuchi, Sahoko Miyama, Kiyoshi Hayasaka, Hideki Hoshino, Tetsuzo Tagawa, Mitsuhiro Kato, Hiroshi Arai, Noriko Miyake, Takahito Wada, Naomi Kondo, Shigeru Kimura, Masaya Kubota, Akira Sudo, and Akira Nishimura
- Subjects
Genetics ,Mutation ,Ohtahara syndrome ,Nonsense mutation ,Biology ,medicine.disease ,medicine.disease_cause ,Syntaxin binding ,Frameshift mutation ,Epileptic spasms ,Neurology ,medicine ,Missense mutation ,Neurology (clinical) ,Haploinsufficiency - Abstract
Summary Purpose: De novo STXBP1 mutations have been found in individuals with early infantile epileptic encephalopathy with suppression-burst pattern (EIEE). Our aim was to delineate the clinical spectrum of subjects with STXBP1 mutations, and to examine their biologic aspects. Methods: STXBP1 was analyzed in 29 and 54 cases of cryptogenic EIEE and West syndrome, respectively, as a second cohort. RNA splicing was analyzed in lymphoblastoid cells from a subject harboring a c.663 + 5G>A mutation. Expression of STXBP1 protein with missense mutations was examined in neuroblastoma2A cells. Results: A total of seven novel STXBP1 mutations were found in nine EIEE cases, but not in West syndrome. The mutations include two frameshift mutations, three nonsense mutations, a splicing mutation, and a recurrent missense mutation in three unrelated cases. Including our previous data, 10 of 14 individuals (71%) with STXBP1 aberrations had the onset of spasms after 1 month, suggesting relatively later onset of epileptic spasms. Nonsense-mediated mRNA decay associated with abnormal splicing was demonstrated. Transient expression revealed that STXBP1 proteins with missense mutations resulted in degradation in neuroblastoma2A cells. Discussion: Collectively, STXBP1 aberrations can account for about one-third individuals with EIEE (14 of 43). These genetic and biologic data clearly showed that haploinsufficiency of STXBP1 is the important cause for cryptogenic EIEE.
- Published
- 2010
16. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy
- Author
-
Mitsuhiro Kato, Satoko Kumada, Keisuke Hamada, Hitoshi Osaka, Tatsuro Kumada, Kazuhiro Ogata, Syu-ichi Hirai, Naomichi Matsumoto, Hirotomo Saitsu, Jun Tohyama, Yukiko Yoshimura, Katsuhisa Uruno, Kiyomi Nishiyama, Atsuo Fukuda, Akira Nishimura, Ippei Okada, Takeshi Mizuguchi, and Kiyoshi Hayasaka
- Subjects
Adult ,Male ,Heterozygote ,Ohtahara syndrome ,Protein Conformation ,Molecular Sequence Data ,Mutation, Missense ,Epilepsies, Myoclonic ,Biology ,Syntaxin binding ,Neuroblastoma ,Munc18 Proteins ,Mutant protein ,Tumor Cells, Cultured ,Genetics ,medicine ,Humans ,Missense mutation ,STXBP1 ,Amino Acid Sequence ,In Situ Hybridization, Fluorescence ,Sequence Homology, Amino Acid ,Genome, Human ,Qa-SNARE Proteins ,Circular Dichroism ,Infant, Newborn ,Wild type ,Brain ,Infant ,Nucleic Acid Hybridization ,Electroencephalography ,Microarray Analysis ,SPTAN1 ,medicine.disease ,Magnetic Resonance Imaging ,Radiography ,Female ,Chromosome Deletion ,Chromosomes, Human, Pair 9 ,Haploinsufficiency - Abstract
Early infantile epileptic encephalopathy with suppression-burst (EIEE), also known as Ohtahara syndrome, is one of the most severe and earliest forms of epilepsy. Using array-based comparative genomic hybridization, we found a de novo 2.0-Mb microdeletion at 9q33.3-q34.11 in a girl with EIEE. Mutation analysis of candidate genes mapped to the deletion revealed that four unrelated individuals with EIEE had heterozygous missense mutations in the gene encoding syntaxin binding protein 1 (STXBP1). STXBP1 (also known as MUNC18-1) is an evolutionally conserved neuronal Sec1/Munc-18 (SM) protein that is essential in synaptic vesicle release in several species. Circular dichroism melting experiments revealed that a mutant form of the protein was significantly thermolabile compared to wild type. Furthermore, binding of the mutant protein to syntaxin was impaired. These findings suggest that haploinsufficiency of STXBP1 causes EIEE.
- Published
- 2008
17. Application of genomic in situ hybridization for phylogenetic study between Mangifera indica L. and eight wild species of Mangifera
- Author
-
Wichan Eiadthong, Young A Choi, Keizo Yonemori, Kiyomi Nishiyama, and Chitose Honsho
- Subjects
Mangifera sylvatica ,biology ,medicine.diagnostic_test ,Phylogenetic tree ,fungi ,food and beverages ,Chromosome ,Horticulture ,biology.organism_classification ,Phylogenetics ,Botany ,medicine ,Anacardiaceae ,Amplified fragment length polymorphism ,Mangifera ,Fluorescence in situ hybridization - Abstract
The phylogenetic relationship between mango ( Mangifera indica L.) and eight wild species of Mangifera were analyzed by comparing signal intensity of genomic in situ hybridization (GISH) on somatic metaphase chromosomes of M. indica , using labeled DNA of eight wild Mangifera species. The eight wild species were divided into four groups based on intensity and number of hybridization signals on chromosomes of M. indica in GISH analyses. The probe of Mangifera sylvatica Roxb. gave the highest intensities on the chromosome of M. indica , indicating a close relationship between M. indica and M. sylvatica . For the other species, classification of GISH was comparable to that of the phylogenetic analysis using AFLP markers, as previously reported ( Eiadthong et al., 2000 ). This suggested a possibility that GISH analysis can be effectively used in the classification of Mangifera species.
