RESUMO
R3HDM1 (R3H domain containing 1) is an uncharacterized RNA-binding protein that is highly expressed in the human cerebral cortex. We report the first case of a 12-year-old Japanese male with haploinsufficiency of R3HDM1. He presented with mild intellectual disability (ID) and developmental delay. He had a pericentric inversion of 46,XY,inv(2)(p16.1q21.3)dn with breakpoints in intron 19 of R3HDM1 (2q21.3) and the intergenic region (2p16.1). The R3HDM1 levels in his lymphoblastoid cells were reduced to approximately half that of the healthy controls. However, the expression of MIR128-1, in intron 18 of R3HDM1, was not affected via the pericentric inversion. Knockdown of R3HDM1 in mouse embryonic hippocampal neurons suppressed dendritic growth and branching. Notably, the Database of Genomic Variants reported the case of a healthy control with a 488-kb deletion that included both R3HDM1 and MIR128-1. miR-128 has been reported to inhibit dendritic growth and branching in mouse brain neurons, which directly opposes the novel functions of R3HDM1. These findings suggest that deleting both R3HDM1 and MIR128-1 alleviates the symptoms of the disease caused by loss-of-function mutations in R3HDM1 only. Thus, haploinsufficiency of R3HDM1 in the patient may be the cause of the mild ID due to the genetic imbalance between R3HDM1 and MIR128-1.
Assuntos
Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença , Haploinsuficiência/genética , Deficiência Intelectual/genética , Criança , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/patologia , Humanos , Deficiência Intelectual/patologia , MasculinoRESUMO
A heterozygous deletion at Xq27.3q28 including FMR1, AFF2, and IDS causing intellectual disability and characteristic facial features is very rare in females, with only 10 patients having been reported. Here, we examined two female patients with different clinical features harboring the Xq27.3q28 deletion and determined the chromosomal breakpoints. Moreover, we assessed the X chromosome inactivation (XCI) in peripheral blood from both patients. Both patients had an almost overlapping deletion at Xq27.3q28, however, the more severe patient (Patient 1) showed skewed XCI of the normal X chromosome (79:21) whereas the milder patient (Patient 2) showed random XCI. Therefore, deletion at Xq27.3q28 critically affected brain development, and the ratio of XCI of the normal X chromosome greatly affected the clinical characteristics of patients with deletion at Xq27.3q28. As the chromosomal breakpoints were determined, we analyzed a change in chromatin domains termed topologically associated domains (TADs) using published Hi-C data on the Xq27.3q28 region, and found that only patient 1 had a possibility of a drastic change in TADs. The altered chromatin topologies on the Xq27.3q28 region might affect the clinical features of patient 1 by changing the expression of genes just outside the deletion and/or the XCI establishment during embryogenesis resulting in skewed XCI.
Assuntos
Deleção Cromossômica , Deficiência Intelectual/genética , Inativação do Cromossomo X , Pré-Escolar , Cromossomos Humanos X , Análise Citogenética , Feminino , Humanos , Lactente , Japão , Proteína Nuclear Ligada ao X/genéticaRESUMO
SAD kinases regulate presynaptic vesicle clustering and neuronal polarization. A previous report demonstrated that Sada-/- and Sadb-/- double-mutant mice showed perinatal lethality with a severe defect in axon/dendrite differentiation, but their single mutants did not. These results indicated that they were functionally redundant. Surprisingly, we show that on a C57BL/6N background, SAD-A is essential for cortical development whereas SAD-B is dispensable. Sada-/- mice died within a few days after birth. Their cortical lamination pattern was disorganized and radial migration of cortical neurons was perturbed. Birth date analyses with BrdU and in utero electroporation using pCAG-EGFP vector showed a delayed migration of cortical neurons to the pial surface in Sada-/- mice. Time-lapse imaging of these mice confirmed slow migration velocity in the cortical plate. While the neurites of hippocampal neurons in Sada-/- mice could ultimately differentiate in culture to form axons and dendrites, the average length of their axons was shorter than that of the wild type. Thus, analysis on a different genetic background than that used initially revealed a nonredundant role for SAD-A in neuronal migration and differentiation.
