RESUMO
Somatic mutations in UBA1 cause vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, whereas transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we show that these 3 canonical VEXAS variants produce more UBA1b than any of the 6 other possible single-nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with 2 novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but coexpression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We conclude that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease prognosis.
Assuntos
Nucleotídeos , Enzimas Ativadoras de Ubiquitina , Códon de Iniciação , Humanos , Mutação , Enzimas Ativadoras de Ubiquitina/genética , UbiquitinaçãoRESUMO
Importance: VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes. Objective: To determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach. Design, Setting, and Participants: This retrospective observational study evaluated UBA1 variants in exome data from 163â¯096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record data from January 1, 1996, to January 1, 2022. Exposures: Exome sequencing was performed. Main Outcomes and Measures: Outcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of the electronic health record; review of laboratory data; bone marrow biopsy pathology analysis; and in vitro enzymatic assays. Results: In 163â¯096 participants (mean age, 52.8 years; 94% White; 61% women), 11 individuals harbored likely somatic variants at known pathogenic UBA1 positions, with 11 of 11 (100%) having clinical manifestations consistent with VEXAS syndrome (9 male, 2 female). A total of 5 of 11 individuals (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome; however, all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11 [91%]) with concomitant thrombocytopenia (10/11 [91%]). Among the 11 patients identified, there was a pathogenic variant in 1 male participant prior to onset of VEXAS-related signs or symptoms and 2 female participants had disease with heterozygous variants. A previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) was found in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in 1 in 13â¯591 unrelated individuals (95% CI, 1:7775-1:23â¯758), 1 in 4269 men older than 50 years (95% CI, 1:2319-1:7859), and 1 in 26â¯238 women older than 50 years (95% CI, 1:7196-1:147â¯669). Conclusions and Relevance: This study provides an estimate of the prevalence and a description of the clinical manifestations of UBA1 variants associated with VEXAS syndrome within a single regional health system in the US. Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum.
Assuntos
Síndromes Mielodisplásicas , Dermatopatias Genéticas , Enzimas Ativadoras de Ubiquitina , Feminino , Humanos , Masculino , Biópsia , Registros Eletrônicos de Saúde , Prevalência , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/genética , Enzimas Ativadoras de Ubiquitina/genética , Mutação , Estudos Retrospectivos , Exoma , Pessoa de Meia-Idade , Dermatopatias Genéticas/complicações , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/epidemiologia , Dermatopatias Genéticas/genética , Estados Unidos/epidemiologiaRESUMO
OBJECTIVES: Lynch syndrome (LS) accounts for the majority of inherited endometrial cancers (EC), and the identification of probands presents a unique opportunity to treat and prevent multiple cancers. The diagnosis of EC can provide the indication for women with specific risk factors to undergo genetic testing (GT). We sought to evaluate genetic counseling referrals (GCR) and subsequent GT rates in an ethnically diverse group of high-risk women. METHODS: All women diagnosed with EC between 2011 and 2016 were identified. Risk factors for LS including age, family and personal histories of Lynch-related cancers and loss of tumor mismatch repair (MMR) protein expression were identified from laboratory and medical records. Standard two-sided statistical tests were used. RESULTS: Of 583 women diagnosed with EC, 184 (31.6%) were found to have at least one high-risk characteristic for LS. Among these high-risk women, 58% were given GCR and resulting in only 35% undergoing GT. Ten of the 65 high-risk women who had GT (15.4%) were diagnosed with Lynch syndrome, and all ten met high-risk criteria. Two women of Asian race had tumors exhibiting retained MMR protein expression despite germline testing demonstrating Lynch syndrome. CONCLUSIONS: Many high-risk women do not receive GCR despite a high rate of germline mutations among these women. Improving GCR among high-risk women will lead to more subsequent GT to identify more Lynch syndrome families and prevent additional cancers. Among our ethnically diverse cohort, two women diagnosed with LS had retained MMR protein expression. GCR should be offered to women who possess high-risk characteristics despite normal MMR protein expression.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Detecção Precoce de Câncer/estatística & dados numéricos , Neoplasias do Endométrio/diagnóstico , Aconselhamento Genético/estatística & dados numéricos , Testes Genéticos/estatística & dados numéricos , Idoso , Biomarcadores Tumorais/genética , Estudos de Coortes , Neoplasias Colorretais Hereditárias sem Polipose/etnologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Detecção Precoce de Câncer/métodos , Neoplasias do Endométrio/etnologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/prevenção & controle , Feminino , Aconselhamento Genético/métodos , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Encaminhamento e Consulta/estatística & dados numéricos , Fatores de RiscoRESUMO
Repeated exposure to psychostimulants such as amphetamine (AMPH) disrupts cognitive and behavioral processes mediated by the medial prefrontal cortical (mPFC) and basolateral amygdala (BLA). The present study investigated the effects of repeated AMPH exposure on the neuromodulatory actions of dopamine (DA) on BLA-mPFC circuitry and cognitive/emotional processing mediated by these circuits. Rats received five AMPH (2 mg/kg) or saline injections (controls) over 10 d, followed by 2-4 week drug washout. In vivo neurophysiological extracellular recordings in urethane-anesthetized rats were used to obtain data from mPFC neurons that were either inhibited or excited by BLA stimulation. In controls, acute AMPH attenuated BLA-evoked inhibitory or excitatory responses; these effects were mimicked by selective D(2) or D(1) agonists, respectively. However, in AMPH-treated rats, the ability of these dopaminergic manipulations to modulate BLA-driven decreases/increases in mPFC activity was abolished. Repeated AMPH also blunted the excitatory effects of ventral tegmental area stimulation on mPFC neural firing. Behavioral studies assessed the effect of repeated AMPH on decision making with conditioned punishment, a process mediated by BLA-mPFC circuitry and mesocortical DA. These treatments impaired the ability of rats to use conditioned aversive stimuli (footshock-associated cue) to guide the direction of instrumental responding. Collectively, these data suggest that repeated AMPH exposure can lead to persistent disruption of dopaminergic modulation of BLA-mPFC circuitry, which may underlie impairments in cognitive/emotional processing observed in stimulant abusers. Furthermore, they suggest that impairments in decision making guided by aversive stimuli observed in stimulant abusers may be the result of repeated drug exposure.