- Published
- 2006
18. AKT3andPIK3R2mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH
- Author
-
Kazuyuki Nakamura, Yoshinori Tsurusaki, Kiyoshi Hayasaka, Mitsuko Nakashima, Hirotomo Saitsu, Noriko Miyake, Naomichi Matsumoto, Jun Tohyama, Kiyomi Nishiyama, Mitsuhiro Kato, Hirofumi Kodera, and Tadashi Shiohama
- Subjects
Genetics ,medicine ,Megalencephaly ,Biology ,medicine.disease ,Genetics (clinical) ,AKT3 - Published
- 2013
19. Whole exome sequencing identifies KCNQ2 mutations in Ohtahara syndrome
- Author
-
Hirotomo Saitsu, Mitsuhiro Kato, Takako Fujita, Hiroshi Doi, Kiyomi Nishiyama, Naomichi Matsumoto, Yoshinori Tsurusaki, Noriko Miyake, Tomohide Goto, Ayaka Koide, and Kiyoshi Hayasaka
- Subjects
Male ,Ohtahara syndrome ,business.industry ,Computational biology ,medicine.disease ,Epilepsy, Benign Neonatal ,Phenotype ,Neurology ,Mutation ,medicine ,Humans ,KCNQ2 Potassium Channel ,Female ,Neurology (clinical) ,business ,Exome ,Exome sequencing - Published
- 2012
20. Early onset epileptic encephalopathy caused by de novo SCN8A mutations
- Author
-
Esther Leshinsky-Silver, Dorit Lev, Hiroshi Terashima, Rachel Straussberg, Fumiaki Tanaka, Kiyomi Nishiyama, Hirotomo Saitsu, Tally Lerman-Sagie, Satoru Takahashi, Masaya Kubota, Noriko Miyake, Hisashi Kawawaki, Akihiko Tateno, Naomichi Matsumoto, Yoshinori Tsurusaki, Mitsuko Nakashima, Dafna Marom, Chihiro Ohba, Hadassa Goldberg-Stern, Mayumi Matsufuji, Mitsuhiro Kato, and Yasuko Kojima
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Pathology ,Adolescent ,Mutation, Missense ,Genetic analysis ,Intellectual Disability ,Convulsion ,Intellectual disability ,medicine ,Missense mutation ,Humans ,Child ,Gene ,Genetic testing ,Cerebral atrophy ,Epilepsy ,medicine.diagnostic_test ,business.industry ,Infant ,Electroencephalography ,medicine.disease ,Phenotype ,Early Diagnosis ,Neurology ,NAV1.6 Voltage-Gated Sodium Channel ,Child, Preschool ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Spasms, Infantile - Abstract
SummaryObjective De novo SCN8A mutations have been reported in patients with epileptic encephalopathy. Herein we report seven patients with de novo heterozygous SCN8A mutations, which were found in our comprehensive genetic analysis (target capture or whole-exome sequencing) for early onset epileptic encephalopathies (EOEEs). Methods A total of 163 patients with EOEEs without mutations in known genes, including 6 with malignant migrating partial seizures in infancy (MMPSI), and 60 with unclassified EOEEs, were analyzed by target capture (28 samples) or whole-exome sequencing (135 samples). Results We identified de novo SCN8A mutations in 7 patients: 6 of 60 unclassified EOEEs (10.0%), and one of 6 MMPSI cases (16.7%). The mutations were scattered through the entire gene: four mutations were located in linker regions, two in the fourth transmembrane segments, and one in the C-terminal domain. The type of the initial seizures was variable including generalized tonic–clonic, atypical absence, partial, apneic attack, febrile convulsion, and loss of tone and consciousness. Onset of seizures was during the neonatal period in two patients, and between 3 and 7 months of age in five patients. Brain magnetic resonance imaging (MRI) showed cerebellar and cerebral atrophy in one and six patients, respectively. All patients with SCN8A missense mutations showed initially uncontrollable seizures by any drugs, but eventually one was seizure-free and three were controlled at the last examination. All patients showed developmental delay or regression in infancy, resulting in severe intellectual disability. Significance Our data reveal that SCN8A mutations can cause variable phenotypes, most of which can be diagnosed as unclassified EOEEs, and rarely as MMPSI. Together with previous reports, our study further indicates that genetic testing of SCN8A should be considered in children with unclassified severe epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
- Published
- 2014
21. De novo WDR45 mutation in a patient showing clinically Rett syndrome with childhood iron deposition in brain
- Author
-
Chihiro Ohba, Keiichi Ozono, Naomichi Matsumoto, Yoshinori Tsurusaki, Noriko Miyake, Mitsuko Nakashima, Hirotomo Saitsu, Fumiaki Tanaka, Yoshitaka Iijima, Kiyomi Nishiyama, and Shin Nabatame
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Pathology ,medicine.medical_specialty ,Adolescent ,Neurodegeneration with brain iron accumulation ,Iron ,DNA Mutational Analysis ,Substantia nigra ,Rett syndrome ,Biology ,medicine.disease_cause ,MECP2 ,WDR45 ,Neurodevelopmental disorder ,Genetics ,medicine ,Rett Syndrome ,Humans ,Exome ,Genetics (clinical) ,Alleles ,Mutation ,Brain ,High-Throughput Nucleotide Sequencing ,medicine.disease ,Magnetic Resonance Imaging ,nervous system diseases ,Alternative Splicing ,Globus pallidus ,nervous system ,Female ,Carrier Proteins - Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder mostly caused by MECP2 mutations. We identified a de novo WDR45 mutation, which caused a subtype of neurodegeneration with brain iron accumulation, in a patient showing clinically typical RTT. The mutation (c.830+1G>A) led to aberrant splicing in lymphoblastoid cells. Sequential brain magnetic resonance imaging demonstrated that iron deposition in the globus pallidus and the substantia nigra was observed as early as at 11 years of age. Because the patient showed four of the main RTT diagnostic criteria, WDR45 should be investigated in patients with RTT without MECP2 mutations.
