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1.
Am J Med Genet A ; 185(4): 1251-1255, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33442921

RESUMEN

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant genetic syndrome characterized by distinct facial features, broad thumbs, growth restriction, microcephaly, intellectual disability, and developmental delay. Pathogenic variants in both CREBBP and EP300 have been associated with RSTS. Here we present a case of a female with hyperinsulinism and features consistent with RSTS, found to have a pathogenic variant in EP300. While there have been a few rare case reports of hyperinsulinism in RSTS, we suggest that hyperinsulinism might be a more prominent feature in EP300 variant RSTS than previously recognized.


Asunto(s)
Proteína p300 Asociada a E1A/genética , Predisposición Genética a la Enfermedad , Hiperinsulinismo/genética , Síndrome de Rubinstein-Taybi/genética , Femenino , Variación Genética/genética , Genotipo , Humanos , Hiperinsulinismo/patología , Lactante , Recién Nacido , Mutación/genética , Fenotipo , Síndrome de Rubinstein-Taybi/patología , Eliminación de Secuencia/genética
2.
Crit Rev Biochem Mol Biol ; 46(3): 200-15, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21599535

RESUMEN

The increasing prevalence of overnutrition and reduced activity has led to a worldwide epidemic of obesity. In many cases, this is associated with insulin resistance, an inability of the hormone to direct its physiological actions appropriately. A number of disease states accompany insulin resistance such as type 2 diabetes mellitus, the metabolic syndrome, and non-alcoholic fatty liver disease. Though the pathways by which insulin controls hepatic glucose output have been of intense study in recent years, considerably less attention has been devoted to how lipid metabolism is regulated. Thus, both the proximal signaling pathways as well as the more distal targets of insulin remain uncertain. In this review, we consider the signaling pathways by which insulin controls the synthesis and accumulation of lipids in the mammalian liver and, in particular, how this might lead to abnormal triglyceride deposition in liver during insulin-resistant states.


Asunto(s)
Glucosa/metabolismo , Insulina/química , Insulina/metabolismo , Metabolismo de los Lípidos , Hígado/metabolismo , Hígado/patología , Transducción de Señal , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Dislipidemias/metabolismo , Hígado Graso/epidemiología , Hígado Graso/metabolismo , Hígado Graso/fisiopatología , Glucosa/química , Humanos , Resistencia a la Insulina , Lípidos/biosíntesis , Lípidos/química , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Proteína Oncogénica v-akt/química , Proteína Oncogénica v-akt/metabolismo , Receptor de Insulina/química , Receptor de Insulina/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/química , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Factores de Transcripción/química , Factores de Transcripción/metabolismo , Triglicéridos/metabolismo
3.
JCEM Case Rep ; 1(2): luad029, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37908465

RESUMEN

Misinterpretation of common endocrine hormonal immunoassays can distort the clinical picture and lead to unnecessary medical workups. Potential assay inference is important to recognize when the clinical presentation and laboratory evaluation are inconsistent. This is demonstrated by the case of an 18-month-old girl who initially presented with ketotic hypoglycemia and was found on diagnostic fasting evaluation to have the triad of hypoglycemia, inappropriately high insulin levels, and low C-peptide levels-point-of-care glucose 43 mg/dL (2.39 mmol/L) (confirmatory 52 mg/dL [2.89 mmol/L]), insulin 48.1 µIU/mL (334 pmol/L), and C-peptide 0.2 ng/mL (0.07 nmol/L) concerning for factitious insulin (insulin:C-peptide ratio 4.77). On repeat diagnostic fast, insulin assays measured by liquid chromatography-mass spectrometry were incongruent with prior testing by immunoassay, demonstrating a falsely elevated insulin level when measured by immunoassay, likely due to human antimouse antibody interference (HAMA 181 ng/mL). This case represents a diagnostic challenge in which is it imperative to recognize possible immunoassay interference. It is critical to establish the difference between insulin assay interference and factitious insulin through use of alternative laboratory methods as misdiagnosis could lead to the serious implication of Munchausen by proxy resulting in the removal of a child from their home and potentially parents being charged with a crime.