Assuntos
Anfetamina/farmacologia , Tonsila do Cerebelo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Dopamina/metabolismo , Emoções/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Potenciais de Ação/efeitos dos fármacos , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/fisiologia , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Esquema de Medicação , Interações Medicamentosas , Extinção Psicológica/efeitos dos fármacos , Técnicas In Vitro , Masculino , Inibição Neural/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Punição/psicologia , Ratos , Ratos Sprague-Dawley , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologiaRESUMO
Despite improvements in the understanding of cancer causation, much remains unknown regarding the mechanisms by which genomic and non-genomic factors initiate carcinogenesis, drive cell invasion and metastasis, and enable cancer to develop. Technological advances have enabled the analysis of whole genomes, comprising thousands of tumours across populations worldwide, with the aim of identifying mutation signatures associated with particular tumour types. Large collaborative efforts have resulted in the identification and improved understanding of causal factors, and have shed light on new opportunities to prevent cancer. In this new era in cancer genomics, discoveries from studies conducted on an international scale can inform evidence-based strategies in cancer control along the cancer care continuum, from prevention to treatment. In this Review, we present the relevant history and emerging frontiers of cancer genetics and genomics from the perspective of global cancer prevention. We highlight the importance of local context in the adoption of new technologies and emergent evidence, with illustrative examples from worldwide. We emphasize the challenges in implementing important genomic findings in clinical settings with disparate resource availability and present a conceptual framework for the translation of such findings into clinical practice, and evidence-based policies in order to maximize the utility for a population.
Assuntos
Genômica/métodos , Neoplasias/genética , Neoplasias/prevenção & controle , Brasil , Análise Custo-Benefício , Efeito Fundador , Predisposição Genética para Doença , Genômica/economia , Mutação em Linhagem Germinativa , Humanos , Análise da Randomização Mendeliana , Mutação , Neoplasias/epidemiologia , Estados UnidosRESUMO
Mental illness is a substantive issue for graduate students. We investigated experiences of mental illness during training among genetic counseling students, a subgroup of graduate students for which little data exists on this topic. Genetic counseling students and recent graduates (n = 227) completed an online survey, from who 11 were selected to participate in semi-structured telephone interviews. Thematic analysis and member checking were employed to interpret the interviews. An overarching theme of importance to participants' mental health during genetic counseling training was safety, with subthemes of: trust/confidentiality, stigma and fear of labeling, developing a unique professional identity, and ability to engage in self care strategies. Our data could help genetic counseling training programs develop strategies to support students' mental health.
Assuntos
Aconselhamento Genético/psicologia , Transtornos Mentais/psicologia , Saúde Mental , Autoeficácia , Estudantes/psicologia , Adaptação Psicológica , Adulto , Confidencialidade , Feminino , Humanos , Masculino , Transtornos Mentais/diagnóstico , Pessoa de Meia-Idade , Estigma Social , Inquéritos e Questionários , Universidades , Adulto JovemRESUMO
Food restriction and deprivation are known to modulate drug-related behaviors. However, the mechanisms through which metabolic manipulations intercede the rewarding effects of drug reward are unknown. Neuropeptide Y (NPY) is thought to be critically involved in the regulation of energy balance. Central administration of NPY induces feeding in sated animals, and importantly, is reported to increase the rewarding properties of food. NPY has also been shown to be involved in drug-related behavior. We have recently demonstrated that NPY injections augmented on-going heroin self-administration and induced a reinstatement of heroin seeking. The present study sought to support and expand our previous finding on NPY's role in addictive drugs-related behaviors by examining the effects of NPY on cocaine-induced locomotor hyperactivity and cocaine self-administration. In Experiment 1, rats received NPY injections (0.0, 2.5, 5.0microg/rat, ICV), followed by cocaine administration (0.0, 1.0, 5.0, and 10.0mg/kg, IP) and their locomotor activity was monitored over 90min. In Experiment 2, rats were trained to self-administer cocaine (0.50mg/kg/infusion) during one 3-h session per day for 12 days. Once trained, NPY (0.0, 4.0, 10.0microg/rat, ICV) was administered 15min prior to the self-administration session. Results revealed that NPY injections augmented cocaine-induced hyperactivity and moderately increased cocaine self-administration. Together with our previous findings, these results suggest that NPY is involved, albeit to a limited extent, in the augmenting effect of food deprivation on drug-related behaviors.