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OBJECTIVE: Phase III clinical trials demonstrated the efficacy of enzalutamide and apalutamide in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and PSA doubling time ≤10 months. Although these drugs have been shown to vary in their adverse event (AE) profiles, the differences in their efficacy profiles remain to be evaluated. Therefore, this retrospective study was conducted to evaluate the efficacy of these drugs in patients with nmCRPC. METHODS: This study evaluated 191 patients with nmCRPC treated with enzalutamide (n = 137) or apalutamide (n = 54) in the first-line setting at Jikei University Hospital or its affiliated hospitals between May 2014 and November 2022. Endpoints were defined as oncological outcomes (i.e., PSA response, PFS, PSA-PFS, MFS, CSS, and OS) and AEs. RESULTS: No significant differences were noted in patient backgrounds between the two groups. Patients exhibiting a maximum PSA response of >50% and >90% accounted for 74.5% and 48.9% of patients in the enzalutamide group, and 75.9% and 42.6% of patients in the apalutamide group, respectively, with no significant difference between the groups. The median PSA-PFS was 10 months in the enzalutamide group but not in the apalutamide group, with no significant difference between the groups (P = 0.48). No significant differences were observed in MFS, CSS, or OS between the groups. Patients reporting AEs of all grades and grade 3 or higher accounted for 56.2% and 4.3% of those in the enzalutamide group and 57.4% and 7.4% of those in the apalutamide group, respectively. The most common AE was fatigue (26.3%) in the enzalutamide group and skin rash (27.8%) in the apalutamide group. CONCLUSION: In this retrospective study of their efficacy and safety, enzalutamide and apalutamide were shown to exhibit comparable oncological outcomes but quite different AE profiles, suggesting that their differential use may be warranted based on these findings.
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Benzamidas , Nitrilos , Feniltiohidantoína , Neoplasias de la Próstata Resistentes a la Castración , Tiohidantoínas , Humanos , Masculino , Nitrilos/uso terapéutico , Feniltiohidantoína/uso terapéutico , Feniltiohidantoína/efectos adversos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Estudios Retrospectivos , Tiohidantoínas/uso terapéutico , Tiohidantoínas/efectos adversos , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Antígeno Prostático Específico/sangre , Resultado del TratamientoRESUMEN
Noonan syndrome (NS) is caused by pathogenic variants in genes encoding components of the RAS/MAPK pathway and presents with a number of symptoms, including characteristic facial features, congenital heart diseases, and short stature. Advances in genetic analyses have contributed to the identification of pathogenic genes in NS as well as genotype-phenotype relationships; however, updated evidence for the detection rate of pathogenic genes with the inclusion of newly identified genes is lacking in Japan. Accordingly, we examined the genetic background of 116 individuals clinically diagnosed with NS and the frequency of short stature. We also investigated genotype-phenotype relationships in the context of body mass index (BMI). Genetic testing revealed the responsible variants in 100 individuals (86%), where PTPN11 variants were the most prevalent (43%) and followed by SOS1 (12%) and RIT1 (9%). The frequency of short stature was the lowest in subjects possessing RIT1 variants. No genotype-phenotype relationships in BMI were observed among the genotypes. In conclusion, this study provides evidence for the detection rate of pathogenic genes and genotype-phenotype relationships in Japanese patients with NS, which will be of clinical importance for accelerating our understanding of the genetic backgrounds of Japanese patients with NS.
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In newborn screening (NBS), it is important to consider the availability of multiplex assays or other tests that can be integrated into existing systems when attempting to implement NBS for new target diseases. Recent developments in innovative testing technology have made it possible to simultaneously screen for severe primary immunodeficiency (PID) and spinal muscular atrophy (SMA) using quantitative real-time polymerase chain reaction (qPCR) assays. We describe our experience of optional NBS for severe PID and SMA in Osaka, Japan. A multiplex TaqMan qPCR assay was used for the optional NBS program. The assay was able to quantify the levels of T-cell receptor excision circles and kappa-deleting recombination excision circles, which is useful for severe combined immunodeficiency and B-cell deficiency screening, and can simultaneously detect the homozygous deletion of SMN1 exon 7, which is useful for NBS for SMA. In total, 105,419 newborns were eligible for the optional NBS program between 1 August 2020 and 31 August 2023. A case each of X-linked agammaglobulinemia and SMA were diagnosed through the optional NBS and treated at early stages (before symptoms appeared). Our results show how multiplex PCR-based NBS can benefit large-scale NBS implementation projects for new target diseases.
