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EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the interface between the fibrillin microfibril scaffold and the elastin core. How EMILIN1 contributes to connective tissue integrity is not fully understood. Here, we report bi-allelic EMILIN1 loss-of-function variants causative for an entity combining cutis laxa, arterial tortuosity, aneurysm formation, and bone fragility, resembling autosomal-recessive cutis laxa type 1B, due to EFEMP2 (FBLN4) deficiency. In both humans and mice, absence of EMILIN1 impairs EFEMP2 extracellular matrix deposition and LOX activity resulting in impaired elastogenesis, reduced collagen crosslinking, and aberrant growth factor signaling. Collagen fiber ultrastructure and histopathology in EMILIN1- or EFEMP2-deficient skin and aorta corroborate these findings and murine Emilin1-/- femora show abnormal trabecular bone formation and strength. Altogether, EMILIN1 connects elastic fiber network with collagen fibril formation, relevant for both bone and vascular tissue homeostasis.
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Enfermedades Óseas Metabólicas , Cutis Laxo , Animales , Humanos , Ratones , Colágeno/genética , Cutis Laxo/genética , Elastina/metabolismo , Proteínas de la Matriz Extracelular/metabolismoRESUMEN
BACKGROUND: Biallelic ZBTB11 variants have previously been associated with an ultrarare subtype of autosomal recessive intellectual developmental disorder (MRT69). OBJECTIVE: The aim was to provide insights into the clinical and genetic characteristics of ZBTB11-related disorders (ZBTB11-RD), with a particular emphasis on progressive complex movement abnormalities. METHODS: Thirteen new and 16 previously reported affected individuals, ranging in age from 2 to 50 years, with biallelic ZBTB11 variants underwent clinical and genetic characterization. RESULTS: All patients exhibited a range of neurodevelopmental phenotypes with varying severity, encompassing ocular and neurological features. Eleven new patients presented with complex abnormal movements, including ataxia, dystonia, myoclonus, stereotypies, and tremor, and 7 new patients exhibited cataracts. Deep brain stimulation was successful in treating 1 patient with generalized progressive dystonia. Our analysis revealed 13 novel variants. CONCLUSIONS: This study provides additional insights into the clinical features and spectrum of ZBTB11-RD, highlighting the progressive nature of movement abnormalities in the background of neurodevelopmental phenotype. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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OBJECTIVE: To develop consensus-based algorithms for genetic testing in patients with common craniofacial conditions. DESIGN: An online collaborative consisting of online meetings, independent work, and feedback across groups. Setting/Participants: A collaborative of genetics and pediatrics providers from three regional craniofacial centers (four institutions). METHODS: Collaborative participants agreed upon a shared initial framework, developed algorithms independently, and presented/tested the algorithms with a national audience. Algorithms were modified based on consensus feedback. RESULTS: The collaborative group developed final algorithms for genetic testing in patients with orofacial cleft, branchial arch conditions, and craniosynostosis. CONCLUSIONS: Timely and accurate diagnosis of genetic conditions can support medical management recommendations that result in safer surgical interventions. Algorithms can help guide best-practices for testing, particularly in institutions without easy access to genetics providers.
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We sought to understand how the coronavirus disease 2019 (COVID-19) pandemic has affected the well-being, clinical training, and medical education for clinical trainees in medical genetics and genomics residency and fellowship programs. All clinical genetics trainees in the Accreditation Council for Graduate Medical Education (ACGME)-accredited training programs were invited to complete a survey. 31 out of 174 trainees completed the survey. With regards to well-being, 18 trainees reported increased anxiety, 10 had increased depression, 3 increased financial strain, 13 worsening work-life balance, and 13 worsening physical health. There was increased telehealth utilization in both outpatient (3% before the pandemic vs. 67% during the pandemic) and inpatient clinical encounters (0% vs. 29%). The most commonly reported challenges in telehealth use were inadequate physical examination and technical problems during visits. Twenty trainees believed that the pandemic has negatively impacted overall clinical training while none reported a positive impact. We concluded that the COVID-19 pandemic has negatively impacted most clinical genetics trainees in ACGME-accredited training programs. Telehealth has been increasingly used with some challenges. Further studies are needed on how to optimally integrate what we have learned into the training of medical genetics and genomics in the post-pandemic era.