Assuntos
Movimento Celular/fisiologia , Córtex Cerebral/embriologia , Córtex Cerebral/enzimologia , Neurônios/enzimologia , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Axônios/enzimologia , Células Cultivadas , Feminino , Isoenzimas , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genéticaRESUMO
Several genes related to mitochondrial functions have been identified as causative genes of neuropathy or ataxia. Cytochrome c oxidase assembly factor 7 (COA7) may have a role in assembling mitochondrial respiratory chain complexes that function in oxidative phosphorylation. Here we identified four unrelated patients with recessive mutations in COA7 among a Japanese case series of 1396 patients with Charcot-Marie-Tooth disease (CMT) or other inherited peripheral neuropathies, including complex forms of CMT. We also found that all four patients had characteristic neurological features of peripheral neuropathy and ataxia with cerebellar atrophy, and some patients showed leukoencephalopathy or spinal cord atrophy on MRI scans. Validated mutations were located at highly conserved residues among different species and segregated with the disease in each family. Nerve conduction studies showed axonal sensorimotor neuropathy. Sural nerve biopsies showed chronic axonal degeneration with a marked loss of large and medium myelinated fibres. An immunohistochemical assay with an anti-COA7 antibody in the sural nerve from the control patient showed the positive expression of COA7 in the cytoplasm of Schwann cells. We also observed mildly elevated serum creatine kinase levels in all patients and the presence of a few ragged-red fibres and some cytochrome c oxidase-negative fibres in a muscle biopsy obtained from one patient, which was suggestive of subclinical mitochondrial myopathy. Mitochondrial respiratory chain enzyme assay in skin fibroblasts from the three patients showed a definitive decrease in complex I or complex IV. Immunocytochemical analysis of subcellular localization in HeLa cells indicated that mutant COA7 proteins as well as wild-type COA7 were localized in mitochondria, which suggests that mutant COA7 does not affect the mitochondrial recruitment and may affect the stability or localization of COA7 interaction partners in the mitochondria. In addition, Drosophila COA7 (dCOA7) knockdown models showed rough eye phenotype, reduced lifespan, impaired locomotive ability and shortened synaptic branches of motor neurons. Our results suggest that loss-of-function COA7 mutation is responsible for the phenotype of the presented patients, and this new entity of disease would be referred to as spinocerebellar ataxia with axonal neuropathy type 3.
Assuntos
Complexo IV da Cadeia de Transporte de Elétrons/genética , Neuropatia Hereditária Motora e Sensorial/complicações , Neuropatia Hereditária Motora e Sensorial/genética , Mutação/genética , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/genética , Adolescente , Animais , Animais Geneticamente Modificados , Encéfalo/diagnóstico por imagem , Células Cultivadas , Drosophila , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Saúde da Família , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Predisposição Genética para Doença/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Neuropatia Hereditária Motora e Sensorial/diagnóstico por imagem , Humanos , Discos Imaginais/metabolismo , Discos Imaginais/ultraestrutura , Locomoção/efeitos dos fármacos , Locomoção/genética , Masculino , Pessoa de Meia-Idade , Neurônios Motores/patologia , Junção Neuromuscular/genética , Junção Neuromuscular/patologia , Junção Neuromuscular/ultraestrutura , Desempenho Psicomotor/fisiologia , Interferência de RNA/fisiologia , Medula Espinal/diagnóstico por imagem , Ataxias Espinocerebelares/diagnóstico por imagem , Adulto JovemRESUMO
Partial trisomy 2p syndrome is occasionally associated with neural tube defects (NTDs), such as anencephaly, encephalocele, and spina bifida, in addition to common features of intellectual disability, developmental delay, and characteristic facial appearance. The 2p24 region has been reported to be associated with NTDs. Here, we report the cases of 2 siblings with trisomy 2p24.3-pter and monosomy 5p14.3-pter caused by the paternal translocation t(2;5)(p24.3;p14.3). Of the two siblings, the elder sister had spina bifida. We determined the nucleotide sequences of the chromosomal breakpoints and found that the sizes of trisomy 2p and monosomy 5p segments were 18.77 and 17.89 Mb, respectively. NTDs were present in four of seven previously reported patients with trisomy 2p and monosomy 5p as well as in one of the two patients examined in the present study. Although the monosomy 5p of the nine patients were similar in size, the two patients reported here had the smallest size of trisomy 2p. When the clinical features of the nine patients were compared to the present two patients, the elder sister had postaxial polydactyly of the left foot in addition to the characteristic facial appearance and spina bifida, indicating that these features were associated with trisomy 2p24.3-pter. To our knowledge, this is the first study on spina bifida to determine the nucleotide sequences of breakpoints for trisomy 2p24.3-pter and monosomy 5p14.3-pter. Increased gene dosages of dosage-sensitive genes or genes at the trisomy segment (2p24.3) of the presented patients could be associated with NTDs of patients with trisomy 2p.
