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1.
J Am Chem Soc ; 145(45): 24862-24876, 2023 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-37930639

RESUMEN

Controlling the one-handed helicity in synthetic polymers is crucial for developing helical polymer-based advanced chiral materials. We now report that an extremely small amount of chiral biphenylylacetylene (BPA) monomers (ca. 0.3-0.5 mol %) allows complete control of the one-handed helicity throughout the polymer chains mostly composed of achiral BPAs. Chiral substituents introduced at the 2-position of the biphenyl units of BPA positioned in the vicinity of the polymer backbones contribute to a significant amplification of the helical bias, as interpreted by theoretical modeling and simulation. The helical structures, such as the helical pitch and absolute helical handedness (right- or left-handed helix) of the one-handed helical copolymers, were unambiguously determined by high-resolution atomic force microscopy combined with X-ray diffraction. The exceptionally strong helix-biasing power of the chiral BPA provides a highly durable and practically useful chiral material for the separation of enantiomers in chromatography by copolymerization of an achiral functional BPA with a small amount of the chiral BPA (0.5 mol %) due to the robust helical scaffold of the one-handed helical copolymer.

2.
Clin Genet ; 103(4): 383-391, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36645289

RESUMEN

The SUZ12 gene encodes a subunit of polycomb repressive complex 2 (PRC2) that is essential for development by silencing the expression of multiple genes. Germline heterozygous variants in SUZ12 have been found in Imagawa-Matsumoto syndrome (IMMAS) characterized by overgrowth and multiple dysmorphic features. Similarly, both EZH2 and EED also encode a subunit of PRC2 each and their pathogenic variants cause Weaver syndrome and Cohen-Gibson syndrome, respectively. Clinical manifestations of these syndromes significantly overlap, although their different prevalence rates have recently been noted: generalized overgrowth, intellectual disability, scoliosis, and excessive loose skin appear to be less prevalent in IMMAS than in the other two syndromes. We could not determine any apparent genotype-phenotype correlation in IMMAS. The phenotype of neurofibromatosis type 1 arising from NF1 deletion was also shown to be modified by the deletion of SUZ12, 560 kb away. This review deepens our understanding of the clinical and genetic characteristics of IMMAS together with other overgrowth syndromes related to PRC2. We also report on a novel IMMAS patient carrying a splicing variant (c.1023+1G>C) in SUZ12. This patient had a milder phenotype than other previously reported IMMAS cases, with no macrocephaly or overgrowth phenotypes, highlighting the clinical variation in IMMAS.


Asunto(s)
Anomalías Múltiples , Anomalías Craneofaciales , Discapacidad Intelectual , Humanos , Anomalías Múltiples/genética , Anomalías Craneofaciales/genética , Discapacidad Intelectual/genética , Fenotipo , Complejo Represivo Polycomb 2/genética
3.
Genomics ; 114(5): 110468, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36041635

RESUMEN

Recent studies suggest that transcript isoforms significantly overlap (approximately 60%) between brain tissue and Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs). Interestingly, 14 cohesion-related genes with variants that cause Cornelia de Lange Syndrome (CdLS) are highly expressed in the brain and LCLs. In this context, we first performed RNA sequencing of LCLs from 22 solved (with pathogenic variants) and 19 unsolved (with no confirmed variants) CdLS cases. Next, an RNA sequencing pipeline was developed using solved cases with two different methods: short variant analysis (for single-nucleotide and indel variants) and aberrant splicing detection analysis. Then, 19 unsolved cases were subsequently applied to our pipeline, and four pathogenic variants in NIPBL (one inframe deletion and three intronic variants) were newly identified. Two of three intronic variants were located at Alu elements in deep-intronic regions, creating cryptic exons. RNA sequencing with LCLs was useful for identifying hidden variants in exome-negative cases.