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COVID-19 , Genética Médica , Internado y Residencia , COVID-19/epidemiología , Becas , Genómica , Humanos , PandemiasRESUMEN
BACKGROUND: Ubiquitination has a central role in numerous biological processes, including cell development, stress responses and ageing. Perturbed ubiquitination has been implicated in human diseases ranging from cancer to neurodegenerative diseases. SIAH1 encodes a RING-type E3 ubiquitin ligase involved in protein ubiquitination. Among numerous other roles, SIAH1 regulates metabotropic glutamate receptor signalling and affects neural cell fate. Moreover, SIAH1 positively regulates Wnt signalling through ubiquitin-mediated degradation of Axin and accumulation of ß-catenin. METHODS: Trio exome sequencing followed by Sanger validation was undertaken in five individuals with syndromic developmental delay. Three-dimensional structural modelling was used to predict pathogenicity of affected residues. Wnt stimulatory activity was measured by luciferase reporter assays and Axin degradation assays in HEK293 cells transfected with wild-type and mutant SIAH1 expression plasmids. RESULTS: We report five unrelated individuals with shared features of developmental delay, infantile hypotonia, dysmorphic features and laryngomalacia, in whom exome sequencing identified de novo monoallelic variants in SIAH1. In silico protein modelling suggested alteration of conserved functional sites. In vitro experiments demonstrated loss of Wnt stimulatory activity with the SIAH1 mutants, suggesting variant pathogenicity. CONCLUSION: Our results lend support to SIAH1 as a candidate Mendelian disease gene for a recognisable syndrome, further strengthening the connection between SIAH1 and neurodevelopmental disorders. Furthermore, the results suggest that dysregulation of the Wnt/ß-catenin pathway may be involved in the pathogenesis.
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Discapacidades del Desarrollo/genética , Predisposición Genética a la Enfermedad , Hipotonía Muscular/genética , Proteínas Nucleares/genética , Ubiquitina-Proteína Ligasas/genética , Proteína Axina/genética , Niño , Preescolar , Discapacidades del Desarrollo/patología , Cara/anomalías , Cara/patología , Femenino , Células HEK293 , Humanos , Lactante , Masculino , Hipotonía Muscular/patología , Proteolisis , Vía de Señalización Wnt/genética , beta Catenina/genéticaRESUMEN
Teebi hypertelorism syndrome (THS; OMIM 145420) is a rare craniofacial disorder characterized by hypertelorism, prominent forehead, short nose with broad or depressed nasal root. Some cases of THS have been attributed to SPECC1L variants. Homozygous variants in CDH11 truncating the transmembrane and intracellular domains have been implicated in Elsahy-Waters syndrome (EWS; OMIM 211380) with hypertelorism. We report THS due to CDH11 heterozygous missense variants on 19 subjects from 9 families. All affected residues in the extracellular region of Cadherin-11 (CHD11) are highly conserved across vertebrate species and classical cadherins. Six of the variants that cluster around the EC2-EC3 and EC3-EC4 linker regions are predicted to affect Ca2+ binding that is required for cadherin stability. Two of the additional variants [c.164G > C, p.(Trp55Ser) and c.418G > A, p.(Glu140Lys)] are also notable as they are predicted to directly affect trans-homodimer formation. Immunohistochemical study demonstrates that CDH11 is strongly expressed in human facial mesenchyme. Using multiple functional assays, we show that five variants from the EC1, EC2-EC3 linker, and EC3 regions significantly reduced the cell-substrate trans adhesion activity and one variant from EC3-EC4 linker results in changes in cell morphology, focal adhesion, and migration, suggesting dominant negative effect. Characteristic features in this cohort included depressed nasal root, cardiac and umbilical defects. These features distinguished this phenotype from that seen in SPECC1L-related hypertelorism syndrome and CDH11-related EWS. Our results demonstrate heterozygous variants in CDH11, which decrease cell-cell adhesion and increase cell migratory behavior, cause a form of THS, as termed CDH11-related THS.