Assuntos
Síndrome de Cri-du-Chat/genética , Defeitos do Tubo Neural/genética , Disrafismo Espinal/genética , Trissomia/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 5/genética , Síndrome de Cri-du-Chat/fisiopatologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Defeitos do Tubo Neural/diagnóstico por imagem , Defeitos do Tubo Neural/fisiopatologia , Irmãos , Disrafismo Espinal/diagnóstico por imagem , Disrafismo Espinal/fisiopatologia , Translocação Genética/genética , Trissomia/diagnóstico , Trissomia/fisiopatologiaRESUMO
BACKGROUND: Short-chain enoyl-CoA hydratase-ECHS1-catalyses many metabolic pathways, including mitochondrial short-chain fatty acid ß-oxidation and branched-chain amino acid catabolic pathways; however, the metabolic products essential for the diagnosis of ECHS1 deficiency have not yet been determined. The objective of this report is to characterise ECHS1 and a mild form of its deficiency biochemically, and to determine the candidate metabolic product that can be efficiently used for neonatal diagnosis. METHODS: We conducted a detailed clinical, molecular genetics, biochemical and metabolic analysis of sibling patients with ECHS1 deficiency. Moreover, we purified human ECHS1, and determined the substrate specificity of ECHS1 for five substrates via different metabolic pathways. RESULTS: Human ECHS1 catalyses the hydration of five substrates via different metabolic pathways, with the highest specificity for crotonyl-CoA and the lowest specificity for tiglyl-CoA. The patients had relatively high (â¼7%) residual ECHS1 enzyme activity for crotonyl-CoA and methacrylyl-CoA caused by the compound heterozygous mutations (c.176A>G, (p.N59S) and c.413C>T, (p.A138V)) with normal mitochondrial complex I-IV activities. Affected patients excrete large amounts of N-acetyl-S-(2-carboxypropyl)cysteine, a metabolite of methacrylyl-CoA. CONCLUSIONS: Laboratory data and clinical features demonstrated that the patients have a mild form of ECHS1 deficiency harbouring defective valine catabolic and ß-oxidation pathways. N-Acetyl-S-(2-carboxypropyl) cysteine level was markedly high in the urine of the patients, and therefore, N-acetyl-S-(2-carboxypropyl)cysteine was regarded as a candidate metabolite for the diagnosis of ECHS1 deficiency. This metabolite is not part of current routine metabolic screening protocols, and its inclusion, therefore, holds immense potential in accurate diagnosis.
