RESUMEN
The Ras-Erk pathway is frequently overactivated in human tumors. Neurofibromatosis types 1 and 2 (NF1, NF2) are characterized by multiple tumors of Schwann cell origin. The NF1 tumor suppressor neurofibromin is a principal Ras-GAP accelerating Ras inactivation, whereas the NF2 tumor suppressor merlin is a scaffold protein coordinating multiple signaling pathways. We have previously reported that merlin interacts with Ras and p120RasGAP. Here, we show that merlin can also interact with the neurofibromin/Spred1 complex via merlin-binding sites present on both proteins. Further, merlin can directly bind to the Ras-binding domain (RBD) and the kinase domain (KiD) of Raf1. As the third component of the neurofibromin/Spred1 complex, merlin cannot increase the Ras-GAP activity; rather, it blocks Ras binding to Raf1 by functioning as a 'selective Ras barrier'. Merlin-deficient Schwann cells require the Ras-Erk pathway activity for proliferation. Accordingly, suppression of the Ras-Erk pathway likely contributes to merlin's tumor suppressor activity. Taken together, our results, and studies by others, support targeting or co-targeting of this pathway as a therapy for NF2 inactivation-related tumors.
Asunto(s)
Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Neurofibromina 1/metabolismo , Neurofibromina 2/metabolismo , Proteínas Represoras/metabolismo , Células de Schwann/patología , Proteínas ras/metabolismo , Animales , Células Cultivadas , Quinasas MAP Reguladas por Señal Extracelular/genética , Neurofibromina 1/genética , Neurofibromina 2/genética , Ratas , Proteínas Represoras/genética , Células de Schwann/metabolismo , Proteínas ras/genéticaRESUMEN
BACKGROUND: Compound epidermal growth factor receptor (EGFR) mutations are less responsive to tyrosine kinase inhibitors (TKIs) than single EGFR mutations in non-small cell lung cancer (NSCLC). However, the detailed clinical characteristics and prognosis of various compound EGFR mutations remain to be elucidated. METHODS: We retrospectively studied the next-generation sequencing (NGS) data of treatment-naïve tumors from 1025 NSCLC patients with compound EGFR mutations, which were sub-categorized into different combinations of common mutations (19-Del and EGFR exon 21 p.L858R), rare mutations, and variants of uncertain significance (VUSs). Prognosis and drug resistance to first-line TKIs were analyzed in 174 and 95 patients, respectively. RESULTS: Compound EGFR mutations were enriched with EGFR exon 21 p.L858R and rare mutations, but not 19-Del (P < 0.001). The common + rare and rare + rare subtypes had fewer concurrent mutations in the PI3K pathway (P = 0.032), while the rare + rare and common + VUSs subtypes showed increased association with smoking- and temozolomide-related mutational signatures, respectively (P < 0.001). The rare mutation-dominant subtypes (rare + VUSs and rare + rare) had the worst clinical outcomes to first-line TKIs (P < 0.001), which was further confirmed using an external cohort (P = 0.0066). VUSs in the rare + VUSs subtype selectively reside in the EGFR kinase domain (P < 0.001), implying these tumors might select additional mutations to disrupt the regulation/function of the kinase domain. CONCLUSIONS: Different subtypes of compound EGFR mutations displayed distinct clinical features and genetic architectures, and rare mutation-dominant compound EGFR mutations were associated with enriched kinase domain-resided VUSs and poor clinical outcomes. Our findings help better understand the oncogenesis of compound EGFR mutations and forecast prognostic outcomes of personalized treatments.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Estudios Retrospectivos , Fosfatidilinositol 3-Quinasas/genética , Inhibidores de Proteínas Quinasas , Resultado del Tratamiento , Mutación , Receptores ErbB/genéticaRESUMEN
Mutations in epidermal growth factor receptor and anaplastic lymphoma kinase are common driver events in non-small cell lung cancer (NSCLC), which are associated with a high frequency of bone metastases (BMs). While the bone marrow represents a specialized immune microenvironment, the immune repertoire of BMs remains unknown. Considering the higher incidence of BMs in driver gene-positive NSCLCs, and the unique biology of the bone, herein, we assessed the infiltrating immune cells and T cell receptor (TCR) profile of BMs in driver-positive NSCLCs. Immune profile of BMs in driver gene-positive NSCLC were assessed in 10 patients, where 6 had driver gene-positive mutation. TCR and bulk RNA sequencing were performed on malignant bone samples. The diversity and clonality of the TCR repertoire were analyzed. The cellular components were inferred from bulk gene expression profiles computationally by CIBERSORT. Although BMs were generally regarded as immune-cold tumors, immune cell composition analyses showed co-existence of cytotoxic and suppressor immune cells in driver-positive BM samples, as compared to primary lung. Analysis of the TCR repertoire indicated a trend of higher diversity and similar clonality in the driver-positive compared with the driver-negative subsets. In addition, we identified two cases that showed the opposite response to immune checkpoint blockade. A comparison of these two patients' BM samples showed more highly amplified clones, fewer M2 macrophages and more activated natural killer cells in the responder. In summary, BMs in NSCLC are heterogeneous in their immune microenvironment, which might be related to differential clinical outcomes to immune checkpoint blockade.