- Published
- 2014
22. PIGO mutations in intractable epilepsy and severe developmental delay with mild elevation of alkaline phosphatase levels
- Author
-
Yoshinori Tsurusaki, Hirofumi Kodera, Mitsuko Nakashima, Kiyomi Nishiyama, Kazuyuki Nakamura, Naomichi Matsumoto, Yoshiko Murakami, Noriko Miyake, Hirotomo Saitsu, Rie Anzai, Hitoshi Osaka, and Taroh Kinoshita
- Subjects
Male ,medicine.medical_specialty ,Glycosylation ,Glycosylphosphatidylinositols ,Developmental Disabilities ,Hemoglobinuria, Paroxysmal ,Biology ,Compound heterozygosity ,Severity of Illness Index ,Subclass ,chemistry.chemical_compound ,Fatal Outcome ,Seizures ,Internal medicine ,Intellectual Disability ,medicine ,Humans ,Abnormalities, Multiple ,Child ,Gene ,Exome sequencing ,Genetics ,Epilepsy ,CD24 ,Infant ,Membrane Proteins ,Phosphorus Metabolism Disorders ,medicine.disease ,Alkaline Phosphatase ,Hypoplasia ,Pedigree ,Endocrinology ,Neurology ,chemistry ,Mutation ,Alkaline phosphatase ,lipids (amino acids, peptides, and proteins) ,Female ,Neurology (clinical) - Abstract
Aberrations in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway constitute a subclass of congenital disorders of glycosylation, and mutations in seven genes involved in this pathway have been identified. Among them, mutations in PIGV and PIGO, which are involved in the late stages of GPI-anchor synthesis, and PGAP2, which is involved in fatty-acid GPI-anchor remodeling, are all causative for hyperphosphatasia with mental retardation syndrome (HPMRS). Using whole exome sequencing, we identified novel compound heterozygous PIGO mutations (c.389C>A [p.Thr130Asn] and c.1288C>T [p.Gln430*]) in two siblings, one of them having epileptic encephalopathy. GPI-anchored proteins (CD16 and CD24) on blood granulocytes were slightly decreased compared with a control and his mother. Our patients lacked the characteristic features of HPMRS, such as facial dysmorphology (showing only a tented mouth) and hypoplasia of distal phalanges, and had only a mild elevation of serum alkaline phosphatase (ALP). Our findings therefore expand the clinical spectrum of GPI-anchor deficiencies involving PIGO mutations to include epileptic encephalopathy with mild elevation of ALP.
- Published
- 2013
23. Isolation and characterization of new microsatellite markers in mango (Mangifera indica)
- Author
-
Keizo Yonemori, Kiyomi Nishiyama, Chitose Honsho, and Wichan Eiadthong
- Subjects
Ecology ,fungi ,food and beverages ,Biology ,Biochemistry ,General Biochemistry, Genetics and Molecular Biology ,Horticulture ,Specific primers ,Botany ,Genotype ,Microsatellite ,Mangifera ,Genomic library ,Cultivar - Abstract
Six microsatellite loci that were isolated from a microsatellite-enriched genomic library of mango (Mangifera indica) along with their specific primer sets were each characterized by using 36 cultivars collected mainly in Thailand. The observed and expected heterozygosities ranged from 0 to 0.83 and from 0.29 to 0.73, respectively. The number of putative alleles are two to six. Three of the six alleles have frequencies of over 75%. The high frequency may be attributed to the bias in the origin of cultivars. Among 36 mango cultivars tested, 29 cultivars showed a unique pattern by six primer sets, whereas seven cultivars cannot be identified because of genotype similarities. This suggests the potentials for identification of mango cultivars by microsatellite markers.
- Published
- 2005
24. De novo mutations in SLC35A2 encoding a UDP-galactose transporter cause early-onset epileptic encephalopathy
- Author
-
Shuji Mizumoto, Kazuyuki Nakamura, Yoshinao Wada, Yoshinori Tsurusaki, Isao Yuasa, Mizue Iai, Noriko Miyake, Mitsuko Nakashima, Kazuyuki Sugahara, Hirotomo Saitsu, Kiyomi Nishiyama, Kazuhiro Haginoya, Hitoshi Osaka, Kiyoshi Hayasaka, Yoshihiro Maegaki, Hirofumi Kodera, Nobuhiko Okamoto, Naomichi Matsumoto, Yukiko Kondo, and Mitsuhiro Kato
- Subjects
Glycosylation ,Monosaccharide Transport Proteins ,Mutant ,DNA Mutational Analysis ,Gene Expression ,Biology ,Frameshift mutation ,Cell Line ,chemistry.chemical_compound ,symbols.namesake ,Mice ,Mutant protein ,Gene Order ,Genetics ,RNA Isoforms ,Missense mutation ,Animals ,Humans ,Exome ,Allele ,Age of Onset ,Child ,Genetics (clinical) ,Sanger sequencing ,chemistry.chemical_classification ,Infant, Newborn ,Brain ,Facies ,High-Throughput Nucleotide Sequencing ,Infant ,Electroencephalography ,Magnetic Resonance Imaging ,Protein Transport ,Phenotype ,chemistry ,Mutation ,symbols ,Female ,Glycoprotein ,Spasms, Infantile - Abstract
Early-onset epileptic encephalopathies (EOEE) are severe neurological disorders characterized by frequent seizures accompanied by developmental regression or retardation. Whole-exome sequencing of 12 patients together with five pairs of parents and subsequent Sanger sequencing in additional 328 EOEE patients identified two de novo frameshift and one missense mutations in SLC35A2 at Xp11.23, respectively. The three patients are all females. X-inactivation analysis of blood leukocyte DNA and mRNA analysis using lymphoblastoid cells derived from two patients with a frameshift mutation indicated that only the wild-type SLC35A2 allele was expressed in these cell types, at least in part likely as a consequence of skewed X-inactivation. SLC35A2 encodes a UDP-galactose transporter (UGT), which selectively supplies UDP-galactose from the cytosol to the Golgi lumen. Transient expression experiments revealed that the missense mutant protein was correctly localized in the Golgi apparatus. In contrast, the two frameshift mutant proteins were not properly expressed, suggesting that their function is severely impaired. Defects in the UGT can cause congenital disorders of glycosylation. Of note, no abnormalities of glycosylation were observed in three serum glycoproteins, which is consistent with favorably skewed X-inactivation. We hypothesize that a substantial number of neurons might express the mutant SLC35A2 allele and suffer from defective galactosylation, resulting in EOEE.