4.
Mol Metab ; 66: 101610, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36209784

RESUMEN

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic insulin-producing ß cells are specifically destroyed by the immune system. Understanding the initiation and progression of human T1D has been hampered by the lack of appropriate models that can reproduce the complexity and heterogeneity of the disease. The development of platforms combining multiple human pluripotent stem cell (hPSC) derived tissues to model distinct aspects of T1D has the potential to provide critical novel insights into the etiology and pathogenesis of the human disease. SCOPE OF REVIEW: In this review, we summarize the state of hPSC differentiation approaches to generate cell types and tissues relevant to T1D, with a particular focus on pancreatic islet cells, T cells, and thymic epithelium. We present current applications as well as limitations of using these hPSC-derived cells for disease modeling and discuss efforts to optimize platforms combining multiple cell types to model human T1D. Finally, we outline remaining challenges and emphasize future improvements needed to accelerate progress in this emerging field of research. MAJOR CONCLUSIONS: Recent advances in reprogramming approaches to create patient-specific induced pluripotent stem cell lines (iPSCs), genome engineering technologies to efficiently modify DNA of hPSCs, and protocols to direct their differentiation into mature cell types have empowered the use of stem cell derivatives to accurately model human disease. While challenges remain before complex interactions occurring in human T1D can be modeled with these derivatives, experiments combining hPSC-derived ß cells and immune cells are already providing exciting insight into how these cells interact in the context of T1D, supporting the viability of this approach.


Asunto(s)
Diabetes Mellitus Tipo 1 , Células Madre Pluripotentes Inducidas , Células Secretoras de Insulina , Células Madre Pluripotentes , Humanos , Diabetes Mellitus Tipo 1/metabolismo , Células Madre Pluripotentes/metabolismo , Células Secretoras de Insulina/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Diferenciación Celular
5.
Diabetes Res Clin Pract ; 186: 109828, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35301072

RESUMEN

AIMS: Friedreich's Ataxia (FRDA) is a progressive neuromuscular disorder typically caused by GAA triplet repeat expansions in both frataxin gene alleles. FRDA can be complicated by diabetes mellitus (DM). The objective of this study was to describe the prevalence of, risk factors for, and management practices of FRDA-related DM. METHODS: FACOMS, a prospective, multi-site natural history study, includes 1,104 individuals. Extracted data included the presence of DM and other co-morbidities, genetic diagnosis, and markers of disease severity. We performed detailed medical record review and a survey for the subset of individuals with FRDA-related DM followed at one FACOMS site, Children's Hospital of Philadelphia. RESULTS: FRDA-related DM was reported by 8.7% of individuals. Age, severe disease, and FRDA cardiac complications were positively associated with DM risk. FRDA-related DM was generally well-controlled, as reflected by HbA1c, though diabetic ketoacidosis did occur. Insulin is the mainstay of treatment (64-74% overall); in adults, metformin use was common and newer glucose-lowering agents were used rarely. CONCLUSIONS: Clinical factors identify individuals at increased risk for FRDA-related DM. Future studies should test strategies for FRDA-related DM screening and management, in particular the potential role for novel glucose-lowering therapies in preventing or delaying FRDA-related cardiac disease.


Asunto(s)
Diabetes Mellitus , Ataxia de Friedreich , Adulto , Niño , Diabetes Mellitus/epidemiología , Diabetes Mellitus/genética , Cetoacidosis Diabética/complicaciones , Ataxia de Friedreich/complicaciones , Ataxia de Friedreich/epidemiología , Glucosa , Humanos , Proteínas de Unión a Hierro/genética , Estudios Prospectivos , Factores de Riesgo , Expansión de Repetición de Trinucleótido
6.
Front Endocrinol (Lausanne) ; 12: 682625, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34149620

RESUMEN

A mechanistic understanding of the genetic basis of complex diseases such as diabetes mellitus remain elusive due in large part to the activity of genetic disease modifiers that impact the penetrance and/or presentation of disease phenotypes. In the face of such complexity, rare forms of diabetes that result from single-gene mutations (monogenic diabetes) can be used to model the contribution of individual genetic factors to pancreatic ß-cell dysfunction and the breakdown of glucose homeostasis. Here we review the contribution of protein coding and non-protein coding genetic disease modifiers to the pathogenesis of diabetes subtypes, as well as how recent technological advances in the generation, differentiation, and genome editing of human pluripotent stem cells (hPSC) enable the development of cell-based disease models. Finally, we describe a disease modifier discovery platform that utilizes these technologies to identify novel genetic modifiers using induced pluripotent stem cells (iPSC) derived from patients with monogenic diabetes caused by heterozygous mutations.