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Atrofia Muscular Espinal , Tamizaje Neonatal , Recién Nacido , Humanos , Tamizaje Neonatal/métodos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Homocigoto , Japón , Eliminación de Secuencia , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genéticaRESUMEN
BACKGROUND: Rauch-Steindl syndrome (RAUST) is a very rare genetic syndrome caused by a pathogenic variant in NSD2 on chromosome 4p16.3. Although NSD2 was previously thought to be the major gene in Wolf-Hirschhorn syndrome (WHS), a contiguous gene syndrome of chromosome 4p16.3 deletion, RAUST has been found to present different facial and clinical features from WHS. In this study, we report the details of two newly diagnosed individuals with RAUST in order to better understand the molecular and clinical features of RAUST. METHODS: Whole-genome sequencing was performed on two individuals with psychomotor delay and growth failure. Detailed clinical evaluation of growth parameters, craniofacial features, electroencephalogram (EEG), magnetic resonance imaging of the brain, and developmental assessment were performed. RESULTS: Both individuals had de novo truncating variants in NSD2. One had a novel variant (c.2470C>T, p.Arg824*), and the other had a recurrent variant (c.4028del, p.Pro1343Glnfs*49). Both exhibited characteristic RAUST facial features, growth failure, and mild psychomotor delay. A novel finding of RAUST was seen in individual 2, a Chiari malformation type 1, and both showed delayed bone age. They lacked common WHS features such as congenital heart defects, cleft lip/palate, and seizures (EEG with abnormal findings). CONCLUSION: We present a novel variant and clinical presentations of RAUST, expand the molecular and clinical diversity of RAUST, and improve our understanding of this rare syndrome, which is distinct from WHS. Further researches are needed on more RAUST cases and on functional analysis of NSD2.
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Labio Leporino , Fisura del Paladar , Síndrome de Wolf-Hirschhorn , Humanos , Deleción Cromosómica , Labio Leporino/genética , Fisura del Paladar/genética , Insuficiencia de Crecimiento/genética , Convulsiones/genética , Síndrome de Wolf-Hirschhorn/genética , Síndrome de Wolf-Hirschhorn/patologíaRESUMEN
Nucleotide variations or deletions in the NK2 homeobox 1 gene (NKX2-1), located at 14q13.3, lead to symptoms associated with the brain, lungs, and thyroid, and the combination of these phenotypes is clinically recognized as the brain-lung-thyroid syndrome. Many types of nucleotide variants of NKX2-1 have been identified, and phenotypic variability has been reported. Chromosomal deletions involving NKX2-1 have also been reported; however, phenotypic differences between patients with nucleotide variants of NKX2-1 and patients with chromosomal deletions involving NKX2-1 have not been well established. Recently, we identified seven patients with 14q13 microdeletions involving the NKX2-1. Most patients exhibited developmental delay. This inquiry arises regarding the potential existence of haploinsufficiency effects beyond those attributed to NKX2-1 within the 14q13 microdeletion. However, a literature review has shown that developmental delay is not rare in patients with nucleotide alterations in NKX2-1. Rather, motor function impairment may have affected the total developmental assessment, and the haploinsufficiency of genes contiguous to NKX2-1 is unlikely to contribute to developmental delay.
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Kabuki syndrome (KS) is characterized by growth impairment, psychomotor delay, congenital heart disease, and distinctive facial features. KMT2D and KDM6A have been identified as the causative genes of KS. Craniosynostosis (CS) has been reported in individuals with KS; however, its prevalence and clinical implications remain unclear. In this retrospective study, we investigated the occurrence of CS in individuals with genetically diagnosed KS and examined its clinical significance. Among 42 individuals with genetically diagnosed KS, 21 (50%) exhibited CS, with 10 individuals requiring cranioplasty. No significant differences were observed based on sex, causative gene, and molecular consequence among individuals with KS who exhibited CS. Both individuals who underwent evaluation with three-dimensional computed tomography (3DCT) and those who required surgery tended to exhibit cranial dysmorphology. Notably, in several individuals, CS was diagnosed before KS, suggesting that CS could be one of the clinical features by which clinicians can diagnose KS. This study highlights that CS is one of the noteworthy complications in KS, emphasizing the importance of monitoring cranial deformities in the health management of individuals with KS. The findings suggest that in individuals where CS is a concern, conducting 3DCT evaluations for CS and digital impressions are crucial.