- Published
- 2013
25. Whole-exome sequencing identified a homozygous FNBP4 mutation in a family with a condition similar to microphthalmia with limb anomalies
- Author
-
Eriko Koshimizu, André Mégarbané, Hirotomo Saitsu, Yoshinori Tsurusaki, Mitsuko Nakashima, Naomichi Matsumoto, Hiroshi Doi, Satoko Miyatake, Noriko Miyake, Kiyomi Nishiyama, Ippei Okada, Yukiko Kondo, Haruka Hamanoue, and Hirofumi Kodera
- Subjects
Male ,education ,Biology ,Microphthalmia ,Exon ,Locus heterogeneity ,Genetics ,medicine ,Humans ,Family ,Osteonectin ,Waardenburg Syndrome ,Genetics (clinical) ,Exome sequencing ,Pathogenic mutation ,Homozygote ,Intracellular Signaling Peptides and Proteins ,Exons ,Disease gene identification ,medicine.disease ,Pedigree ,Mutation (genetic algorithm) ,Mutation ,Female ,Abnormality ,Carrier Proteins ,Sequence Analysis - Abstract
Microphthalmia with limb anomalies (MLA), also known as Waardenburg anophthalmia syndrome or ophthalmoacromelic syndrome, is a rare autosomal recessive disorder. Recently, we and others successfully identified SMOC1 as the causative gene for MLA. However, there are several MLA families without SMOC1 abnormality, suggesting locus heterogeneity in MLA. We aimed to identify a pathogenic mutation in one Lebanese family having an MLA-like condition without SMOC1 mutation by whole-exome sequencing (WES) combined with homozygosity mapping. A c.683C>T (p.Thr228Met) in FNBP4 was found as a primary candidate, drawing the attention that FNBP4 and SMOC1 may potentially modulate BMP signaling.
- Published
- 2013
26. CASK aberrations in male patients with Ohtahara syndrome and cerebellar hypoplasia
- Author
-
Hirotomo, Saitsu, Mitsuhiro, Kato, Hitoshi, Osaka, Nobuko, Moriyama, Hideki, Horita, Kiyomi, Nishiyama, Yuriko, Yoneda, Yukiko, Kondo, Yoshinori, Tsurusaki, Hiroshi, Doi, Noriko, Miyake, Kiyoshi, Hayasaka, and Naomichi, Matsumoto
- Subjects
Male ,Epilepsy ,Immunoblotting ,Neuroimaging ,Syndrome ,Real-Time Polymerase Chain Reaction ,Magnetic Resonance Imaging ,Cerebellar Diseases ,Child, Preschool ,Humans ,Female ,Guanylate Kinases ,Gene Deletion ,In Situ Hybridization, Fluorescence ,Oligonucleotide Array Sequence Analysis - Abstract
Ohtahara syndrome (OS) is one of the most severe and earliest forms of epilepsy. STXBP1 and ARX mutations have been reported in patients with OS. In this study, we aimed to identify new genes involved in OS by copy number analysis and whole exome sequencing.Copy number analysis and whole exome sequencing were performed in 34 and 12 patients with OS, respectively. Fluorescence in situ hybridization, quantitative polymerase chain reaction (PCR), and breakpoint-specific and reverse-transcriptase PCR analyses were performed to characterize a deletion. Immunoblotting using lymphoblastoid cells was done to examine expression of CASK protein.Genomic microarray analysis revealed a 111-kb deletion involving exon 2 of CASK at Xp11.4 in a male patient. The deletion was inherited from his mother, who was somatic mosaic for the deletion. Sequencing of the mutant transcript expressed in lymphoblastoid cell lines derived from the patient confirmed the deletion of exon 2 in the mutant transcript with a premature stop codon. Whole exome sequencing identified another male patient who was harboring a c.1AG mutation in CASK, which occurred de novo. Both patients showed severe cerebellar hypoplasia along with other congenital anomalies such as micrognathia, a high arched palate, and finger anomalies. No CASK protein was detected by immunoblotting in lymphoblastoid cells derived from two patients.The detected mutations are highly likely to cause the loss of function of the CASK protein in male individuals. CASK mutations have been reported in patients with intellectual disability with microcephaly and pontocerebellar hypoplasia or congenital nystagmus, and those with FG syndrome. Our data expand the clinical spectrum of CASK mutations to include OS with cerebellar hypoplasia and congenital anomalies at the most severe end.