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Anomalías Múltiples/genética , Cadherinas/genética , Adhesión Celular/genética , Anomalías Craneofaciales/genética , Deformidades Congénitas del Pie/genética , Variación Genética/genética , Deformidades Congénitas de la Mano/genética , Hipertelorismo/genética , Secuencia de Aminoácidos , Movimiento Celular/genética , Femenino , Heterocigoto , Homocigoto , Humanos , Masculino , Linaje , FenotipoRESUMEN
Mercury (Hg) is a pollutant of concern across Canada and transboundary anthropogenic Hg sources presently account for over 95% of national anthropogenic Hg deposition. This study applies novel statistical analyses of 82 high-resolution dated lake sediment cores collected from 19 regions across Canada, including nearby point sources and in remote regions and spanning a full west-east geographical range of â¼4900 km (south of 60°N and between 132 and 64°W) to quantify the recent (1990-2018) spatial and temporal trends in anthropogenic atmospheric Hg deposition. Temporal trend analysis shows significant synchronous decreasing trends in post-1990 anthropogenic Hg fluxes in western Canada in contrast to increasing trends in the east, with spatial patterns largely driven by longitude and proximity to known point source(s). Recent sediment-derived Hg fluxes agreed well with the available wet deposition monitoring. Sediment-derived atmospheric Hg deposition rates also compared well to the modeled values derived from the Hg model, when lake sites located nearby (<100 km) point sources were omitted due to difficulties in comparison between the sediment-derived and modeled values at deposition "hot spots". This highlights the applicability of multi-core approaches to quantify spatio-temporal changes in Hg deposition over broad geographic ranges and assess the effectiveness of regional and global Hg emission reductions to address global Hg pollution concerns.
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Mercurio , Canadá , Monitoreo del Ambiente , Contaminación Ambiental , Sedimentos Geológicos , Lagos , Mercurio/análisisRESUMEN
A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.
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Proteínas de Unión al ADN/genética , Discapacidad Intelectual/genética , Trastornos Neurocognitivos/genética , Sistema Nervioso Central/anomalías , Sistema Nervioso Central/embriología , Codón sin Sentido/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Deformidades Congénitas de las Extremidades/genética , Disostosis Mandibulofacial/genética , Sistema Nervioso Periférico/anomalías , Sistema Nervioso Periférico/enzimologíaRESUMEN
Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by poikiloderma, small stature, sparse hair, skeletal abnormalities, increased risk of osteosarcoma, and decreased bone mass. To date, there has not been a comprehensive evaluation of the prevalence and extent of metabolic bone disease in RTS. Furthermore, the mechanisms that result in this phenotype are largely unknown. In this report, we provide a detailed evaluation of 29 individuals with RTS with respect to their metabolic bone status including bone mineral density, calcium kinetics studies, and markers of bone remodeling. We show that individuals with RTS have decreased areal bone mineral density. Additionally, we demonstrate that the presence of pathogenic variants in RECQL4 and low bone mineral density correlate with the history of increased risk of fractures. Using a RECQL4-deficient mouse model that recapitulates skeletal abnormalities seen in individuals with RTS, we demonstrate that generalized skeletal involvement is likely due to decreased osteogenesis. Our findings are clinically relevant as they may help in the risk stratification of patients with RTS and also in the identification of individuals who may benefit from additional surveillance and management of metabolic bone disease.