Asunto(s)
Síndrome de Cornelia de Lange , Infecciones por Virus de Epstein-Barr , Proteínas de Ciclo Celular/genética , Síndrome de Cornelia de Lange/diagnóstico , Síndrome de Cornelia de Lange/genética , Síndrome de Cornelia de Lange/patología , Herpesvirus Humano 4/genética , Humanos , Nucleótidos , Fenotipo , Isoformas de Proteínas/genética , Análisis de Secuencia de ARN
4.
Hum Mutat ; 42(1): 50-65, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33131168

RESUMEN

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.


Asunto(s)
Variaciones en el Número de Copia de ADN , Exoma , Algoritmos , Exoma/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Reproducibilidad de los Resultados , Secuenciación del Exoma
5.
J Hum Genet ; 66(5): 499-507, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33144663

RESUMEN

The objective of this study was to evaluate the efficacy of whole exome sequencing (WES) for the genetic diagnosis of cases presenting with fetal structural anomalies detected by ultrasonography. WES was performed on 19 cases with prenatal structural anomalies. Genomic DNA was extracted from umbilical cords or umbilical blood obtained shortly after birth. WES data were analyzed on prenatal phenotypes alone, and the data were re-analyzed after information regarding the postnatal phenotype was obtained. Based solely on the fetal phenotype, pathogenic, or likely pathogenic, single nucleotide variants were identified in 5 of 19 (26.3%) cases. Moreover, we detected trisomy 21 in two cases by WES-based copy number variation analysis. The overall diagnostic rate was 36.8% (7/19). They were all compatible with respective fetal structural anomalies. By referring to postnatal phenotype information, another candidate variant was identified by a postnatal clinical feature that was not detected in prenatal screening. As detailed phenotyping is desirable for better diagnostic rates in WES analysis, we should be aware that fetal phenotype is a useful, but sometimes limited source of information for comprehensive genetic analysis. It is important to amass more data of genotype-phenotype correlations, especially to appropriately assess the validity of WES in prenatal settings.


Asunto(s)
Anomalías Congénitas/genética , Secuenciación del Exoma , Feto/anomalías , Ultrasonografía Prenatal , Aborto Eugénico , Adulto , Cesárea , Anomalías Congénitas/diagnóstico por imagen , Anomalías Congénitas/embriología , ADN/sangre , ADN/genética , Variaciones en el Número de Copia de ADN , Síndrome de Down/diagnóstico por imagen , Síndrome de Down/embriología , Síndrome de Down/genética , Femenino , Sangre Fetal/química , Muerte Fetal/etiología , Edad Gestacional , Humanos , Leucocitos/química , Leucocitos/ultraestructura , Polimorfismo de Nucleótido Simple , Embarazo , Resultado del Embarazo
6.
J Hum Genet ; 65(9): 811, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32536687

RESUMEN

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

7.
J Hum Genet ; 64(5): 487-492, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30765867

RESUMEN

We herein report two individuals with novel nonsense mutations in STAG2 on Xq25, encoding stromal antigen 2, a component of the cohesion complex. A male fetus (Case 1) clinically presented with holoprosencephaly, cleft palate and lip, blepharophimosis, nasal bone absence, and hypolastic left heart by ultrasonography at 15 gestational weeks. Another female patient (Case 2) showed a distinct phenotype with white matter hypoplasia, cleft palate, developmental delay (DD), and intellectual disability (ID) at 7 years. Whole-exome sequencing identified de novo nonsense mutations in STAG2: c.3097C>T, p.(Arg1033*) in Case 1 and c.2229G>A, p.(Trp743*) in Case 2. X-inactivation was highly skewed in Case 2. To date, only 10 STAG2 pathogenic variants (four nonsense, four missense, and two frameshift) have been reported in patients with multiple congenital anomalies, ID, and DD. Although Case 2 showed similar clinical features to the reported female patients with STAG2 abnormalities, Case 1 showed an extremely severe phenotype, which could be explained by the first detected truncating variant in males.