- Published
- 2012
27. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly
- Author
-
Hiroshi Arai, Shinji Saitoh, Satoru Takahashi, Yoshinori Tsurusaki, Toshiyuki Kumagai, Hitoshi Osaka, Takamichi Yamamoto, Kazuhiro Haginoya, Jun-ichi Takanashi, Takahito Wada, Mami Yamasaki, Yuriko Yoneda, Noriko Kondo, Ayako Hattori, Kiyomi Nishiyama, Mitsuhiro Kato, Noriko Miyake, Akira Kumakura, Yoshinobu Sugo, Akihisa Okumura, Yoshiro Otsuki, Makoto Nabetani, Shin-ichi Shimizu, Norihisa Koyama, Satoko Miyatake, Akiyoshi Kakita, Kenji Yokochi, Hirotomo Saitsu, Yoichi Mino, Hiroshi Doi, Naomichi Matsumoto, Satori Hirai, and Shinichi Hirabayashi
- Subjects
Hemolytic anemia ,Collagen Type IV ,Pathology ,medicine.medical_specialty ,Anemia, Hemolytic ,Hemiplegia ,Biology ,medicine.disease_cause ,Frameshift mutation ,medicine ,Missense mutation ,Humans ,Child ,Genetics ,Mutation ,Brain Diseases ,Cerebral degeneration ,Infant ,Cortical dysplasia ,medicine.disease ,Porencephaly ,Malformations of Cortical Development ,Phenotype ,Neurology ,Schizencephaly ,Child, Preschool ,Neurology (clinical) - Abstract
Objective: Recently, COL4A1 mutations have been reported in porencephaly and other cerebral vascular diseases, often associated with ocular, renal, and muscular features. In this study, we aimed to clarify the phenotypic spectrum and incidence of COL4A1 mutations. Methods: We screened for COL4A1 mutations in 61 patients with porencephaly and 10 patients with schizencephaly, which may be similarly caused by disturbed vascular supply leading to cerebral degeneration, but can be distinguished depending on time of insult. Results: COL4A1 mutations were identified in 15 patients (21%, 10 mutations in porencephaly and 5 mutations in schizencephaly), who showed a variety of associated findings, including intracranial calcification, focal cortical dysplasia, pontocerebellar atrophy, ocular abnormalities, myopathy, elevated serum creatine kinase levels, and hemolytic anemia. Mutations include 10 missense, a nonsense, a frameshift, and 3 splice site mutations. Five mutations were confirmed as de novo events. One mutation was cosegregated with familial porencephaly, and 2 mutations were inherited from asymptomatic parents. Aberrant splicing was demonstrated by reverse transcriptase polymerase chain reaction analyses in 2 patients with splice site mutations. Interpretation: Our study first confirmed that COL4A1 mutations are associated with schizencephaly and hemolytic anemia. Based on the finding that COL4A1 mutations were frequent in patients with porencephaly and schizencephaly, genetic testing for COL4A1 should be considered for children with these conditions. ANN NEUROL 2013.
- Published
- 2012
28. Early onset West syndrome with severe hypomyelination and coloboma-like optic discs in a girl with SPTAN1 mutation
- Author
-
Karin, Writzl, Zvonka Rener, Primec, Barbara Gnidovec, Stražišar, Damjan, Osredkar, Nuška, Pečarič-Meglič, Branka Stirn, Kranjc, Kiyomi, Nishiyama, Naomichi, Matsumoto, and Hirotomo, Saitsu
- Subjects
Microfilament Proteins ,Mutation ,Optic Nerve Diseases ,Humans ,Infant ,Electroencephalography ,Female ,Fluorescein Angiography ,Carrier Proteins ,Magnetic Resonance Imaging ,Spasms, Infantile ,Myelin Sheath ,Demyelinating Diseases - Abstract
Recent study has shown that mutations in the alpha-II-spectrin (SPTAN1) gene cause early onset intractable seizures, severe developmental delay, diffuse hypomyelination, and widespread brain atrophy. We report a Slovene girl with hypotonia, lack of visual attention, early onset epileptic encephalopathy, and severe developmental delay. The patient presented with segmental myoclonic jerks at the age of 6 weeks, and infantile spasms at the age of 3.5 months. Her seizures were resistant to treatment. Multiple electroencephalography recordings showed deterioration of the background activity, followed by multifocal abnormalities before progressing to hypsarrhythmia. Ophthalmologic examination revealed bilateral dysplastic, coloboma-like optic discs. Brain magnetic resonance imaging showed diffusely reduced white matter and brainstem volumes with hypomyelination. A de novo heterozygous in-frame deletion was detected in SPTAN1: c.6619_6621delGAG (p.E2270del). This report supports the causative relationship between SPTAN1 mutations and early onset intractable seizures with severe hypomyelination and widespread brain volume reduction. Coloboma-like optic discs might be an additional feature observed in patients with SPTAN1 mutations.