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Fracturas Óseas/metabolismo , Fracturas Óseas/patología , Síndrome Rothmund-Thomson/metabolismo , Síndrome Rothmund-Thomson/patología , Adulto , Animales , Densidad Ósea/fisiología , Remodelación Ósea/fisiología , Niño , Preescolar , Femenino , Humanos , Masculino , Ratones , Mutación , Osteogénesis/fisiología , RecQ Helicasas/genética , RecQ Helicasas/metabolismo , Factores de RiesgoRESUMEN
PURPOSE: Osteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI. METHODS: Using data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves. RESULTS: In children, the median z-scores for height in OI types I, III, and IV were -0.66, -6.91, and -2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was -4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P < 0.001), age, bisphosphonate use, and rodding (P < 0.05). CONCLUSION: From the largest cohort of individuals with OI, we provide median values for height, weight, and BMI z-scores that can aid the evaluation of overall growth in the clinic setting. This study is an important first step in the generation of OI-specific growth curves.
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Estatura/fisiología , Peso Corporal/fisiología , Osteogénesis Imperfecta/epidemiología , Adolescente , Adulto , Índice de Masa Corporal , Niño , Preescolar , Difosfonatos/uso terapéutico , Femenino , Humanos , Masculino , América del Norte , Osteogénesis Imperfecta/tratamiento farmacológico , Osteogénesis Imperfecta/fisiopatología , Pamidronato/uso terapéutico , Adulto JovenRESUMEN
Ethylmalonic encephalopathy (EE) is a rapidly progressive autosomal recessive mitochondrial disease caused by biallelic pathogenic variants in the ETHE1 gene that encodes the mitochondrial sulfur dioxygenase. It is characterized by neurodevelopmental delay and regression, pyramidal and extrapyramidal signs, recurrent petechiae, chronic diarrhea, and orthostatic acrocyanosis. Laboratory findings include elevated serum levels of lactate and C4-C5 acylcarnitines, and elevated urinary excretion of ethylmalonic acid and C4-C6 acylglycines, notably isobutyrylglycine and 2-methylbutyrylglycine. These findings are attributed to deficiency of the mitochondrial sulfur dioxygenase resulting in toxic accumulation of hydrogen sulfide metabolites in vascular endothelium and mucosal cells of the large intestine. Medical management has thus far been directed toward decreasing the accumulation of hydrogen sulfide metabolites using a combination of metronidazole and N-acetylcysteine. More recently, orthotopic liver transplant (OLT) has been reported as a new therapeutic option for EE. Here, we report two additional cases of EE who achieved psychomotor developmental improvement after 7- and 22-months following OLT. The second case serves as the longest developmental outcome follow-up reported, thus far, following OLT for EE. This report provides additional evidence to validate OLT as a promising therapeutic approach for what was considered to be a fatal disease.
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Encefalopatías Metabólicas Innatas/terapia , Trasplante de Hígado , Púrpura/terapia , Biomarcadores , Encefalopatías Metabólicas Innatas/diagnóstico , Encefalopatías Metabólicas Innatas/genética , Consanguinidad , Femenino , Humanos , Lactante , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/métodos , Imagen por Resonancia Magnética , Masculino , Proteínas Mitocondriales/genética , Mutación , Proteínas de Transporte Nucleocitoplasmático/genética , Fenotipo , Púrpura/diagnóstico , Púrpura/genética , Resultado del TratamientoRESUMEN
PURPOSE: Benzoate and phenylbutyrate are widely used in the treatment of urea cycle disorders, but detailed studies on pharmacokinetics and comparative efficacy on nitrogen excretion are lacking. METHODS: We conducted a randomized, three-arm, crossover trial in healthy volunteers to study pharmacokinetics and comparative efficacy of phenylbutyrate (NaPB; 7.15 gâ¢m-2BSAâ¢day-1), benzoate (NaBz; 5.5 gâ¢m-2BSAâ¢day-1), and a combination of two medications (MIX arm; 3.575 g NaPB and 2.75 g NaBzâ¢m-2BSAâ¢day-1) on nitrogen excretion. Stable isotopes were used to study effects on urea production and dietary nitrogen disposal. RESULTS: The conjugation efficacy for both phenylbutyrate and benzoate was 65%; conjugation was superior at the lower dose used in the MIX arm. Whereas NaPB and MIX treatments were more effective at excreting nitrogen than NaBz, nitrogen excretion as a drug conjugate was similar between phenylbutyrate and MIX arms. Nitrogen excreted per USD was higher with combination therapy compared with NaPB. CONCLUSION: Phenylbutyrate was more effective than benzoate at disposing nitrogen. Increasing phenylbutyrate dose may not result in higher nitrogen excretion due to decreased conjugation efficiency at higher doses. Combinatorial therapy with phenylbutyrate and benzoate has the potential to significantly decrease treatment cost without compromising the nitrogen disposal efficacy.