Assuntos
Acetilcisteína/análogos & derivados , Enoil-CoA Hidratase/deficiência , Redes e Vias Metabólicas , Erros Inatos do Metabolismo/enzimologia , Acetilcisteína/metabolismo , Acetilcisteína/urina , Acil Coenzima A/metabolismo , Criança , Pré-Escolar , Enoil-CoA Hidratase/metabolismo , Feminino , Humanos , Japão , Masculino , Erros Inatos do Metabolismo/fisiopatologia , Mutação , Valina/metabolismoRESUMO
Xq28 duplication syndrome including MECP2 is a neurodevelopmental disorder characterized by axial hypotonia at infancy, severe intellectual disability, developmental delay, mild characteristic facial appearance, epilepsy, regression, and recurrent infections in males. We identified a Japanese family of Xq28 duplications, in which the patients presented with cerebellar ataxia, severe constipation, and small feet, in addition to the common clinical features. The 488-kb duplication spanned from L1CAM to EMD and contained 17 genes, two pseudo genes, and three microRNA-coding genes. FISH and nucleotide sequence analyses demonstrated that the duplication was tandem and in a forward orientation, and the duplication breakpoints were located in AluSc at the EMD side, with a 32-bp deletion, and LTR50 at the L1CAM side, with "tc" and "gc" microhomologies at the duplication breakpoints, respectively. The duplicated segment was completely segregated from the grandmother to the patients. These results suggest that the duplication was generated by fork-stalling and template-switching at the AluSc and LTR50 sites. This is the first report to determine the size and nucleotide sequences of the duplicated segments at Xq28 of three generations of a family and provides the genotype-phenotype correlation of the patients harboring the specific duplicated segment.
Assuntos
Povo Asiático/genética , Cromossomos Humanos X , Duplicação Gênica , Deficiência Intelectual Ligada ao Cromossomo X/genética , Proteína 2 de Ligação a Metil-CpG/genética , Adolescente , Adulto , Sequência de Bases , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Linhagem , Adulto JovemRESUMO
Mitochondrial trifunctional protein (MTP) is a hetero-octamer composed of four α- and four ß-subunits that catalyzes the final three steps of mitochondrial ß-oxidation of long chain fatty acids. HADHA and HADHB encode the α-subunit and the ß-subunit of MTP, respectively. To date, only two cases with MTP deficiency have been reported to be associated with hypoparathyroidism and peripheral polyneuropathy. Here, we report on two siblings with autosomal recessive infantile onset hypoparathyroidism, peripheral polyneuropathy, and rhabdomyolysis. Sequence analysis of HADHA and HADHB in both siblings shows that they were homozygous for a mutation in exon 14 of HADHB (c.1175C>T, [p.A392V]) and the parents were heterozygous for the mutation. Biochemical analysis revealed that the patients had MTP deficiency. Structural analysis indicated that the A392V mutation identified in this study and the N389D mutation previously reported to be associated with hypoparathyroidism are both located near the active site of MTP and affect the conformation of the ß-subunit. Thus, the present patients are the second and third cases of MTP deficiency associated with missense HADHB mutation and infantile onset hypoparathyroidism. Since MTP deficiency is a treatable disease, MTP deficiency should be considered when patients have hypoparathyroidism as the initial presenting feature in infancy.
Assuntos
Hipoparatireoidismo/congênito , Subunidade beta da Proteína Mitocondrial Trifuncional/genética , Mutação , Polineuropatias/diagnóstico , Polineuropatias/genética , Adolescente , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Feminino , Humanos , Hipoparatireoidismo/diagnóstico , Hipoparatireoidismo/genética , Lactente , Masculino , Subunidade beta da Proteína Mitocondrial Trifuncional/química , Modelos Moleculares , Linhagem , Fenótipo , Conformação Proteica , Irmãos , Gêmeos DizigóticosRESUMO
Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by moderate or severe intellectual disability, a characteristic facial appearance, microcephaly, epilepsy, agenesis or hypoplasia of the corpus callosum, congenital heart defects, Hirschsprung disease, and urogenital/renal anomalies. It is caused by de novo heterozygous loss of function mutations including nonsense mutations, frameshift mutations, and deletions in ZEB2 at 2q22. ZEB2 encodes the zinc finger E-box binding homeobox 2 protein consisting of 1,214 amino acids. Herein, we report 13 nonsense and 27 frameshift mutations from 40 newly identified MWS patients in Japan. Although the clinical findings of all the Japanese MWS patients with nonsense and frameshift mutations were quite similar to the previous review reports of MWS caused by nonsense mutations, frameshift mutations and deletions of ZEB2, the frequencies of microcephaly, Hirschsprung disease, and urogenital/renal anomalies were small. Patients harbored mutations spanning the region between the amino acids 55 and 1,204 in wild-type ZEB2. There was no obvious genotype-phenotype correlation among the patients. A transfection study demonstrated that the cellular level of the longest form of the mutant ZEB2 protein harboring the p.D1204Rfs*29 mutation was remarkably low. The results showed that the 3'-end frameshift mutation of ZEB2 causes MWS due to ZEB2 instability.