- Published
- 2012
29. Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features
- Author
-
Naomichi Matsumoto, Akie Miyamoto, Mayumi Touyama, Kiyomi Nishiyama, Yuriko Yoneda, Yoshio Makita, Kazuhiro Ogata, Hiroshi Doi, Noriko Miyake, Kenji Naritomi, Naohiro Kurotaki, Yoshinori Tsurusaki, Keisuke Hamada, Hiroaki Tomita, and Hirotomo Saitsu
- Subjects
Adult ,Male ,Adolescent ,Nonsense mutation ,Molecular Sequence Data ,Mutation, Missense ,medicine.disease_cause ,Frameshift mutation ,Young Adult ,Genetics ,medicine ,Missense mutation ,Humans ,Amino Acid Sequence ,Child ,Gene ,Genetics (clinical) ,Mutation ,biology ,Base Sequence ,Sotos Syndrome ,Sotos syndrome ,Facies ,medicine.disease ,NFIX ,Molecular biology ,NFI Transcription Factors ,biology.protein ,Female ,Protein Multimerization ,Haploinsufficiency ,Sequence Alignment - Abstract
Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial features and mental retardation. Haploinsufficiency of NSD1 causes Sotos syndrome. Recently, two microdeletions encompassing Nuclear Factor I-X (NFIX) and a nonsense mutation in NFIX have been found in three individuals with Sotos-like overgrowth features, suggesting possible involvements of NFIX abnormalities in Sotos-like features. Interestingly, seven frameshift and two splice site mutations in NFIX have also been found in nine individuals with Marshall-Smith syndrome. In this study, 48 individuals who were suspected as Sotos syndrome but showing no NSD1 abnormalities were examined for NFIX mutations by high-resolution melt analysis. We identified two heterozygous missense mutations in the DNA-binding/dimerization domain of the NFIX protein. Both mutations occurred at evolutionally conserved amino acids. The c.179T>C (p.Leu60Pro) mutation occurred de novo and the c.362G>C (p.Arg121Pro) mutation was inherited from possibly affected mother. Both mutations were absent in 250 healthy Japanese controls. Our study revealed that missense mutations in NFIX were able to cause Sotos-like features. Mutations in DNA-binding/dimerization domain of NFIX protein also suggest that the transcriptional regulation is abnormally fluctuated because of NFIX abnormalities. In individuals with Sotos-like features unrelated to NSD1 changes, genetic testing of NFIX should be considered.
- Published
- 2012
30. A family of oculofaciocardiodental syndrome (OFCD) with a novel BCOR mutation and genomic rearrangements involving NHS
- Author
-
Hirotomo Saitsu, Jeong Hun Kim, Kiyomi Nishiyama, Yukiko Kondo, Naomichi Matsumoto, Hiroshi Doi, Na Kyung Ryoo, Young Suk Yu, Yoshinori Tsurusaki, Noriko Miyake, and Toshinobu Miyamoto
- Subjects
Adult ,Heart Defects, Congenital ,Heterozygote ,DNA Copy Number Variations ,Copy number analysis ,Biology ,medicine.disease_cause ,Toe syndactyly ,Cataract ,Translocation, Genetic ,Frameshift mutation ,Chromosome Breakpoints ,X Chromosome Inactivation ,Proto-Oncogene Proteins ,Gene duplication ,Gene Order ,Genetics ,medicine ,Humans ,Microphthalmos ,Protein Isoforms ,Child ,Genetics (clinical) ,Nance–Horan syndrome ,Mutation ,Base Sequence ,Heart Septal Defects ,Haplotype ,Brain ,Membrane Proteins ,Nuclear Proteins ,medicine.disease ,Pedigree ,Repressor Proteins ,Haplotypes ,Female ,Oculofaciocardiodental syndrome - Abstract
Oculofaciocardiodental syndrome (OFCD) is an X-linked dominant disorder associated with male lethality, presenting with congenital cataract, dysmorphic face, dental abnormalities and septal heart defects. Mutations in BCOR (encoding BCL-6-interacting corepressor) cause OFCD. Here, we report on a Korean family with common features of OFCD including bilateral 2nd-3rd toe syndactyly and septal heart defects in three affected females (mother and two daughters). Through the mutation screening and copy number analysis using genomic microarray, we identified a novel heterozygous mutation, c.888delG, in the BCOR gene and two interstitial microduplications at Xp22.2-22.13 and Xp21.3 in all the three affected females. The BCOR mutation may lead to a premature stop codon (p.N297IfsX80). The duplication at Xp22.2-22.13 involved the NHS gene causative for Nance-Horan syndrome, which is an X-linked disorder showing similar clinical features with OFCD in affected males, and in carrier females with milder presentation. Considering the presence of bilateral 2nd-3rd toe syndactyly and septal heart defects, which is unique to OFCD, the mutation in BCOR is likely to be the major determinant for the phenotypes in this family.