Asunto(s)
Neoplasias Óseas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Pulmón/patología , Neoplasias Óseas/genética , Receptores de Antígenos de Linfocitos T/genética , Microambiente Tumoral/genéticaRESUMEN
BACKGROUND: Acral melanoma (AM) is the most common subtype in Chinese melanoma patients with a very poor prognosis. However, our understanding of the disease pathogenesis and molecular landscape is limited by the few studies that have been conducted. Here, we profiled the clinical characteristics, mutational landscapes and tumor immune microenvironment of AM patients to gain insights into disease characteristics and potential treatment strategies. METHODS: A total of 90 AM patients were enrolled and their tissue samples were subjected to next-generation sequencing and multiplexed immunohistochemistry tests. Kaplan-Meier curves and log-rank tests were used to analyze the prognostic potential of various genetic aberrations and immune cell compositions in AM. RESULTS: The median disease-free survival was 21.3 months and estimated median overall survival (OS) was 60 months. More advanced stages, older ages and thickness of greater than 4 mm were associated with worse prognosis in AM patients (HR = 2.57, 95% CI 1.25-5.29, p = 0.01; HR = 2.77, 95% CI 1.22-6.28, p = 0.02; HR = 3.43, 95% CI 1.51-7.82, p < 0.01, respectively), while patients who received post-surgical treatments had better survival (HR = 0.36, 95% CI 0.17-0.76, p = 0.01). The most frequently altered genes included BRAF (14.5%), KIT (16.9%), NRAS (12%), NF1 (10.8%), APC (7.2%), and ARID2 (6%). Copy number variations (CNV) were commonly found in CCND1 (19.3%), CDK4 (19.3%), MDM2 (14.5%) and FGF19 (12%). CDK4 amplifications was independently associated with shorter OS in AM patients (HR = 3.61, 95% CI 1.38-9.46, p = 0.01). CD8 + T cells (p < 0.001) and M1 macrophages (p = 0.05) were more highly enriched in the invasive margin than in the tumor center. Patients with higher levels of M1 macrophage infiltration in the invasive margin derived markedly longer OS (HR = 0.43, 95% CI 0.20-0.95, p = 0.03). Interestingly, in CDK4-amplified patients, there tended to be a low level of M1 macrophage infiltration in the invasive margin (p = 0.06), which likely explains the poor prognosis in such patients. CONCLUSIONS: Our study provided a comprehensive portrait of the clinicopathological features, genetic aberrations and tumor microenvironment profiles in AM patients and identified candidate prognostic factors, which may facilitate development of additional therapeutic options and better inform clinical management of AM patients. Based on these prognostic factors, further studies should focus on enhancing the infiltration of M1 macrophages, especially in CDK4-amplified AM patients.
Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Pronóstico , Variaciones en el Número de Copia de ADN/genética , Microambiente Tumoral/genética , Melanoma/patología , Neoplasias Cutáneas/genética , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: Sarcomatoid component occurs in various epithelial malignancies and is associated with an aggressive disease course and poor clinical outcome. As it is largely rare, the molecular events underlying sarcomatoid carcinomas (SCs) remain poorly characterised. Here, we performed targeted next-generation sequencing (NGS) on patients with surgically resected SCs comprising distinct tissues of origin. METHODS: A total of 71 patients with pathological diagnosis of sarcomatoid carcinomas and underwent surgery were retrospectively enrolled in this study. Overall survival (OS) was defined as the time from surgery to death from any cause. Patients alive or lost to follow-up were censored. Genomic DNA from formalin-fixed paraffin-embedded samples was extracted for NGS and tumour mutation burden (TMB) analysis. RESULTS: In general, SCs occurred more commonly in males, except those of the gallbladder. SCs of the lung and the larynx were associated with a higher proportion of smokers (p=0.0015). Alterations in TP53, RB1, TERT and KRAS were highly frequent, with KRAS mutations being a biomarker of poor prognosis (median OS=8 vs 16 months, p=0.03). Multiple alterations in potentially actionable genes, including ROS1 and NTRK1 fusions and ERBB2 amplification, were detected in the extra-pulmonary cohort. A relatively high proportion (30%) of patients with extra-pulmonary SC had high TMB, with a median of 5.39 mutations per Mb. Lastly, copy number variations were common in SCs, and were non-overlapping between the primary and metastatic tumours. CONCLUSION: Taken together, our results suggest that comprehensive genetic testing may be necessary to inform treatment options and identify prognostic biomarkers.
Asunto(s)
Carcinoma/genética , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Anciano , Pueblo Asiatico/genética , Biomarcadores de Tumor , Carcinoma/metabolismo , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Proteínas Oncogénicas/genética , Pronóstico , Proteínas de Unión a Retinoblastoma/genética , Estudios Retrospectivos , Análisis de Secuencia de ADN , Telomerasa/genética , Proteína p53 Supresora de Tumor/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Autism spectrum disorders are associated with some degree of developmental regression in up to 30% of all cases. Rarely, however, is the regression so extreme that a developmentally advanced young child would lose almost all ability to communicate and interact with her surroundings. We applied trio whole exome sequencing to a young woman who experienced extreme developmental regression starting at 2.5 years of age and identified compound heterozygous nonsense mutations in TMPRSS9, which encodes for polyserase-1, a transmembrane serine protease of poorly understood physiological function. Using semiquantitative polymerase chain reaction, we showed that Tmprss9 is expressed in various mouse tissues, including the brain. To study the consequences of TMPRSS9 loss of function on the mammalian brain, we generated a knockout mouse model. Through a battery of behavioral assays, we found that Tmprss9-/- mice showed decreased social interest and social recognition. We observed a borderline recognition memory deficit by novel object recognition in aged Tmprss9-/- female mice, but not in aged Tmprss9-/- male mice or younger adult Tmprss9-/- mice in both sexes. This study provides evidence to suggest that loss of function variants in TMPRSS9 are related to an autism spectrum disorder. However, the identification of more individuals with similar phenotypes and TMPRSS9 loss of function variants is required to establish a robust gene-disease relationship.
Asunto(s)
Trastornos de Ansiedad/patología , Trastorno del Espectro Autista/patología , Codón sin Sentido , Secuenciación del Exoma/métodos , Proteínas de la Membrana/metabolismo , Trastornos de la Memoria/patología , Serina Endopeptidasas/metabolismo , Serina Endopeptidasas/fisiología , Adolescente , Adulto , Animales , Trastornos de Ansiedad/etiología , Trastorno del Espectro Autista/etiología , Trastorno del Espectro Autista/genética , Niño , Preescolar , Femenino , Humanos , Masculino , Proteínas de la Membrana/genética , Trastornos de la Memoria/etiología , Ratones , Ratones Noqueados , Actividad Motora , Fenotipo , Serina Endopeptidasas/genéticaRESUMEN
Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) has been identified as an autosomal-dominant disorder characterized by a complex neurological phenotype, with high prevalence of intellectual disability and optic nerve atrophy/hypoplasia. The syndrome is caused by loss-of-function mutations in NR2F1, which encodes a highly conserved nuclear receptor that serves as a transcriptional regulator. Previous investigations to understand the protein's role in neurodevelopment have mostly used mouse models with constitutive and tissue-specific homozygous knockout of Nr2f1. In order to represent the human disease more accurately, which is caused by heterozygous NR2F1 mutations, we investigated a heterozygous knockout mouse model and found that this model recapitulates some of the neurological phenotypes of BBSOAS, including altered learning/memory, hearing defects, neonatal hypotonia and decreased hippocampal volume. The mice showed altered fear memory, and further electrophysiological investigation in hippocampal slices revealed significantly reduced long-term potentiation and long-term depression. These results suggest that a deficit or alteration in hippocampal synaptic plasticity may contribute to the intellectual disability frequently seen in BBSOAS. RNA-sequencing (RNA-Seq) analysis revealed significant differential gene expression in the adult Nr2f1+/- hippocampus, including the up-regulation of multiple matrix metalloproteases, which are known to be critical for the development and the plasticity of the nervous system. Taken together, our studies highlight the important role of Nr2f1 in neurodevelopment. The discovery of impaired hippocampal synaptic plasticity in the heterozygous mouse model sheds light on the pathophysiology of altered memory and cognitive function in BBSOAS.