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Anomalías Múltiples , Craneosinostosis , Cara/anomalías , Enfermedades Hematológicas , Enfermedades Vestibulares , Humanos , Estudios Retrospectivos , Prevalencia , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/epidemiología , Anomalías Múltiples/genética , Enfermedades Hematológicas/complicaciones , Enfermedades Hematológicas/diagnóstico , Enfermedades Hematológicas/epidemiología , Enfermedades Vestibulares/diagnóstico , Enfermedades Vestibulares/epidemiología , Enfermedades Vestibulares/genética , Craneosinostosis/complicaciones , Craneosinostosis/diagnóstico , Craneosinostosis/epidemiología , Histona Demetilasas/genética , MutaciónRESUMEN
Introduction: Chromosomal microarray (CMA) is a highly accurate and established method for detecting copy number variations (CNVs) in clinical genetic testing. CNVs are important etiological factors for disorders such as intellectual disability, developmental delay, and multiple congenital anomalies. Recently developed analytical methods have facilitated the identification of smaller CNVs. Therefore, reanalyzing CMA data using a smaller CNV calling threshold may yield useful information. However, this method was left to the discretion of each institution. Methods: We reanalyzed the CMA data of 131 patients using a smaller CNV call threshold: 50 kb 50 probes for gain and 25 kb 25 probes for loss. We interpreted the reanalyzed CNVs based on the most recently available information. In the reanalysis, we filtered the data using the Clinical Genome Resource dosage sensitivity gene list as an index to quickly and efficiently check morbid genes. Results: The number of copy number loss was approximately 20 times greater, and copy number gain was approximately three times greater compared to those in the previous analysis. We detected new likely pathogenic CNVs in four participants: a 236.5 kb loss within ARID1B, a 50.6 kb loss including EHMT1, a 46.5 kb loss including EHMT1, and an 89.1 kb loss within the FOXP1 gene. Conclusion: The method employed in this study is simple and effective for CMA data reanalysis using a smaller CNV call threshold. Thus, this method is efficient for both ongoing and repeated analyses. This study may stimulate further discussion of reanalysis methodology in clinical laboratories.
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The mechanism of chromosomal rearrangement associated with inverted-duplication-deletion (INV-DUP-DEL) pattern formation has been investigated by many researchers, and several possible mechanisms have been proposed. Currently, fold-back and subsequent dicentric chromosome formation has been established as non-recurrent INV-DUP-DEL pattern formation mechanisms. In the present study, we analyzed the breakpoint junctions of INV-DUP-DEL patterns in five patients using long-read whole-genome sequencing and detected 2.2-6.1 kb copy-neutral regions in all five patients. At the end of the INV-DUP-DEL, two patients exhibited chromosomal translocations, which are recognized as telomere capture, and one patient showed direct telomere healing. The remaining two patients had additional small-sized intrachromosomal segments at the end of the derivative chromosomes. These findings have not been previously reported but they may only be explained by the presence of telomere capture breakage. Further investigations are required to better understand the mechanisms underlying this finding.
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OBJECTIVE: This study aimed to establish an optional newborn screening program for spinal muscular atrophy (SMA-NBS) in Osaka. METHODS: A multiplex TaqMan real-time quantitative polymerase chain reaction assay was used to screen for SMA. Dried blood spot samples obtained for the optional NBS program for severe combined immunodeficiency, which covers about 50% of the newborns in Osaka, were used. To obtain informed consent, participating obstetricians provided information about the optional NBS program to all parents by giving leaflets to prospective parents and uploading the information onto the internet. We prepared a workflow so that babies that were diagnosed with SMA through the NBS could be treated immediately. RESULTS: From 1 February 2021 to 30 September 2021, 22,951 newborns were screened for SMA. All of them tested negative for survival motor neuron (SMN)1 deletion, and there were no false-positives. Based on these results, an SMA-NBS program was established in Osaka and included in the optional NBS programs run in Osaka from 1 October 2021. A positive baby was found by screening, diagnosed with SMA (the baby possessed 3 copies of the SMN2 gene and was pre-symptomatic), and treated immediately. CONCLUSION: The workflow of the Osaka SMA-NBS program was confirmed to be useful for babies with SMA.