Asunto(s)
Diabetes Mellitus/genética , Edición Génica , Células Secretoras de Insulina , Células Madre Pluripotentes , Animales , Estudio de Asociación del Genoma Completo , Humanos
7.
Stem Cell Res ; 50: 102112, 2020 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-33316598

RESUMEN

Remarkable strides have been made over the past decade on the development of pancreatic ß-cells from human stem cells through directed differentiation, allowing for modeling of ß-cell development, function and disease. However, in vitro models and future therapeutic applications will require the use of stem cell-derived islets with multiple monohormonal endocrine cells types, including α, ß, and δ cells. Using the previously reported Mel1 InsGFP/w human embryonic stem cell (hESC) line, we have knocked-in Red Fluorescence Protein (RFP) under the control of the endogenous somatostatin promoter using CRISPR/Cas9, generating a dual insulin and somatostatin reporter hESC line.

8.
Endocrinology ; 161(2)2020 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-31960055

RESUMEN

Human in vitro model systems of diabetes are critical to both study disease pathophysiology and offer a platform for drug testing. We have generated a set of tools in the human ß-cell line EndoC-ßH1 that allows the efficient and inexpensive characterization of ß-cell physiology and phenotypes driven by disruption of candidate genes. First, we generated a dual reporter line that expresses a preproinsulin-luciferase fusion protein along with GCaMP6s. This reporter line allows the quantification of insulin secretion by measuring luciferase activity and calcium flux, a critical signaling step required for insulin secretion, via fluorescence microscopy. Using these tools, we demonstrate that the generation of the reporter human ß-cell line was highly efficient and validated that luciferase activity could accurately reflect insulin secretion. Second, we used a lentiviral vector carrying the CRISPR-Cas9 system to generate candidate gene disruptions in the reporter line. We also show that we can achieve gene disruption in ~90% of cells using a CRISPR-Cas9 lentiviral system. As a proof of principle, we disrupt the ß-cell master regulator, PDX1, and show that mutant EndoC-ßH1 cells display impaired calcium responses and fail to secrete insulin when stimulated with high glucose. Furthermore, we show that PDX1 mutant EndoC-ßH1 cells exhibit decreased expression of the ß-cell-specific genes MAFA and NKX6.1 and increased GCG expression. The system presented here provides a platform to quickly and easily test ß-cell functionality in wildtype and cells lacking a gene of interest.


Asunto(s)
Señalización del Calcio , Línea Celular , Genes Reporteros , Secreción de Insulina , Células Secretoras de Insulina , Sistemas CRISPR-Cas , Regulación hacia Abajo , Técnicas de Inactivación de Genes , Proteínas de Homeodominio/genética , Humanos , Transactivadores/genética
9.
JCI Insight ; 4(21)2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31672937

RESUMEN

Islet transplantation is an effective therapy for achieving and maintaining normoglycemia in patients with type 1 diabetes mellitus. However, the supply of transplantable human islets is limited. Upon removal from the pancreas, islets rapidly disintegrate and lose function, resulting in a short interval for studies of islet biology and pretransplantation assessment. Here, we developed a biomimetic platform that can sustain human islet physiology for a prolonged period ex vivo. Our approach involved the creation of a multichannel perifusion system to monitor dynamic insulin secretion and intracellular calcium flux simultaneously, enabling the systematic evaluation of glucose-stimulated insulin secretion under multiple conditions. Using this tool, we developed a nanofibrillar cellulose hydrogel-based islet-preserving platform (iPreP) that can preserve islet viability, morphology, and function for nearly 12 weeks ex vivo, and with the ability to ameliorate glucose levels upon transplantation into diabetic hosts. Our platform has potential applications in the prolonged maintenance of human islets, providing an expanded time window for pretransplantation assessment and islet studies.


Asunto(s)
Celulosa/química , Hidrogeles/química , Islotes Pancreáticos , Nanofibras/química , Preservación Biológica/métodos , Adolescente , Adulto , Femenino , Humanos , Técnicas In Vitro , Trasplante de Islotes Pancreáticos/métodos , Masculino , Persona de Mediana Edad
10.
Cell Stem Cell ; 25(2): 273-289.e5, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31374199

RESUMEN

Human monogenic diabetes, caused by mutations in genes involved in beta cell development and function, has been a challenge to study because multiple mouse models have not fully recapitulated the human disease. Here, we use genome edited human embryonic stem cells to understand the most common form of monogenic diabetes, MODY3, caused by mutations in the transcription factor HNF1A. We found that HNF1A is necessary to repress an alpha cell gene expression signature, maintain endocrine cell function, and regulate cellular metabolism. In addition, we identified the human-specific long non-coding RNA, LINKA, as an HNF1A target necessary for normal mitochondrial respiration. These findings provide a possible explanation for the species difference in disease phenotypes observed with HNF1A mutations and offer mechanistic insights into how the HNF1A gene may also influence type 2 diabetes.


Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Células Madre Embrionarias Humanas/fisiología , Páncreas/patología , Respiración de la Célula , Células Cultivadas , Diabetes Mellitus Tipo 2/patología , Regulación de la Expresión Génica , Factor Nuclear 1-alfa del Hepatocito/genética , Humanos , Proteínas de la Leche , Mutación/genética , Páncreas/fisiología , Fenotipo , ARN Largo no Codificante/genética
11.
Cell Metab ; 18(1): 99-105, 2013 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-23823480

RESUMEN

Insulin rapidly suppresses hepatic glucose production and slowly decreases expression of genes encoding gluconeogenic proteins. In this study, we show that an immediate effect of insulin is to redirect newly synthesized glucose-6-phosphate to glycogen without changing the rate of gluconeogenesis. This process requires hepatic Akt2, as revealed by blunted insulin-mediated suppression of glycogenolysis in the perfused mouse liver, elevated hepatic glucose production during a euglycemic-hyperinsulinemic clamp, or diminished glycogen accumulation during clamp or refeeding in mice without hepatic Akt2. Surprisingly, the absence of Akt2 disrupted glycogen metabolism independent of GSK3α and GSK3ß phosphorylation, which is thought to be an essential step in the pathway by which insulin regulates glycogen synthesis through Akt. These data show that (1) the immediate action of insulin to suppress hepatic glucose production functions via an Akt2-dependent redirection of glucose-6-phosphate to glycogen, and (2) insulin increases glucose phosphorylation and conversion to glycogen independent of GSK3.


Asunto(s)
Glucógeno Sintasa Quinasa 3/fisiología , Glucógeno/metabolismo , Glucogenólisis/fisiología , Hígado/metabolismo , Periodo Posprandial/fisiología , Transducción de Señal/fisiología , Animales , Modelos Animales de Enfermedad , Técnica de Clampeo de la Glucosa , Glucosa-6-Fosfato/metabolismo , Hiperinsulinismo/metabolismo , Hiperinsulinismo/fisiopatología , Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Proto-Oncogénicas c-akt/deficiencia , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo
12.
Nat Med ; 18(3): 388-95, 2012 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-22344295

RESUMEN

Considerable data support the idea that forkhead box O1 (Foxo1) drives the liver transcriptional program during fasting and is then inhibited by thymoma viral proto-oncogene 1 (Akt) after feeding. Here we show that mice with hepatic deletion of Akt1 and Akt2 were glucose intolerant, insulin resistant and defective in their transcriptional response to feeding in the liver. These defects were normalized with concomitant liver-specific deletion of Foxo1. Notably, in the absence of both Akt and Foxo1, mice adapted appropriately to both the fasted and fed state, and insulin suppressed hepatic glucose production normally. A gene expression analysis revealed that deletion of Akt in liver led to the constitutive activation of Foxo1-dependent gene expression, but again, concomitant ablation of Foxo1 restored postprandial regulation, preventing the inhibition of the metabolic response to nutrient intake caused by deletion of Akt. These results are inconsistent with the canonical model of hepatic metabolism in which Akt is an obligate intermediate for proper insulin signaling. Rather, they show that a major role of hepatic Akt is to restrain the activity of Foxo1 and that in the absence of Foxo1, Akt is largely dispensable for insulin- and nutrient-mediated hepatic metabolic regulation in vivo.


Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Insulina/metabolismo , Hígado/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Células Cultivadas , Ingestión de Alimentos , Ayuno/metabolismo , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica , Intolerancia a la Glucosa/metabolismo , Hepatocitos/citología , Hepatocitos/metabolismo , Insulina/genética , Resistencia a la Insulina/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal
13.
Cell Metab ; 14(4): 516-27, 2011 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-21982711

RESUMEN

Under conditions of obesity and insulin resistance, the serine/threonine protein kinase Akt/PKB is required for lipid accumulation in liver. Two forkhead transcription factors, FoxA2 and FoxO1, have been suggested to function downstream of and to be negatively regulated by Akt and are proposed as key determinants of hepatic triglyceride content. In this study, we utilize genetic loss of function experiments to show that constitutive activation of neither FoxA2 nor FoxO1 can account for the protection from steatosis afforded by deletion of Akt2 in liver. Rather, another downstream target positively regulated by Akt, the mTORC1 complex, is required in vivo for de novo lipogenesis and Srebp1c expression. Nonetheless, activation of mTORC1 and SREBP1c is not sufficient to drive postprandial lipogenesis in the absence of Akt2. These data show that insulin signaling through Akt2 promotes anabolic lipid metabolism independent of Foxa2 or FoxO1 and through pathways additional to the mTORC1-dependent activation of SREBP1c.