- Published
- 2012
31. Association of genomic deletions in the STXBP1 gene with Ohtahara syndrome
- Author
-
Naomichi Matsumoto, Yoshinori Tsurusaki, A Senju, Yuriko Yoneda, Noriko Miyake, Hiroshi Doi, Saori Tanabe, T Kimura, Hirotomo Saitsu, Kiyomi Nishiyama, Masayuki Shimono, Yukiko Kondo, Mitsuhiro Kato, and Kiyoshi Hayasaka
- Subjects
Genetics ,Ohtahara syndrome ,Genome, Human ,Syndrome ,Biology ,Gene deletion ,medicine.disease ,Genome ,Epilepsy ,Munc18 Proteins ,medicine ,STXBP1 ,Humans ,Epilepsy, Generalized ,Gene ,Genetics (clinical) ,Gene Deletion - Published
- 2012
32. De novo 5q14.3 translocation 121.5-kb upstream of MEF2C in a patient with severe intellectual disability and early-onset epileptic encephalopathy
- Author
-
Hiroshi Doi, Yuki Sasaki, Ippei Okada, Kiyomi Nishiyama, Noboru Igarashi, Osamu Shimokawa, Naomichi Matasumoto, Mitsuhiro Kato, Hirotomo Saitsu, Yoshinori Tsurusaki, Tomoki Kosho, Kiyoshi Hayasaka, Noriko Miyake, and Naoki Harada
- Subjects
RNA, Untranslated ,Generalized clonic seizures ,Abnormal Karyotype ,Chromosomal translocation ,MADS Domain Proteins ,Bioinformatics ,Translocation, Genetic ,Epilepsy ,Chromosome Breakpoints ,Seizures ,Intellectual Disability ,Intellectual disability ,Genetics ,Medicine ,Humans ,Cloning, Molecular ,Child ,Genetics (clinical) ,In Situ Hybridization, Fluorescence ,business.industry ,MEF2 Transcription Factors ,Breakpoint ,Infant ,Electroencephalography ,medicine.disease ,Physical Chromosome Mapping ,Magnetic Resonance Imaging ,Hypsarrhythmia ,Hypotonia ,Blotting, Southern ,Myogenic Regulatory Factors ,Child, Preschool ,Chromosomes, Human, Pair 5 ,Female ,medicine.symptom ,Agenesis of Corpus Callosum ,business ,Haploinsufficiency - Abstract
Recent studies have shown that haploinsufficiency of MEF2C causes severe intellectual disability, epilepsy, hypotonia, and cerebral malformations. We report on a female patient with severe intellectual disability, early-onset epileptic encephalopathy, and hypoplastic corpus callosum, possessing a de novo balanced translocation, t(5;15)(q13.3;q26.1). The patient showed upward gazing and tonic seizure of lower extremities followed by generalized clonic seizures at 4 months of age. Electroencephalogram showed hypsarrhythmia when asleep. By using fluorescent in situ hybridization (FISH), southern hybridization and inverse PCR, the translocation breakpoints were determined at the nucleotide level. The 5q14.3 breakpoint was localized 121.5-kb upstream of MEF2C. The 15q26.2 breakpoint was mapped 119-kb downstream of LOC91948 non-coding RNA. We speculate that the translocation may disrupt the proper regulation of MEF2C expression in the developing brain, resulting in severe intellectual disability and early-onset epileptic encephalopathy.
- Published
- 2011
33. A de novo CASK mutation in pontocerebellar hypoplasia type 3 with early myoclonic epilepsy and tetralogy of Fallot
- Author
-
Hirofumi Kodera, Shigeru Ohki, Tohru Okanishi, Kazuyuki Nakamura, Naomichi Matsumoto, Kiyomi Nishiyama, Yoshinori Tsurusaki, Hideo Enoki, Mitsuko Nakashima, Hirotomo Saitsu, Noriko Miyake, Kenji Yokochi, and Hideo Jinnou
- Subjects
Genetics ,business.industry ,Pontocerebellar hypoplasia ,General Medicine ,medicine.disease ,Frameshift mutation ,Developmental Neuroscience ,Pediatrics, Perinatology and Child Health ,Mutation (genetic algorithm) ,medicine ,Myoclonic epilepsy ,Neurology (clinical) ,CASK ,business ,Tetralogy of Fallot - Published
- 2014
34. STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern
- Author
-
Hirotomo, Saitsu, Mitsuhiro, Kato, Ippei, Okada, Kenji E, Orii, Tsukasa, Higuchi, Hideki, Hoshino, Masaya, Kubota, Hiroshi, Arai, Tetsuzo, Tagawa, Shigeru, Kimura, Akira, Sudo, Sahoko, Miyama, Yuichi, Takami, Toshihide, Watanabe, Akira, Nishimura, Kiyomi, Nishiyama, Noriko, Miyake, Takahito, Wada, Hitoshi, Osaka, Naomi, Kondo, Kiyoshi, Hayasaka, and Naomichi, Matsumoto
- Subjects
Male ,Munc18 Proteins ,Infant, Newborn ,Mutation, Missense ,Brain ,Humans ,Infant ,Electroencephalography ,Epilepsy, Generalized ,Female ,Haploinsufficiency ,Spasms, Infantile - Abstract
De novo STXBP1 mutations have been found in individuals with early infantile epileptic encephalopathy with suppression-burst pattern (EIEE). Our aim was to delineate the clinical spectrum of subjects with STXBP1 mutations, and to examine their biologic aspects.STXBP1 was analyzed in 29 and 54 cases of cryptogenic EIEE and West syndrome, respectively, as a second cohort. RNA splicing was analyzed in lymphoblastoid cells from a subject harboring a c.663 + 5GA mutation. Expression of STXBP1 protein with missense mutations was examined in neuroblastoma2A cells.A total of seven novel STXBP1 mutations were found in nine EIEE cases, but not in West syndrome. The mutations include two frameshift mutations, three nonsense mutations, a splicing mutation, and a recurrent missense mutation in three unrelated cases. Including our previous data, 10 of 14 individuals (71%) with STXBP1 aberrations had the onset of spasms after 1 month, suggesting relatively later onset of epileptic spasms. Nonsense-mediated mRNA decay associated with abnormal splicing was demonstrated. Transient expression revealed that STXBP1 proteins with missense mutations resulted in degradation in neuroblastoma2A cells.Collectively, STXBP1 aberrations can account for about one-third individuals with EIEE (14 of 43). These genetic and biologic data clearly showed that haploinsufficiency of STXBP1 is the important cause for cryptogenic EIEE.