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Atrofia Muscular Espinal , Tamizaje Neonatal , Humanos , Recién Nacido , Pueblos del Este de Asia , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Tamizaje Neonatal/métodos , Proyectos Piloto , Estudios Prospectivos , Proteína 1 para la Supervivencia de la Neurona Motora/genética , JapónRESUMEN
Interstitial microdeletions in the proximal region of the long arm of chromosome 6 are rare. Herein we have reported 12 patients with developmental delays associated with interstitial microdeletions in 6q ranging from q12 to q22. The microdeletions were detected by chromosomal microarray testing. To confirm the clinical significance of these deletions, genotype-phenotype correlation analysis was performed using genetic and predicted loss-of-function data. SIM1 was recognized as the gene responsible for developmental delay, particularly in Prader-Willi syndrome-like phenotypes. Other genes possibly related to developmental delay were ZNF292, PHIP, KCNQ5, and NUS1. To further establish the correlation between the genotype and phenotype, more patient information is required.
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BACKGROUND: Two imprinting control centres, H19/IGF2:IG-differentialy methylated region (DMR) and KCNQ1OT1:TSS-DMR, reside on chromosome 11p15.5. Paternal deletions involving the KCNQ1OT1:TSS-DMR result in variable phenotypes, namely, normal phenotype, Silver-Russel syndrome (SRS) and fetal demise. However, expression analyses for CDKN1C in these patients are very limited. CASES: Patient 1 (adult woman) and patient 2 (boy in early childhood) showed prenatal and postnatal growth failure and clinical suspicion of SRS. MOLECULAR ANALYSES: Both patients showed hypermethylation of the KCNQ1OT1:TSS-DMR caused by the paternal heterozygous de novo deletions involving the KCNQ1OT1:TSS-DMR, but not including CDKN1C enhancers. The deletion sizes were 5 kb and 12 kb for patients 1 and 2, respectively. CDKN1C gene expressions in immortalised leucocytes of both patients were increased compared with those of controls. CONCLUSION: Paternal deletions involving the KCNQ1OT1:TSS-DMR, but not including CDKN1C enhancers, disrupt KCNQ1OT1 expression, strongly activate CDKN1C expression and consequently cause severe growth failure.
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ARN Largo no Codificante , Síndrome de Silver-Russell , Embarazo , Femenino , Humanos , Preescolar , Impresión Genómica/genética , Herencia Paterna , Síndrome de Silver-Russell/genética , Metilación de ADN/genética , Fenotipo , Insuficiencia de Crecimiento/genética , ARN Largo no Codificante/genética , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genéticaRESUMEN
Menke-Hennekam syndrome-1 (MKHK1) is a congenital disorder caused by the heterozygous variants in exon 30 or 31 of CREBBP (CREB binding protein) gene mapped on 16p13.3. It is characterized by psychomotor delay, variable impairment of intellectual disability (ID), feeding difficulty, autistic behavior, hearing impairment, short stature, microcephaly, and facial dysmorphisms. The CREBBP loss-of-function variants cause Rubinstein-Taybi syndrome-1 (RSTS1). The function of CREBBP leading to MKHK1 has not been clarified so far, and the phenotype of MKHK1 significantly differs from that of RSTS1. We examined six patients with de novo pathogenic variants affecting the last exon of CREBBP, and they shared the clinical features of MKHK1. This study revealed that one frameshift and three nonsense variants of CREBBP cause MKHK1, and inferred that the nonsense variants of the last exon could further help in the elucidation of the etiology of MKHK1.