Asunto(s)
Metabolismo de los Lípidos/fisiología , Hígado/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismo , Animales , Antirreumáticos/farmacología , Aurotioglucosa/farmacología , Dieta Alta en Grasa , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/deficiencia , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Factor Nuclear 3-beta del Hepatocito/metabolismo , Insulina/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Ratones Noqueados , Complejos Multiproteicos , Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-akt/deficiencia , Proteínas Proto-Oncogénicas c-akt/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Serina-Treonina Quinasas TOR , Triglicéridos/metabolismo
14.
Cell Metab ; 10(5): 405-18, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19883618

RESUMEN

Insulin drives the global anabolic response to nutrient ingestion, regulating both carbohydrate and lipid metabolism. Previous studies have demonstrated that Akt2/protein kinase B is critical to insulin's control of glucose metabolism, but its role in lipid metabolism has remained controversial. Here, we show that Akt2 is required for hepatic lipid accumulation in obese, insulin-resistant states induced by either leptin deficiency or high-fat diet feeding. Lep(ob/ob) mice lacking hepatic Akt2 failed to amass triglycerides in their livers, associated with and most likely due to a decrease in lipogenic gene expression and de novo lipogenesis. However, Akt2 is also required for steatotic pathways unrelated to fatty acid synthesis, as mice fed high-fat diet had reduced liver triglycerides in the absence of hepatic Akt2 but did not exhibit changes in lipogenesis. These data demonstrate that Akt2 is a requisite component of the insulin-dependent regulation of lipid metabolism during insulin resistance.


Asunto(s)
Resistencia a la Insulina/fisiología , Leptina/metabolismo , Metabolismo de los Lípidos/fisiología , Hígado/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Grasas de la Dieta/administración & dosificación , Leptina/antagonistas & inhibidores , Leptina/genética , Ratones , Ratones Noqueados , Ratones Obesos , Obesidad/etiología , Obesidad/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Triglicéridos/metabolismo
15.
Exp Cell Res ; 292(1): 78-88, 2004 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-14720508

RESUMEN

Members of the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) family are transmembrane proteins that are essential for the function of intracellular Ca(2+) storage organelles. We found that overexpression of avian muscle SERCA1a in transfected mouse fibroblasts led to the appearance of tubular membrane bundles that we termed plaques. These structures were generated in transfected cells when SERCA1a protein expression approached the endogenous level measured in chicken skeletal muscle. Plaque membranes had associated ribosomes and contained endoplasmic reticulum (ER) proteins. Endogenous ER protein levels were not elevated in SERCA1a-expressing cells, indicating that plaques were not generalized proliferations of ER but rather a reorganization of existing organelle membrane. Plaque formation also was observed in cells expressing a green fluorescent protein-SERCA1a fusion protein (GFP-SERCA1a). GFP-SERCA1a molecules displayed extensive lateral mobility between plaques, suggesting the presence of membrane continuities between these structures. Plaques were induced in cells expressing cDNA encoding a catalytically silent SERCA1a mutant indicating that ER redistribution was driven by a structural feature of the enzyme. SERCA1a-induced plaque formation shares some characteristics of sarcoplasmic reticulum (SR) biogenesis during muscle differentiation, and high-level SERCA1a expression in vivo may contribute to the formation of SR from ER during embryonic myogenesis.


Asunto(s)
ATPasas Transportadoras de Calcio/metabolismo , Retículo Endoplásmico/metabolismo , Fibroblastos/metabolismo , Membranas Intracelulares/metabolismo , Músculo Esquelético/enzimología , Retículo Sarcoplasmático/enzimología , Animales , Calcio/metabolismo , ATPasas Transportadoras de Calcio/genética , Línea Celular , Embrión de Pollo , Citosol/química , Fibroblastos/ultraestructura , Proteínas Fluorescentes Verdes , Membranas Intracelulares/ultraestructura , Proteínas Luminiscentes/metabolismo , Ratones , Mutación , Orgánulos/metabolismo , Orgánulos/ultraestructura , Proteínas Recombinantes de Fusión/metabolismo , Transfección
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