Asunto(s)
Anomalías Múltiples/genética , Antígenos Nucleares/genética , Codón sin Sentido , Mutación Missense , Anomalías Múltiples/patología , Proteínas de Ciclo Celular , Niño , Femenino , Humanos , Masculino , Factores Sexuales
8.
J Hum Genet ; 64(10): 967-978, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31337854

RESUMEN

Cornelia de Lange syndrome (CdLS) is a rare multisystem disorder with specific dysmorphic features. Pathogenic genetic variants encoding cohesion complex subunits and interacting proteins (e.g., NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major causes of CdLS. However, there are many clinically diagnosed cases of CdLS without pathogenic variants in these genes. To identify further genetic causes of CdLS, we performed whole-exome sequencing in 57 CdLS families, systematically evaluating both single nucleotides variants (SNVs) and copy number variations (CNVs). We identified pathogenic genetic changes in 36 out of 57 (63.2 %) families, including 32 SNVs and four CNVs. Two known CdLS genes, NIPBL and SMC1A, were mutated in 23 and two cases, respectively. Among the remaining 32 individuals, four genes (ANKRD11, EP300, KMT2A, and SETD5) each harbored a pathogenic variant in a single individual. These variants are known to be involved in CdLS-like. Furthermore, pathogenic CNVs were detected in NIPBL, MED13L, and EHMT1, along with pathogenic SNVs in ZMYND11, MED13L, and PHIP. These three latter genes were involved in diseases other than CdLS and CdLS-like. Systematic clinical evaluation of all patients using a recently proposed clinical scoring system showed that ZMYND11, MED13L, and PHIP abnormality may cause CdLS or CdLS-like.


Asunto(s)
Proteínas de Ciclo Celular/genética , Proteínas Co-Represoras/genética , Proteínas de Unión al ADN/genética , Síndrome de Cornelia de Lange/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Complejo Mediador/genética , Proteínas Cromosómicas no Histona/genética , Variaciones en el Número de Copia de ADN , Síndrome de Cornelia de Lange/patología , Proteína p300 Asociada a E1A/genética , Familia , Femenino , Estudios de Asociación Genética , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Masculino , Metiltransferasas/genética , Mutación , Proteína de la Leucemia Mieloide-Linfoide/genética , Polimorfismo de Nucleótido Simple , Proteínas Represoras/genética , Secuenciación del Exoma
9.
Hum Genome Var ; 8(1): 34, 2021 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-34404773

RESUMEN

Mutations in a number of genes related to chromosomal segregation reportedly cause developmental disorders, e.g., chromosome alignment-maintaining phosphoprotein 1 (CHAMP1). We report on an 8-year-old Japanese girl who presented with a developmental disorder and microcephaly and carries a novel nonsense mutation in CHAMP1. Therefore, CHAMP1 mutation should be considered as a differential diagnosis of global developmental delay and microcephaly.

10.
Brain Dev ; 43(8): 863-866, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34090716

RESUMEN

BACKGROUND: Joubert syndrome is an autosomal recessive or X-linked genetic disease with a cerebellar vermis defect or hypoplasia, hypotonia, ocular dyskinesia, and mental retardation. In neonates, respiratory problems such as apnea and tachypnea are notable. CASE REPORT: We report a patient Joubert syndrome with a homozygous NPHP1 variant, who had head titubation with irritability, including exaggerated jitteriness and a marked Morrow reflex appeared soon after birth without neonatal respiratory problems. These symptoms decreased gradually and disappeared until 1 year. CONCLUSION: Irritability with head titubation may be an early clinical clue for the clinician to suspect Joubert syndrome.