Asunto(s)
Factor de Transcripción COUP I/fisiología , Depresión/patología , Hipocampo/patología , Trastornos de la Memoria/patología , Plasticidad Neuronal , Atrofias Ópticas Hereditarias/patología , Animales , Conducta Animal , Depresión/etiología , Depresión/metabolismo , Femenino , Hipocampo/metabolismo , Masculino , Trastornos de la Memoria/etiología , Trastornos de la Memoria/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Atrofias Ópticas Hereditarias/etiología , Atrofias Ópticas Hereditarias/metabolismoRESUMEN
PURPOSE: Neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and autism spectrum disorder (ASD), exhibit genetic and phenotypic heterogeneity, making them difficult to differentiate without a molecular diagnosis. The Clinical Genome Resource Intellectual Disability/Autism Gene Curation Expert Panel (GCEP) uses systematic curation to distinguish ID/ASD genes that are appropriate for clinical testing (ie, with substantial evidence supporting their relationship to disease) from those that are not. METHODS: Using the Clinical Genome Resource gene-disease validity curation framework, the ID/Autism GCEP classified genes frequently included on clinical ID/ASD testing panels as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship. RESULTS: As of September 2021, 156 gene-disease pairs have been evaluated. Although most (75%) were determined to have definitive roles in NDDs, 22 (14%) genes evaluated had either Limited or Disputed evidence. Such genes are currently not recommended for use in clinical testing owing to the limited ability to assess the effect of identified variants. CONCLUSION: Our understanding of gene-disease relationships evolves over time; new relationships are discovered and previously-held conclusions may be questioned. Without periodic re-examination, inaccurate gene-disease claims may be perpetuated. The ID/Autism GCEP will continue to evaluate these claims to improve diagnosis and clinical care for NDDs.
Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Trastorno Autístico/diagnóstico , Trastorno Autístico/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genéticaRESUMEN
Anaplastic lymphoma kinase ( ALK ) rearrangement defines a unique nonsmall cell lung cancer (NSCLC) molecular subtype, of which the patients could potentially benefit from anti- ALK therapies. So far, the outcomes of the canonical echinoderm microtubule-associated protein-like ( EML-ALK ) patients subjected to ALK inhibitors are well established. However, given the increasing complexity of ALK fusion partners, as detected by high-throughput sequencing, the responses of those with rare ALK fusion events remain to be explored. Here, we report a lung adenocarcinoma patient with brain metastasis harboring an ARHGAP5 downstream intergenic region ALK fusion, as detected by using DNA-based next-generation sequencing, who experienced a partial response to alectinib treatment. While whole- transcriptome RNA sequencing (RNA-seq) failed to identify potential ALK fusion transcripts, subsequent targeted deep RNA-seq revealed the expression of EML4-ALK transcripts in the tumor tissue. Given the increasing application of the ALK-tyrosine kinase inhibitors (TKIs), it is extremely crucial to define the patients who could be suitable for this treatment in clinic. The present case has provided supporting evidence that noncanonical ALK rearrangements on the genomic level are often functionally relevant and targetable by ALK-TKI, particularly in cases with sub-optimal quantity and quality for RNA validation.
Asunto(s)
Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Quinasa de Linfoma Anaplásico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Carbazoles , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , ADN Intergénico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas Asociadas a Microtúbulos/genética , Piperidinas , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , ARNRESUMEN
15q13.3 microdeletion syndrome is characterized by a wide spectrum of neurodevelopmental disorders, including developmental delay, intellectual disability, epilepsy, language impairment, abnormal behaviors, neuropsychiatric disorders, and hypotonia. This syndrome is caused by a deletion on chromosome 15q, which typically encompasses six genes. Here, through studies on OTU deubiquitinase 7A (Otud7a) knockout mice, we identify OTUD7A as a critical gene responsible for many of the cardinal phenotypes associated with 15q13.3 microdeletion syndrome. Otud7a-null mice show reduced body weight, developmental delay, abnormal electroencephalography patterns and seizures, reduced ultrasonic vocalizations, decreased grip strength, impaired motor learning/motor coordination, and reduced acoustic startle. We show that OTUD7A localizes to dendritic spines and that Otud7a-null mice have decreased dendritic spine density compared to their wild-type littermates. Furthermore, frequency of miniature excitatory postsynaptic currents (mEPSCs) is reduced in the frontal cortex of Otud7a-null mice, suggesting a role of Otud7a in regulation of dendritic spine density and glutamatergic synaptic transmission. Taken together, our results suggest decreased OTUD7A dosage as a major contributor to the neurodevelopmental phenotypes associated with 15q13.3 microdeletion syndrome, through the misregulation of dendritic spine density and activity.