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Síndrome de Rubinstein-Taybi , Proteína de Unión a CREB/genética , Exones/genética , Estudios de Asociación Genética , Humanos , Japón , Fenotipo , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/patologíaRESUMEN
BACKGROUND: Aromatic L-amino acid decarboxylase (AADC) deficiency, caused by a pathogenic variant in the dopa decarboxylase (DDC) gene, is a rare neurometabolic disorder in which catecholamine and serotonin are not synthesized. From a large number of reports, it has been recognized that most affected patients show severe developmental delay in a bedridden state and are unable to speak. On the other hand, patients with a mild phenotype with AADC deficiency have been reported, but they number only a few cases. Therefore, the variation of phenotypes of the disease appears to be broad, and it may be challenging to diagnose an atypical phenotype as AADC deficiency. CASE REPORT: We report novel compound heterozygous variants in DDC (c.202G > A and c.254C > T) in two sisters, whose main complaint was mild developmental delay, by whole-exome sequencing (WES). Additionally, we describe their clinical features and provide an image that shows the variants located at different sites responsible for the catalysis of AADC in a three-dimensional structure. The patients were prescribed a Monoamine oxidase (MAO) inhibitor after diagnosis. INTERPRETATION: Our cases indicate that a comprehensive genomic approach helps to diagnose AADC deficiency with atypical features, and underscore the significance of understanding the variations of this disorder for diagnosis and appropriate treatment.
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Errores Innatos del Metabolismo de los Aminoácidos , Descarboxilasas de Aminoácido-L-Aromático/deficiencia , Discapacidades del Desarrollo , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Descarboxilasas de Aminoácido-L-Aromático/genética , Niño , Discapacidades del Desarrollo/etiología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Femenino , Humanos , Fenotipo , Hermanos , Secuenciación del ExomaRESUMEN
Angelman syndrome is a neurodevelopmental disorder characterized by intellectual disability (ID), a distinctive gait pattern, abnormal behaviors, severe impairment in language development, and characteristic facial features. Most cases are caused by the absence of a maternal contribution to the imprinted region on chromosome 15q11-q13. Here, we present the first reported case of a 3-year-old boy with an atypical phenotype of Angelman syndrome due to uniparental isodisomy with two recessive homozygous pathogenic variants: in HERC2 and AP3B2. Known phenotypes related to HERC2 and AP3B2 include ID and early infantile epileptic encephalopathy, respectively. The patient had severe global developmental delay and profound ID and showed a happy demeanor, stereotypic laughter, and hand-flapping movements, but also irritability. Craniofacial dysmorphic features, including brachycephaly, strabismus, wide ala nasi, short philtrum, wide open mouth, and slight hypopigmentation were seen. Progressive microcephaly was noted. Magnetic resonance imaging of the brain showed delayed myelination and cerebral atrophy. Trio whole exome sequencing and CGH-SNP array analysis revealed paternal uniparental isodisomy of chromosome 15 and two coexisting recessive diseases resulting from homozygous HERC2 and AP3B2 pathogenic variants. The pathogenic variant in HERC2 was inherited from his heterozygous-carrier father, and the variant in AP3B2 was de novo. We suppose that these unusual features were the combination of the effect of three concomitant disorders.
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Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Síndrome de Angelman/genética , Discapacidad Intelectual/genética , Ubiquitina-Proteína Ligasas/genética , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/patología , Preescolar , Cromosomas Humanos Par 15/genética , Predisposición Genética a la Enfermedad , Homocigoto , Humanos , Discapacidad Intelectual/patología , Masculino , Fenotipo , Disomía Uniparental/genética , Secuenciación del ExomaRESUMEN
Hypotonia, ataxia and delayed development syndrome (HADDS) (MIM#617330) is a neurodevelopmental disorder caused by heterozygous pathogenic variants in EBF3 (MIM; 607,407), which is located on chromosome 10q26, and was first reported in 2017. To date, missense, nonsense and frameshift variants have been reported as causes of HADDS, and EBF3 pathogenic variants have been predicted to result in nonsense-mediated mRNA decay and haploinsufficiency. It was also reported that total deletion of EBF3 associated with a 10q26.3 microdeletion also causes HADDS symptoms, supporting the concept that HADDS results from haploinsufficiency of EBF3. Here, we report eight unrelated individuals with heterozygous pathogenic variants of EBF3 or haploinsufficiency of EBF3 due to 10q26 deletion, who exhibit clinical findings including craniofacial features of HADDS. In a detailed examination of clinical manifestations in this study, revealed that neurogenic bladder was diagnosed in infancy (the median 6.5 months), was more frequent than previously reported, and required cystostomy in all but one case. For psychomotor delay, it was also found that their motor/skills values were significantly lower than their cognition/adaptation values (p = 0.0016; paired t-test). Therefore, that HADDS is a recognizable syndrome that shares its characteristic facial features, and that neurogenic bladder diagnosed in infancy and psychomotor delay with marked delay in motor/skills are noteworthy findings in the diagnosis and management of individuals with HADDS.