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Benzoatos/farmacocinética , Fenilbutiratos/farmacocinética , Trastornos Innatos del Ciclo de la Urea/tratamiento farmacológico , Adulto , Benzoatos/farmacología , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Nitrógeno/metabolismo , Fenilbutiratos/farmacología , Urea/metabolismoRESUMEN
Pulmonary complications are a significant cause for morbidity and mortality in osteogenesis imperfecta (OI). However, to date, there have been few studies that have systematically evaluated pulmonary function in individuals with OI. We analyzed spirometry measurements, including forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1 ), in a large cohort of individuals with OI (n = 217) enrolled in a multicenter, observational study. We show that individuals with the more severe form of the disease, OI type III, have significantly reduced FVC and FEV1 which do not follow the expected trends of the normal population. We also show that "normalization" of FVC and FEV1 using general population data to generate percent predicted values underestimates the pulmonary involvement in OI. Within each subtype of OI, we used linear mixed models to find potential correlations between FEV1 and FVC with the clinical variables including mobility, bisphosphonate use, and scoliosis. Our results are an important step in understanding the extent of pulmonary involvement in individuals with OI and for developing pulmonary endpoints for use in the routine patient care as well as in the investigation of new therapies.
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Pulmón/fisiopatología , Osteogénesis Imperfecta/fisiopatología , Adolescente , Adulto , Anciano , Niño , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Osteogénesis Imperfecta/diagnóstico , Pruebas de Función Respiratoria , Índice de Severidad de la Enfermedad , Espirometría , Capacidad Vital , Adulto JovenRESUMEN
Family history and physical exam findings are often the first clues that prompt medical providers to consider clinical genetics evaluation. There is standardized nomenclature for both the pedigree and description of physical features. Systematic evaluation of patients through obtaining family history and careful physical examination is essential to the formulation of a differential diagnosis and plan in the clinical genetics evaluation. The goal of this article is to provide an overview of family history and dysmorphology exam, and their relevance for the clinical genetics evaluation.
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Examen Físico , Humanos , Diagnóstico DiferencialRESUMEN
The diagnostic yield of exome sequencing (ES) has primarily been evaluated in individuals of European ancestry, with less focus on underrepresented minority (URM) and underserved (US) patients. We evaluated the diagnostic yield of ES in a cohort of predominantly US and URM pediatric and prenatal patients suspected to have a genetic disorder. Eligible pediatric patients had multiple congenital anomalies and/or neurocognitive disabilities and prenatal patients had one or more structural anomalies, disorders of fetal growth, or fetal effusions. URM and US patients were prioritized for enrollment and underwent ES at a single academic center. We identified definitive positive or probable positive results in 201/845 (23.8%) patients, with a significantly higher diagnostic rate in pediatric (26.7%) compared to prenatal patients (19.0%) (P = 0.01). For both pediatric and prenatal patients, the diagnostic yield and frequency of inconclusive findings did not differ significantly between URM and non-URM patients or between patients with US status and those without US status. Our results demonstrate a similar diagnostic yield of ES between prenatal and pediatric URM/US patients and non-URM/US patients for positive and inconclusive results. These data support the use of ES to identify clinically relevant variants in patients from diverse populations.