Assuntos
Estudos de Associação Genética , Doença de Hirschsprung/genética , Proteínas de Homeodomínio/genética , Deficiência Intelectual/genética , Microcefalia/genética , Proteínas Repressoras/genética , Adolescente , Adulto , Alelos , Linhagem Celular , Criança , Pré-Escolar , Códon sem Sentido , Fácies , Feminino , Mutação da Fase de Leitura , Expressão Gênica , Doença de Hirschsprung/diagnóstico , Doença de Hirschsprung/epidemiologia , Proteínas de Homeodomínio/metabolismo , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/epidemiologia , Japão , Masculino , Microcefalia/diagnóstico , Microcefalia/epidemiologia , Fenótipo , Prevalência , Estabilidade Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/metabolismo , Adulto Jovem , Homeobox 2 de Ligação a E-box com Dedos de ZincoRESUMO
BACKGROUND: Approximately 10-20 % of individuals develop a recrudescent or persistent fever after intravenous immunoglobulin (IVIG) infusion for the initial treatment of Kawasaki disease. The aim of this study was to evaluate the efficacy and safety of the initial IVIG treatment of Kawasaki disease based on duration of infusion. METHODS: This retrospective, single-center study included 53 patients with Kawasaki disease who were initially treated with 2 g/kg of IVIG by means of a single infusion from June 2018 to August 2019. We classified patients into two groups based on the duration of the infusion: the 12-h group and the 24-h group. We compared the treatment response of the primary IVIG and its adverse events using the Mann-Whitney U test and Fisher's exact or Chi-square tests. RESULTS: There were no significant differences in the response to initial IVIG treatment between the two groups. The duration from treatment onset to defervescence was shorter in the 12-h group than the 24-h group (7 h vs. 12 h, respectively, p = 0.07); however, this was not significant. There were no significant between-group differences regarding adverse events. CONCLUSION: We concluded that the initial 12-h IVIG treatment was comparable to the 24-h treatment in terms of efficacy and safety. This will enable physicians to feel confident about pursuing a shorter course of treatment with similar results as conventional treatment and decide on administering additional therapy to their patients.
RESUMO
We evaluated the effect of chronic exercise on insulin secretion in response to high-glucose by using a perifusion method with isolated pancreatic islets from normal rats. Male Wistar rats were assigned to one of two groups: a sedentary group and a trained group. Running exercise was carried out on a treadmill for one hour per day, five days per week, for six, nine, or 12 weeks. The chronic exercise significantly enhanced the insulin secretion ability of pancreatic islets in response to the high-glucose stimulation upon nine and 12 weeks of exercise. The insulin content in the pancreas and the weight of the pancreas did not change upon nine weeks of exercise. Potassium-stimulated insulin secretion was also increased in the islets isolated from rats that trained for nine weeks compared with that in sedentary rats, suggesting that insulin secretion events downstream of membrane depolarization are involved in targets of the exercise effect. These findings suggest that chronic exercise could be a useful strategy not only for the maintenance of peripheral insulin sensitivity but also for the promotion of islet function to secrete insulin in non-diabetics.