Asunto(s)
Trastornos de los Cromosomas/enzimología , Trastornos de los Cromosomas/genética , Enzimas Desubicuitinizantes/genética , Endopeptidasas/genética , Discapacidad Intelectual/enzimología , Discapacidad Intelectual/genética , Convulsiones/enzimología , Convulsiones/genética , Potenciales de Acción , Animales , Secuencia de Bases , Conducta Animal , Deleción Cromosómica , Cromosomas Humanos Par 15/enzimología , Cromosomas Humanos Par 15/genética , Espinas Dendríticas/metabolismo , Modelos Animales de Enfermedad , Electroencefalografía , Endopeptidasas/deficiencia , Epilepsia/enzimología , Epilepsia/genética , Epilepsia/fisiopatología , Femenino , Homocigoto , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Sinapsis/metabolismoRESUMEN
Copy-number variants (CNVs) of chromosome 15q13.3 manifest clinically as neuropsychiatric disorders with variable expressivity. CHRNA7, encoding for the α7 nicotinic acetylcholine receptor (nAChR), has been suggested as a candidate gene for the phenotypes observed. Here, we used induced pluripotent stem cells (iPSCs) and neural progenitor cells (NPCs) derived from individuals with heterozygous 15q13.3 deletions and heterozygous 15q13.3 duplications to investigate the CHRNA7-dependent molecular consequences of the respective CNVs. Unexpectedly, both deletions and duplications lead to decreased α7 nAChR-associated calcium flux. For deletions, this decrease in α7 nAChR-dependent calcium flux is expected due to haploinsufficiency of CHRNA7. For duplications, we found that increased expression of CHRNA7 mRNA is associated with higher expression of nAChR-specific and resident ER chaperones, indicating increased ER stress. This is likely a consequence of inefficient chaperoning and accumulation of α7 subunits in the ER, as opposed to being incorporated into functional α7 nAChRs at the cell membrane. Here, we showed that α7 nAChR-dependent calcium signal cascades are downregulated in both 15q13.3 deletion and duplication NPCs. While it may seem surprising that genomic changes in opposite direction have consequences on downstream pathways that are in similar direction, it aligns with clinical data, which suggest that both individuals with deletions and duplications of 15q13.3 manifest neuropsychiatric disease and cognitive deficits.
Asunto(s)
Señalización del Calcio/genética , Trastornos de los Cromosomas/genética , Variaciones en el Número de Copia de ADN/genética , Estrés del Retículo Endoplásmico/genética , Dosificación de Gen/genética , Células Madre Pluripotentes Inducidas/citología , Discapacidad Intelectual/genética , Células-Madre Neurales/citología , Convulsiones/genética , Receptor Nicotínico de Acetilcolina alfa 7/genética , Adolescente , Niño , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 15/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Receptor Nicotínico de Acetilcolina alfa 7/biosíntesisRESUMEN
BACKGROUND: Nonsense and frameshift mutations in the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13, have been reported to cause Schaaf-Yang syndrome (SYS), a genetic disorder that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties and autism spectrum disorder. Prader-Willi syndrome (PWS) is a genetic disorder characterised by severe infantile hypotonia, hypogonadotrophic hypogonadism, early childhood onset obesity/hyperphagia, developmental delay/intellectual disability and short stature. Scoliosis and growth hormone insufficiency are also prevalent in PWS.There is extensive documentation of the endocrine and metabolic phenotypes for PWS, but not for SYS. This study served to investigate the hormonal, metabolic and body composition phenotype of SYS and its potential overlap with PWS. METHODS: In nine individuals with SYS (5 female/4 male; aged 5-17 years), we measured serum ghrelin, glucose, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3, follicle-stimulating hormone, luteinising hormone, thyroid-stimulating hormone, free T4, uric acid and testosterone, and performed a comprehensive lipid panel. Patients also underwent X-ray and dual-energy X-ray absorptiometry analyses to assess for scoliosis and bone mineral density. RESULTS: Low IGF-1 levels despite normal weight/adequate nutrition were observed in six patients, suggesting growth hormone deficiency similar to PWS. Fasting ghrelin levels were elevated, as seen in individuals with PWS. X-rays revealed scoliosis >10° in three patients, and abnormal bone mineral density in six patients, indicated by Z-scores of below -2 SDs. CONCLUSION: This is the first analysis of the hormonal, metabolic and body composition phenotype of SYS. Our findings suggest that there is marked, but not complete overlap between PWS and SYS.