- Published
- 2010
35. Dominant-Negative Mutations in α-II Spectrin Cause West Syndrome with Severe Cerebral Hypomyelination, Spastic Quadriplegia, and Developmental Delay
- Author
-
Kiyomi Nishiyama, Kazuhiro Ogata, Hirotomo Saitsu, Rie Miyata, Hideki Hoshino, Tomonori Furukawa, Tatsuro Kumada, Atsuo Fukuda, Ippei Okada, Keisuke Hamada, Tomohide Goto, Takanori Yamagata, Mitsuhiro Kato, Naomichi Matsumoto, Akira Nishimura, Syu-ichi Hirai, Noriko Miyake, Toshiro Nagai, Masayuki Komada, Kiyoshi Egawa, Jun Tohyama, Kazuhiro Haginoya, Takeshi Mizuguchi, Shinji Saitoh, Yasuo Hachiya, Hitoshi Osaka, and Kenji Hayashi
- Subjects
Developmental Disabilities ,Molecular Sequence Data ,Biology ,medicine.disease_cause ,Quadriplegia ,Transfection ,Article ,Mice ,Genetics ,medicine ,STXBP1 ,Animals ,Humans ,Genetics(clinical) ,Spectrin ,Amino Acid Sequence ,Cerebral hypomyelination ,Genetics (clinical) ,Cells, Cultured ,Myelin Sheath ,Mutation ,Sodium channel ,Brain ,Infant ,SPTAN1 ,Axon initial segment ,Molecular biology ,Phenotype ,Haploinsufficiency ,Spasms, Infantile - Abstract
A de novo 9q33.3-q34.11 microdeletion involving STXBP1 has been found in one of four individuals (group A) with early-onset West syndrome, severe hypomyelination, poor visual attention, and developmental delay. Although haploinsufficiency of STXBP1 was involved in early infantile epileptic encephalopathy in a previous different cohort study (group B), no mutations of STXBP1 were found in two of the remaining three subjects of group A (one was unavailable). We assumed that another gene within the deletion might contribute to the phenotype of group A. SPTAN1 encoding alpha-II spectrin, which is essential for proper myelination in zebrafish, turned out to be deleted. In two subjects, an in-frame 3 bp deletion and a 6 bp duplication in SPTAN1 were found at the initial nucleation site of the alpha/beta spectrin heterodimer. SPTAN1 was further screened in six unrelated individuals with WS and hypomyelination, but no mutations were found. Recombinant mutant (mut) and wild-type (WT) alpha-II spectrin could assemble heterodimers with beta-II spectrin, but alpha-II (mut)/beta-II spectrin heterodimers were thermolabile compared with the alpha-II (WT)/beta-II heterodimers. Transient expression in mouse cortical neurons revealed aggregation of alpha-II (mut)/beta-II and alpha-II (mut)/beta-III spectrin heterodimers, which was also observed in lymphoblastoid cells from two subjects with in-frame mutations. Clustering of ankyrinG and voltage-gated sodium channels at axon initial segment (AIS) was disturbed in relation to the aggregates, together with an elevated action potential threshold. These findings suggest that pathological aggregation of alpha/beta spectrin heterodimers and abnormal AIS integrity resulting from SPTAN1 mutations were involved in pathogenesis of infantile epilepsy.
- Published
- 2010
36. Ethylene regulation of fruit softening and cell wall disassembly in Charentais melon
- Author
-
Alan B. Bennett, Kenji Kato, Jocelyn K. C. Rose, Koichiro Ushijima, Jean-Claude Pech, Alain Latché, Monique Guis, Ryohei Nakano, Yasutaka Kubo, Lu Wangjin, Kristen A. Bennett, Akitsugu Inaba, Kiyomi Nishiyama, Mondher Bouzayen, Institut National de la Recherche Agronomique - INRA (FRANCE), University of California - UC Davis (USA), Cornell University (USA), Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE), and Okayama University (JAPAN)
- Subjects
Agronomie ,1-MCP ,Physiology ,Charentais melon ,Melon fruit ,Cell wall disassembly ,Plant Science ,Biotechnologies ,Biology ,Fruit softening ,Polymerase Chain Reaction ,Cell wall ,Expansin ,Cell Wall ,Cucumis melo ,Cell wall modification ,Softening ,DNA Primers ,food and beverages ,Ripening ,Ethylenes ,Xyloglucan endotransglucosylase ,Plants, Genetically Modified ,Biochemistry ,Enzyme ,Fruit ,Pollen ,Gene expression ,Transgenic plant ,Biologie végétale - Abstract
Cell wall disassembly in ripening fruit is highly complex, involving the dismantling of multiple polysaccharide networks by diverse families of wall-modifying proteins. While it has been reported in several species that multiple members of each such family are expressed in the same fruit tissue, it is not clear whether this reflects functional redundancy, with protein isozymes from a single enzyme class performing similar roles and contributing equally to wall degradation, or whether they have discrete functions, with some isoforms playing a predominant role. Experiments reported here sought to distinguish between cell wall-related processes in ripening melon that were softening-associated and softening-independent. Cell wall polysaccharide depolymerization and the expression of wall metabolism-related genes were examined in transgenic melon (Cucumis melo var. cantalupensis Naud.) fruit with suppressed expression of the 1-aminocyclopropane-1-carboxylate oxidase (ACO) gene and fruits treated with ethylene and 1-methylcyclopropene (1-MCP). Softening was completely inhibited in the transgenic fruit but was restored by treatment with exogenous ethylene. Moreover, post-harvest application of 1-MCP after the onset of ripening completely halted subsequent softening, suggesting that melon fruit softening is ethylene-dependent. Size exclusion chromatography of cell wall polysaccharides, from the transgenic fruits, with or without exogenous ethylene, indicated that the depolymerization of both pectins and xyloglucans was also ethylene dependent. However, northern analyses of a diverse range of cell wall-related genes, including those for polygalacturonases, xyloglucan endotransglucosylase/hydrolases, expansin, and beta-galactosidases, identified specific genes within single families that could be categorized as ethylene-dependent, ethylene-independent, or partially ethylene-dependent. These results support the hypothesis that while individual cell wall-modifying proteins from each family contribute to cell wall disassembly that accompanies fruit softening, other closely related family members are regulated in an ethylene-independent manner and apparently do not directly participate in fruit softening.
- Published
- 2007
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.