Assuntos
Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Condicionamento Físico Animal , Animais , Teste de Esforço , Glucose/administração & dosagem , Insulina/administração & dosagem , Secreção de Insulina , Masculino , Potássio/administração & dosagem , Ratos , Ratos Wistar , Comportamento SedentárioRESUMO
High-throughput sequencing has identified vast numbers of variants in genetic disorders. However, the significance of variants at the exon-intron junction remains controversial. Even though most cases of Mowat-Wilson syndrome (MOWS) are caused by heterozygous loss-of-function variants in ZEB2, the pathogenicity of variants at exon-intron junction is often indeterminable. We identified four intronic variants in 5/173 patients with clinical suspicion for MOWS, and evaluated their pathogenicity by in vitro analyses. The minigene analysis showed that c.73+2T>G caused most of the transcripts skipping exon 2, while c.916+6T>G led to partial skipping of exon 7. No splicing abnormalities were detected in both c.917-21T>C and c.3067+6A>T. The minigene analysis reproduced the splicing observed in the blood cells of the patient with c.73+2T>G. The degree of the exon skipping was concordant with the severity of MOWS; while the patient with c.73+2T>G was typical MOWS, the patient with c.916+6T>G showed milder phenotype which has been seldom reported. Our results demonstrate that mRNA splicing assays using the minigenes are valuable for determining the clinical significance of intronic variants in patients with not only MOWS but also other genetic diseases with splicing aberrations and may explain atypical or milder cases, such as the current patient.
Assuntos
Splicing de RNA , Humanos , Íntrons , Virulência , ÉxonsRESUMO
BRESEK/BRESHECK syndrome is a multiple congenital malformation characterized by brain anomalies, intellectual disability, ectodermal dysplasia, skeletal deformities, ear or eye anomalies, and renal anomalies or small kidneys, with or without Hirschsprung disease and cleft palate or cryptorchidism. This syndrome has only been reported in three male patients. Here, we report on the fourth male patient presenting with brain anomaly, intellectual disability, growth retardation, ectodermal dysplasia, vertebral (skeletal) anomaly, Hirschsprung disease, low-set and large ears, cryptorchidism, and small kidneys. These manifestations fulfill the clinical diagnostic criteria of BRESHECK syndrome. Since all patients with BRESEK/BRESHECK syndrome are male, and X-linked syndrome of ichthyosis follicularis with atrichia and photophobia is sometimes associated with several features of BRESEK/BRESHECK syndrome such as intellectual disability, vertebral and renal anomalies, and Hirschsprung disease, we analyzed the causal gene of ichthyosis follicularis with atrichia and photophobia syndrome, MBTPS2, in the present patient and identified an p.Arg429His mutation. This mutation has been reported to cause the most severe type of ichthyosis follicularis with atrichia and photophobia syndrome, including neonatal and infantile death. These results demonstrate that the p.Arg429His mutation in MBTPS2 causes BRESEK/BRESHECK syndrome.
Assuntos
Anormalidades Congênitas/genética , Displasia Ectodérmica/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doença de Hirschsprung/genética , Deficiência Intelectual/genética , Metaloendopeptidases/genética , Encéfalo/anormalidades , Anormalidades Congênitas/diagnóstico , Fragmentação do DNA , Análise Mutacional de DNA , Orelha/anormalidades , Displasia Ectodérmica/complicações , Displasia Ectodérmica/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Estudo de Associação Genômica Ampla , Transtornos do Crescimento/genética , Doença de Hirschsprung/complicações , Doença de Hirschsprung/diagnóstico , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico , Rim/anormalidades , Masculino , Biologia Molecular , Mutação , LinhagemRESUMO
Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide (YWHAE), on chromosome 17p13.3, has been shown to play a crucial role in neuronal development. The deletion of YWHAE, but not platelet-activating factor acetylhydrolase, isoform 1b, subunit 1 (PAFAH1B1), underlies a newly recognized neurodevelopmental disorder, characterized by significant growth retardation, developmental delay/intellectual disability (DD/ID), distinctive facial appearance, and brain abnormalities. Here, we report on a girl with a terminal deletion of 17p13.3, including YWHAE but not PAFAH1B1, showing normal brain structure on MRI. She had mild developmental delay, a distinctive facial appearance, and severe growth retardation despite normal growth hormone levels, which was improved by growth hormone therapy. Expression analysis of YWHAE and PAFAH1B1 yielded results consistent with array CGH and FISH results. These results indicate that the dosage effect of YWHAE varies from severe to very mild structural brain abnormalities, and suggest that the expression of YWHAE is associated with a complex mechanism of neuronal development.