Asunto(s)
Trastorno del Espectro Autista/sangre , Discapacidades del Desarrollo/sangre , Síndrome de Prader-Willi/sangre , Escoliosis/sangre , Adolescente , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Glucemia/genética , Densidad Ósea , Niño , Preescolar , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Trastornos de Alimentación y de la Ingestión de Alimentos/sangre , Trastornos de Alimentación y de la Ingestión de Alimentos/genética , Trastornos de Alimentación y de la Ingestión de Alimentos/fisiopatología , Femenino , Hormona Folículo Estimulante/sangre , Ghrelina/sangre , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Hormona Luteinizante/sangre , Masculino , Hipotonía Muscular/sangre , Hipotonía Muscular/genética , Hipotonía Muscular/fisiopatología , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/fisiopatología , Proteínas/genética , Escoliosis/genética , Escoliosis/fisiopatología , Testosterona/sangreRESUMEN
Optic nerve hypoplasia (ONH) is the most common congenital optic nerve anomaly and a leading cause of blindness in the USA. Although most cases of ONH occur as isolated cases within their respective families, the advancement in molecular diagnostic technology has made us realise that a substantial fraction of cases has identifiable genetic causes, typically de novo mutations. An increasing number of genes has been reported, mutations of which can cause ONH. Many of the genes involved serve as transcription factors, participating in an intricate multistep process critical to eye development and neurogenesis in the neural retina. This review will discuss the respective genes and mutations, human phenotypes, and animal models that have been created to gain a deeper understanding of the disorders. The identification of the underlying gene and mutation provides an important step in diagnosis, medical care and counselling for the affected individuals and their families. We envision that future research will lead to further disease gene identification, but will also teach us about gene-gene and gene-environment interactions relevant to optic nerve development. How much of the functional impairment of the various forms of ONH is a reflection of altered morphogenesis versus neuronal homeostasis will determine the prospect of therapeutic intervention, with the ultimate goal of improving the quality of life of the individuals affected with ONH.
Asunto(s)
Predisposición Genética a la Enfermedad , Nervio Óptico/anomalías , Animales , Ensamble y Desensamble de Cromatina/genética , Humanos , Modelos Biológicos , Factores de Transcripción/genéticaRESUMEN
RAS-like protein expressed in many tissues 1 (RIT1) is a disease-associated RAS subfamily small guanosine triphosphatase (GTPase). Recent studies revealed that germ-line and somatic RIT1 mutations can cause Noonan syndrome (NS), and drive proliferation of lung adenocarcinomas, respectively, akin to RAS mutations in these diseases. However, the locations of these RIT1 mutations differ significantly from those found in RAS, and do not affect the three mutational "hot spots" of RAS. Moreover, few studies have characterized the GTPase cycle of RIT1 and its disease-associated mutants. Here we developed a real-time NMR-based GTPase assay for RIT1 and investigated the effect of disease-associated mutations on GTPase cycle. RIT1 exhibits an intrinsic GTP hydrolysis rate similar to that of H-RAS, but its intrinsic nucleotide exchange rate is â¼4-fold faster, likely as a result of divergent residues near the nucleotide binding site. All of the disease-associated mutations investigated increased the GTP-loaded, activated state of RIT1 in vitro, but they could be classified into two groups with different intrinsic GTPase properties. The S35T, A57G, and Y89H mutants exhibited more rapid nucleotide exchange, whereas F82V and T83P impaired GTP hydrolysis. A RAS-binding domain pulldown assay indicated that RIT1 A57G and Y89H were highly activated in HEK293T cells, whereas T83P and F82V exhibited more modest activation. All five mutations are associated with NS, whereas two (A57G and F82V) have also been identified in urinary tract cancers and myeloid malignancies. Characterization of the effects on the GTPase cycle of RIT1 disease-associated mutations should enable better understanding of their role in disease processes.