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Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that is often accompanied by stereotypical motor movements. Health professionals typically assess the severity of these behaviors during therapy, which limits observations to a structured clinical setting. Recent advancements in ubiquitous computing and wearable sensors enable an ability to monitor these motor movements objectively and in real-time while children with ASD are in different environments. In this paper, we present a smartwatch-based system designed to detect stereotypical motor movements. To validate the feasibility ofour approach, we collected data from adults imitating example behaviors captured in YouTube videos of children with ASD, and we then evaluated several classification methods for accuracy. The best model can identify stereotypical motor activities of hand flapping, head banging, and repetitive dropping with 92.6% accuracy (precision 88.8% and recall 87.7%) in the presence of confounding play-type activities. We present the trade-offs between accuracy ofthe assessments and power consumption due to sensing from multiple modalities. Cross-participant validation shows that the results ofusing the model on an unknown subject are promising.
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Trastorno del Espectro Autista/fisiopatología , Aplicaciones Móviles , Monitoreo Ambulatorio/métodos , Trastorno de Movimiento Estereotipado/fisiopatología , Adulto , Trastorno del Espectro Autista/psicología , Niño , Estudios de Factibilidad , Humanos , Monitoreo Ambulatorio/instrumentaciónRESUMEN
Whereas isolated sphenoid wing dysplasia (SWD) is a well-known clinical feature in neurofibromatosis 1 (NF1), extensive cranial defects involving multiple bones have been rarely reported in this disorder. In this report, we describe the clinical course of a 20-year-old male with NF1 and an extensive cranial bone dysplasia. The large sphenoethmoidal defect was associated with transethmoidal and orbital cephalocele as well as inferolateral herniation of the frontal lobe. In spite of the large defect, the individual did not have any symptoms or complications resulting from the osteopathy. We review the current knowledge of the pathogenesis and management of cranial bone dysplasia in NF1.
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Enfermedades del Desarrollo Óseo , Hueso Etmoides/patología , Neurofibromatosis 1/patología , Hueso Esfenoides/patología , Adulto , Enfermedades del Desarrollo Óseo/diagnóstico por imagen , Encefalocele/diagnóstico por imagen , Hueso Etmoides/diagnóstico por imagen , Lóbulo Frontal , Humanos , Masculino , Neurofibromatosis 1/diagnóstico por imagen , Neuroimagen , Órbita , Hueso Esfenoides/diagnóstico por imagen , Adulto JovenRESUMEN
As a powerful regulator of cellular homeostasis and metabolism, adenosine is involved in diverse neurological processes including pain, cognition, and memory. Altered adenosine homeostasis has also been associated with several diseases such as depression, schizophrenia, or epilepsy. Based on its protective properties, adenosine has been considered as a potential therapeutic agent for various brain disorders. Since systemic application of adenosine is hampered by serious side effects such as vasodilatation and cardiac suppression, recent studies aim at improving local delivery by depots, pumps, or cell-based applications. Here, we report on the characterization of adenosine-releasing human embryonic stem cell-derived neuroepithelial stem cells (long-term self-renewing neuroepithelial stem [lt-NES] cells) generated by zinc finger nuclease (ZFN)-mediated knockout of the adenosine kinase (ADK) gene. ADK-deficient lt-NES cells and their differentiated neuronal and astroglial progeny exhibit substantially elevated release of adenosine compared to control cells. Importantly, extensive adenosine release could be triggered by excitation of differentiated neuronal cultures, suggesting a potential activity-dependent regulation of adenosine supply. Thus, ZFN-modified neural stem cells might serve as a useful vehicle for the activity-dependent local therapeutic delivery of adenosine into the central nervous system. Stem Cells Translational Medicine 2018;7:477-486.