Asunto(s)
Anomalías Múltiples/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Cerebelo/anomalías , Proteínas del Citoesqueleto/genética , Anomalías del Ojo/genética , Enfermedades Renales Quísticas/genética , Retina/anomalías , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/patología , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Preescolar , Anomalías del Ojo/complicaciones , Anomalías del Ojo/diagnóstico por imagen , Anomalías del Ojo/patología , Femenino , Movimientos de la Cabeza/fisiología , Humanos , Genio Irritable/fisiología , Enfermedades Renales Quísticas/complicaciones , Enfermedades Renales Quísticas/diagnóstico por imagen , Enfermedades Renales Quísticas/patología , Retina/diagnóstico por imagen , Retina/patología , Temblor/etiología , Temblor/fisiopatología
11.
Hum Genome Var ; 7: 26, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33014403

RESUMEN

Herein, we report two female cases with novel nonsense mutations of STAG2 at Xq25, encoding stromal antigen 2, a component of the cohesion complex. Exome analysis identified c.3097 C>T, p.(Arg1033*) in Case 1 (a fetus with multiple congenital anomalies) and c.2229 G>A, p.(Trp743*) in Case 2 (a 7-year-old girl with white matter hypoplasia and cleft palate). X inactivation was highly skewed in both cases.

12.
Nat Commun ; 10(1): 2506, 2019 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-31175295

RESUMEN

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10-6) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.


Asunto(s)
Variación Genética , Espasmos Infantiles/genética , Proteínas Adaptadoras del Transporte Vesicular/genética , Pueblo Asiatico/genética , Estudios de Casos y Controles , ADN (Citosina-5-)-Metiltransferasas/genética , Epilepsias Mioclónicas/genética , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Lactante , Japón , Síndrome de Lennox-Gastaut/genética , Modelos Logísticos , Mutación , Neurofibromina 1/genética , Polimorfismo de Nucleótido Simple , Análisis de Componente Principal , Canales Catiónicos TRPM/genética , Secuenciación del Exoma
13.
Int J Cancer ; 103(1): 53-60, 2003 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-12455053

RESUMEN

Apoptosis is induced by many kinds of therapy-related inducers, such as hyperthermia and chemotherapeutic agents. However, differences in apoptotic pathways between these inducers remain unclear, although knowing the differences is important to map out a therapeutic strategy. Therefore, we focused on the localization and phosphorylation of Bcl-2 and Bax, key mediators of the apoptotic pathway, after hyperthermia and paclitaxel treatment of PC-10 squamous cell carcinoma cells that excessively expressed Bcl-2 and Bax in the cytoplasm. Paclitaxel treatment markedly induced qualitative changes in Bcl-2, whereas hyperthermia did only quantitative changes in Bax. The levels of Bax increased gradually with the duration of hyperthermia, whereas Bcl-2 levels slightly decreased. On the other hand, paclitaxel treatment induced dose- and time-dependent phosphorylation of Bcl-2. Interestingly, phosphorylated Bcl-2 was observed in the specific subcellular sites, mitochondria- and lysosome-rich fractions. Both treatments disturbed the heterodimerization of Bax with Bcl-2. Hyperthermia, but not paclitaxel treatment, induced a gradual Bax translocation from the cytoplasm to the nucleus. Although both treatments induced a prominent cell cycle disturbance in the G2M phase, paclitaxel treatment induced typical apoptosis, and hyperthermia hardly induced apoptosis. Our results suggest that the subcellular redistribution of Bax and the phosphorylation of Bcl-2 depend on the type of apoptosis inducers, such as hyperthermia and paclitaxel, and Bcl-2 has a central role in the decision of apoptotic outcome. Our data may afford new insights in apoptosis from the aspect of an association of Bcl-2 phosphorylation with intracellular Bax localization.


Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Hipertermia Inducida , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Apoptosis , Western Blotting , Carcinoma de Células Escamosas/metabolismo , Ciclo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Supervivencia Celular/fisiología , Humanos , Neoplasias Pulmonares/metabolismo , Microscopía Confocal , Fosforilación , Pruebas de Precipitina , Transporte de Proteínas , Células Tumorales Cultivadas/metabolismo , Proteína X Asociada a bcl-2
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