Assuntos
Proteínas 14-3-3/genética , Encéfalo/metabolismo , Deleção Cromossômica , Cromossomos Humanos Par 17 , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Sequência de Bases , Criança , Pré-Escolar , Primers do DNA , Feminino , Humanos , Proteínas Associadas aos Microtúbulos/genética , Reação em Cadeia da Polimerase em Tempo RealRESUMO
We report herein on two female siblings exhibiting mild intellectual disability, hypotonia in infancy, postnatal growth retardation, characteristic appearance of the face, fingers, and toes. Their healthy mother had a translocation between 9q34.1 and the 13pter. FISH and array CGH analysis demonstrated that the two children had an additional 8.5 Mb segment of the 9q34.1-qter at 13pter. The clinical features of the present cases were similar to those of previously reported 9q34 duplication cases; however, the present cases did not exhibit other abnormal behaviors, such as autistic features or attention deficit disorders, those are reportedly associated with 9q34 duplications. A 3.0 Mb region (9q34.1-q34.3) within 9q34 duplication in our patients are overlapped with duplication region of previously reported cases and is proposed to be critical for the presentation of several phenotypes associated with 9q34 duplications.
Assuntos
Anormalidades Múltiplas/genética , Duplicação Cromossômica , Cromossomos Humanos Par 9/genética , Pré-Escolar , Deleção Cromossômica , Hibridização Genômica Comparativa , Fácies , Feminino , Duplicação Gênica , Humanos , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/genética , Irmãos , Translocação GenéticaRESUMO
SARS-CoV-2 whole-genome sequencing of samples from COVID-19 patients is useful for informing infection control. Datasets of these genomes assembled from multiple hospitals can give critical clues to regional or national trends in infection. Herein, we report a lineage summary based on data collected from hospitals located in the Tokyo metropolitan area. We performed SARS-CoV-2 whole-genome sequencing of specimens from 198 patients with COVID-19 at 13 collaborating hospitals located in the Kanto region. Phylogenetic analysis and fingerprinting of the nucleotide substitutions were performed to differentiate and classify the viral lineages. More than 90% of the identified strains belonged to Clade 20B, which has been prevalent in European countries since March 2020. Only two lineages (B.1.1.284 and B.1.1.214) were found to be predominant in Japan. However, one sample from a COVID-19 patient admitted to a hospital in the Kanto region in November 2020 belonged to the B.1.346 lineage of Clade 20C, which has been prevalent in the western United States since November 2020. The patient had no history of overseas travel or any known contact with anyone who had travelled abroad. Consequently, the Clade 20C strain belonging to the B.1.346 lineage appeared likely to have been imported from the western United States to Japan across the strict quarantine barrier. B.1.1.284 and B.1.1.214 lineages were found to be predominant in the Kanto region, but a single case of the B.1.346 lineage of clade 20C, probably imported from the western United States, was also identified. These results illustrate that a decentralized network of hospitals offers significant advantages as a highly responsive system for monitoring regional molecular epidemiologic trends.