Asunto(s)
Adenocarcinoma , Neoplasias Pulmonares , Mutación Missense , Proteínas de Neoplasias , Síndrome de Noonan , Neoplasias Urológicas , Proteínas ras , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma del Pulmón , Sustitución de Aminoácidos , Línea Celular , Guanosina Trifosfato/química , Humanos , Hidrólisis , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Síndrome de Noonan/genética , Síndrome de Noonan/metabolismo , Dominios Proteicos , Neoplasias Urológicas/genética , Neoplasias Urológicas/metabolismo , Proteínas ras/química , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
Autism spectrum disorder (ASD) is a highly heritable, clinically diverse group of neurodevelopmental disorders. Its genetic heterogeneity is remarkable, with more than 800 ASD predisposition genes identified to date. They are involved in various biological processes, including chromatin remodeling and gene transcription regulation, cell growth and proliferation, ubiquitination, and neuronal-specific processes, such as synaptic organization and activity, dendritic morphology, and axonogenesis. This review aims to discuss basic autism genetics, explicate ways to investigate ASD in model systems, highlight some key genes and their molecular pathways, and introduce novel theories of ASD pathogenesis, such as imbalance of excitatory and inhibitory brain activity, oligogenic heterozygosity, and the female protective model. © 2016 John Wiley & Sons, Ltd.
Asunto(s)
Trastorno del Espectro Autista/genética , Trastorno Autístico/genética , Proliferación Celular/genética , Ensamble y Desensamble de Cromatina/genética , Humanos , Proteínas del Tejido Nervioso/genética , Factores de Transcripción/genéticaRESUMEN
Noonan syndrome (NS) is a relatively common genetic disorder, characterized by typical facies, short stature, developmental delay, and cardiac abnormalities. Known causative genes account for 70-80% of clinically diagnosed NS patients, but the genetic basis for the remaining 20-30% of cases is unknown. We performed next-generation sequencing on germ-line DNA from 27 NS patients lacking a mutation in the known NS genes. We identified gain-of-function alleles in Ras-like without CAAX 1 (RIT1) and mitogen-activated protein kinase kinase 1 (MAP2K1) and previously unseen loss-of-function variants in RAS p21 protein activator 2 (RASA2) that are likely to cause NS in these patients. Expression of the mutant RASA2, MAP2K1, or RIT1 alleles in heterologous cells increased RAS-ERK pathway activation, supporting a causative role in NS pathogenesis. Two patients had more than one disease-associated variant. Moreover, the diagnosis of an individual initially thought to have NS was revised to neurofibromatosis type 1 based on an NF1 nonsense mutation detected in this patient. Another patient harbored a missense mutation in NF1 that resulted in decreased protein stability and impaired ability to suppress RAS-ERK activation; however, this patient continues to exhibit a NS-like phenotype. In addition, a nonsense mutation in RPS6KA3 was found in one patient initially diagnosed with NS whose diagnosis was later revised to Coffin-Lowry syndrome. Finally, we identified other potential candidates for new NS genes, as well as potential carrier alleles for unrelated syndromes. Taken together, our data suggest that next-generation sequencing can provide a useful adjunct to RASopathy diagnosis and emphasize that the standard clinical categories for RASopathies might not be adequate to describe all patients.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación/genética , Síndrome de Noonan/genética , Alelos , Estudios de Asociación Genética , Humanos , MAP Quinasa Quinasa 1/genética , Sistema de Señalización de MAP Quinasas/genética , Neurofibromina 1/genética , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.