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Discapacidades del Desarrollo/genética , Predisposición Genética a la Enfermedad , Trastornos del Neurodesarrollo/genética , Factores de Transcripción/genética , Adolescente , Ataxia/genética , Ataxia/patología , Niño , Preescolar , Cromosomas Humanos Par 10/genética , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/patología , Femenino , Mutación del Sistema de Lectura/genética , Haploinsuficiencia/genética , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Masculino , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Trastornos del Neurodesarrollo/complicaciones , Trastornos del Neurodesarrollo/patología , Eliminación de Secuencia/genéticaRESUMEN
PURPOSE: To assess the outcomes of high-dose-rate (HDR) brachytherapy and hypofractionated external beam radiation therapy (EBRT) combined with long-term androgen deprivation therapy (ADT) in very-high-risk (VHR) versus high-risk (HR) prostate cancer (PCa), as defined in the National Comprehensive Cancer Network (NCCN) criteria. METHODS: Data from 338 consecutive HR or VHR PCa patients who had undergone this tri-modal therapy between 2005 and 2018 were retrospectively analyzed. Biochemical recurrence (BCR)-free, progression-free, overall, and cancer-specific survival (BCRFS/PFS/OS/CSS) rates were analyzed using the Kaplan-Meier method and Wilcoxon test. Cox regression models were used to evaluate candidate prognostic factors for survival. Cindexes were used to assess model discrimination. RESULTS: Within a median follow-up of 84 months, 68 patients experienced BCR, 58 had disease progression including only 3 with local progression, 27 died of any cause, and 2 died from PCa. The 5year BCRFS, PFS, OS, and CSS rates were 82.2% (HR 86.5%; VHR 70.0%), 90.0% (HR 94.3%; VHR 77.6%), 95.7% (HR, 97.1%; VHR, 91.8%), and 99.6% (HR, 100%; VHR, 98.0%), respectively. In multivariable analyses that adjusted for standard clinicopathologic features, the risk subclassification was associated both PFS and OS (pâ¯= 0.0003 and 0.001, respectively). Adding the risk subclassification improved the accuracy of models in predicting BCRFS, PFS, and OS. CONCLUSION: While the outcome of this trimodal approach appears favorable, VHR PCa patients had significantly worse oncological outcomes than those with HR PCa. The NCCN risk subclassification should be integrated into prognostic tools to guide risk stratification, treatment, and follow-up for unfavorable PCa patients receiving this trimodal therapy.
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Braquiterapia , Neoplasias de la Próstata , Antagonistas de Andrógenos/uso terapéutico , Andrógenos , Braquiterapia/métodos , Humanos , Masculino , Antígeno Prostático Específico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/radioterapia , Estudios RetrospectivosRESUMEN
Establishment of proper chromosome attachments to the spindle requires elimination of erroneous attachments, but the mechanism of this process is not fully understood. During meiosis I, sister chromatids attach to the same spindle pole (mono-oriented attachment), whereas homologous chromosomes attach to opposite poles (bi-oriented attachment), resulting in homologous chromosome segregation. Here, we show that chiasmata that link homologous chromosomes and kinetochore component Dam1 are crucial for elimination of erroneous attachments and oscillation of centromeres between the spindle poles at meiosis I in fission yeast. In chiasma-forming cells, Mad2 and Aurora B kinase, which provides time for attachment correction and destabilizes erroneous attachments, respectively, caused elimination of bi-oriented attachments of sister chromatids, whereas in chiasma-lacking cells, they caused elimination of mono-oriented attachments. In chiasma-forming cells, in addition, homologous centromere oscillation was coordinated. Furthermore, Dam1 contributed to attachment elimination in both chiasma-forming and chiasma-lacking cells, and drove centromere oscillation. These results demonstrate that chiasmata alter attachment correction patterns by enabling error correction factors to eliminate bi-oriented attachment of sister chromatids, and suggest that Dam1 induces elimination of erroneous attachments. The coincidental contribution of chiasmata and Dam1 to centromere oscillation also suggests a potential link between centromere oscillation and attachment elimination.