Assuntos
COVID-19/virologia , Genoma Viral , SARS-CoV-2/genética , Sequenciamento Completo do Genoma/métodos , Humanos , FilogeniaRESUMO
BACKGROUND: SLC19A3 (solute carrier family 19, member 3) is a thiamin transporter with 12 transmembrane domains. Homozygous or compound heterozygous mutations in SLC19A3 cause two distinct clinical phenotypes, biotin-responsive basal ganglia disease and Wernicke's-like encephalopathy. Biotin and/or thiamin are effective therapies for both diseases. METHODS: We conducted on the detailed clinical, brain MRI and molecular genetic analysis of four Japanese patients in a Japanese pedigree who presented with epileptic spasms in early infancy, severe psychomotor retardation, and characteristic brain MRI findings of progressive brain atrophy and bilateral thalami and basal ganglia lesions. RESULTS: Genome-wide linkage analysis revealed a disease locus at chromosome 2q35-37, which enabled identification of the causative mutation in the gene SLC19A3. A pathogenic homozygous mutation (c.958G > C, [p.E320Q]) in SLC19A3 was identified in all four patients and their parents were heterozygous for the mutation. Administration of a high dose of biotin for one year improved neither the neurological symptoms nor the brain MRI findings in one patient. CONCLUSION: Our cases broaden the phenotypic spectrum of disorders associated with SLC19A3 mutations and highlight the potential benefit of biotin and/or thiamin treatments and the need to assess the clinical efficacy of these treatments.
Assuntos
Encéfalo/patologia , Proteínas de Membrana Transportadoras/genética , Encefalopatia de Wernicke/genética , Encefalopatia de Wernicke/patologia , Adolescente , Adulto , Povo Asiático/genética , Doenças dos Gânglios da Base/tratamento farmacológico , Doenças dos Gânglios da Base/genética , Doenças dos Gânglios da Base/patologia , Biotina/uso terapêutico , Criança , Feminino , Estudo de Associação Genômica Ampla , Humanos , Imageamento por Ressonância Magnética , Masculino , Mutação , Tiamina/uso terapêutico , Encefalopatia de Wernicke/tratamento farmacológicoRESUMO
CHD6 is an ATP-dependent chromatin-remodeling enzyme, which has been implicated as a crucial component for maintaining and regulating chromatin structure. CHD6 belongs to the largest subfamily, subfamily III (CHD6-9), of the chromodomain helicase DNA (CHD-binding protein) family of enzymes (CHD1-9). Here we report on a female patient with a balanced translocation t(4;20)(q33;q12) presenting with severe mental retardation and brachydactyly of the toes. We identified the translocation breakpoint in intron 27 of CHD6 at 20q12, while the 4q33 breakpoint was intergenic. Northern blot analysis demonstrated the CHD6 mRNA in the patient's lymphoblastoid cells was decreased to â¼50% of the control cells. To investigate the cellular mechanism of diseases resulting from decreased CHD subfamily III proteins, we knocked down CHD6 or CHD7 by RNA interference in HeLa cells and analyzed chromosome alignment. The both CHD6- and CHD7-knockdown cells showed increased frequency of misaligned chromosomes on metaphase plates. Moreover, an elevated frequency of aneuploidy, the major cause of miscarriages and mental retardation, was observed in patients with CHD6 and CHD7 haploinsufficiency. These results suggest that CHD6 and CHD7 play important roles in chromatin assembly during mitosis and that mitotic delay and/or impaired cell proliferation may be associated with pathogenesis of the diseases caused by CHD6 or CHD7 mutations.
Assuntos
Cromossomos Humanos Par 20 , Cromossomos Humanos Par 4 , Deficiência Intelectual/genética , Translocação Genética , Anormalidades Múltiplas/genética , Adolescente , Adulto , Northern Blotting , DNA Intergênico , Feminino , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Masculino , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Injection of pure spin current using a nonlocal geometry is a promising method for controlling magnetization in spintronic devices from the viewpoints of increasing freedom in device structure and avoiding problems related to charge current. Here, we report an experimental demonstration of magnetization switching of a perpendicular magnetic nanodot induced by vertical injection of pure spin current from a spin polarizer with perpendicular magnetization. In comparison with direct spin injection, the current amplitude required for magnetization switching is of the same order and shows smaller asymmetry between parallel-to-antiparallel and antiparallel-to-parallel switching. Simulation of spin accumulation reveals that, in the case of nonlocal spin injection, the spin torque is symmetric between the parallel and antiparallel configuration because current flows through only the spin polarizer, not the magnetic nanodot. This characteristic of nonlocal spin injection is the origin of the smaller asymmetry of the switching current and can be advantageous in spintronic applications.