Asunto(s)
Estudios de Asociación Genética , Mutación , Síndrome de Noonan/genética , Dominios y Motivos de Interacción de Proteínas/genética , Proteínas Son Of Sevenless/genética , Adolescente , Adulto , Alelos , Sustitución de Aminoácidos , Niño , Análisis Mutacional de ADN , Exoma , Facies , Femenino , Genotipo , Humanos , Masculino , Modelos Moleculares , Síndrome de Noonan/diagnóstico , Fenotipo , Conformación Proteica , Proteínas Son Of Sevenless/química , Adulto JovenRESUMEN
The extracellular volume (ECV) fraction derived from cardiac magnetic resonance (CMR) can reflect various pathologies. The application of ECVs was limited by the strict requirement that hematocrit (Hct0) should be obtained within 24 hours of CMR scan. The aim of this study was to obtain accurate and convenient ECV calculated from the venous Hct and synthetic Hct in CMR. A total of 839 subjects were retrospectively enrolled. The subjects were divided into derivation cohort for local sex-specific models and validation cohort for assessing the accuracy of different ECVs. In the validation cohort, venous Hcts from 7 days before the scan (Hct1 - 7), outside 7 days (Hct> 7), the closest day (Hctclosest), and Hctsyn were compared with Hct0. The agreement and correlation of the conventional ECV (ECV0) with the corresponding ECVs were analyzed. The factors affecting the accuracy of ECVsyn were assessed. ECV1-7 and ECVclosest had the best correlation and smallest bias with ECV0 (R = 0.959 and 0.951, bias = 0.02% and - 0.03%). When using an absolute 2% error as the standard, the performance of ECV1-7 was the best, with an accuracy of 81.0%, followed by ECVclosest (78.8%), ECV> 7 (77.2%) and ECVsyn (70.7%). Abnormally low and high Hcts and decreased left ventricular ejection fractions were associated with miscalculation of ECVsyn, especially patients with dilated cardiomyopathy. We recommend extending the time interval between a Hct and a CMR scan to 7 days for ECV calculation. The synthetic ECV should be used cautiously, especially for patients with extremely low or high Hcts, decreased cardiac function, and dilated cardiomyopathy.
Asunto(s)
Valor Predictivo de las Pruebas , Función Ventricular Izquierda , Humanos , Femenino , Masculino , Hematócrito , Estudios Retrospectivos , Persona de Mediana Edad , Reproducibilidad de los Resultados , Adulto , Anciano , Imagen por Resonancia Cinemagnética , Factores de Tiempo , Interpretación de Imagen Asistida por Computador , Imagen por Resonancia MagnéticaRESUMEN
The emotional conflict task measures emotional conflict resolution and adaptation, but some studies are unable to find resolution or adaptation effects using this task. We examined boundary conditions and replicability of the emotional conflict resolution and adaptation effects through secondary data analysis, systematic review, and meta-analysis of studies in the field. In our data, we were unable to fully replicate the emotional conflict resolution or adaptation effects and found that most studies using this task (n = 94) do not report analysis of emotional conflict resolution, with only 28% (n = 26) studies doing so. Our meta-analysis suggests that studies reporting emotional conflict resolution and adaptation analyses overall report significant but small effects, suggesting the effect is difficult to consistently replicate. Our meta-analysis revealed that controlling for contingency learning may impact the ability of studies to identify conflict resolution. These findings have implications for assessment and interpretation of the emotional conflict task. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Asunto(s)
Adaptación Psicológica , Conflicto Psicológico , Emociones , Humanos , Emociones/fisiología , Reproducibilidad de los Resultados , Negociación/psicología , Análisis de Datos SecundariosRESUMEN
Recent studies show that greenhouse gas (GHG) emissions from urban landscape water are significant and cannot be overlooked, underscoring the need to develop effective strategies for mitigating GHG production from global freshwater systems. Calcium peroxide (CaO2) is commonly used as an eco-friendly reagent for controlling eutrophication in water bodies, but whether CaO2 can reduce GHG emissions remains unclear. This study investigated the effects of CaO2 dosage on the production of methane (CH4) and nitrous oxide (N2O) in urban landscape water under anoxic conditions during summer. The findings reveal that CaO2 addition not only improved the physicochemical and organoleptic properties of simulated urban landscape water but also reduced N2O production by inhibiting the activity of denitrifying bacteria across various dosages. Moreover, CaO2 exhibited selective effects on methanogens. Specifically, the abundance of acetoclastic methanogen Methanosaeta and methylotrophic methanogen Candidatus_Methanofastidiosum increased whereas the abundance of the hydrogenotrophic methanogen Methanoregula decreased at low, medium, and high dosages, leading to higher CH4 production at increased CaO2 dosage. A comprehensive multi-objective evaluation indicated that an optimal dosage of 60 g CaO2/m2 achieved 41.21 % and 84.40 % reductions in CH4 and N2O production, respectively, over a 50-day period compared to the control. This paper not only introduces a novel approach for controlling the production of GHGs, such as CH4 and N2O, from urban landscape water but also suggests a methodology for optimizing CaO2 dosage, providing valuable insights for its practical application.