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Cinetocoros/metabolismo , Meiosis , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Aurora Quinasa B/genética , Aurora Quinasa B/metabolismo , Cromátides/genética , Cromátides/metabolismo , Emparejamiento Cromosómico , Segregación Cromosómica , Proteínas Mad2/genética , Proteínas Mad2/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Schizosaccharomyces , Proteínas de Schizosaccharomyces pombe/genéticaRESUMEN
The catalytic enantioselective synthesis of tetrahydrofurans, which are found in the structures of many biologically active natural products, via a transition-metal-catalyzed hydrogen atom transfer (TM-HAT) and radical-polar crossover (RPC) mechanism is described herein. Hydroalkoxylation of nonconjugated alkenes proceeded efficiently with excellent enantioselectivity (up to 94% ee) using a suitable chiral cobalt catalyst, N-fluoro-2,4,6-collidinium tetrafluoroborate, and diethylsilane. Surprisingly, the absolute configuration of the product was highly dependent on the steric hindrance of the silane. Slow addition of the silane, the dioxygen effect on the solvent, thermal dependence, and DFT calculation results supported the unprecedented scenario of two competing selective mechanisms. For the less-hindered diethylsilane, a high concentration of diffused carbon-centered radicals invoked diastereoenrichment of an alkylcobalt(III) intermediate by a radical chain reaction, which eventually determined the absolute configuration of the product. On the other hand, a more hindered silane resulted in less opportunity for a radical chain reaction, instead facilitating enantioselective kinetic resolution during the late-stage nucleophilic displacement of the alkylcobalt(IV) intermediate.
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The chromosomal region critical in Down syndrome has long been analyzed through genotype-phenotype correlation studies using data from many patients with partial trisomy 21. Owing to that, a relatively small region of human chromosome 21 (35.9 ~ 38.0 Mb) has been considered as Down syndrome critical region (DSCR). In this study, microarray-based comparative genomic hybridization analysis identified complex rearrangements of chromosome 21 in a patient manifesting clinical features partially overlapped with that of Down syndrome. Although the patient did not show up-slanting palpebral fissures and single transverse palmar creases, other symptoms were consistent with Down syndrome. Rearrangements were analyzed by whole-genome sequencing using Nanopore long-read sequencing. The analysis revealed that chromosome 21 was fragmented into seven segments and reassembled by six connected points. Among 12 breakpoints, 5 are located within the short region and overlapped with repeated segments. The rearrangement resulted in a maximum gain of five copies, but no region showed loss of genomic copy numbers. Breakpoint-junctions showed no homologous region. Based on these findings, chromoanasynthesis was considered as the mechanism. Although the distal 21q22.13 region was not included in the aberrant regions, some of the genes located on the duplicated regions, SOD1, SON, ITSN1, RCAN1, and RUNX1, were considered as possible candidate genes for clinical features of the patient. We discussed the critical region for Down syndrome, with the literature review.
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Cromosomas Humanos Par 21/genética , Cromosomas Humanos/genética , Síndrome de Down/genética , Proteínas Adaptadoras del Transporte Vesicular/genética , Aberraciones Cromosómicas , Hibridación Genómica Comparativa/métodos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteínas de Unión al ADN/genética , Síndrome de Down/fisiopatología , Femenino , Dosificación de Gen/genética , Estudios de Asociación Genética , Humanos , Hibridación Fluorescente in Situ/métodos , Lactante , Análisis por Micromatrices/métodos , Antígenos de Histocompatibilidad Menor/genética , Proteínas Musculares/genética , Superóxido Dismutasa-1/genética , Secuenciación Completa del GenomaRESUMEN
NKAP is a ubiquitously expressed nucleoplasmic protein that is currently known as a transcriptional regulatory molecule via its interaction with HDAC3 and spliceosomal proteins. Here, we report a disorder of transcriptional regulation due to missense mutations in the X chromosome gene, NKAP. These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins. Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects. The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis. In affected cases, transcriptome analysis revealed the presence of a unique transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers. These observations indicate the critical role of NKAP in transcriptional regulation and demonstrate that perturbations of the C-terminal region lead to developmental defects in both humans and zebrafish.