RESUMEN
The MBTPS2 gene on the X-chromosome encodes the membrane-bound transcription factor protease, site-2 (MBTPS2) or site-2 protease (S2P) which cleaves and activates several signaling and regulatory proteins from the membrane. The MBTPS2 is critical for a myriad of cellular processes, ranging from the regulation of cholesterol homeostasis to unfolded protein responses. While its functional role has become much clearer in the recent years, how mutations in the MBTPS2 gene lead to several human disorders with different phenotypes including Ichthyosis Follicularis, Atrichia and Photophobia syndrome (IFAP) with or without BRESHECK syndrome, Keratosis Follicularis Spinulosa Decalvans (KFSD), Olmsted syndrome, and Osteogenesis Imperfecta type XIX remains obscure. This review presents the biological role of MBTPS2 in development, summarizes its mutations and implicated disorders, and discusses outstanding unanswered questions.
Asunto(s)
Metaloendopeptidasas , Factores de Transcripción , Humanos , Metaloendopeptidasas/genética , Mutación Missense , Linaje , Péptido HidrolasasRESUMEN
Pathogenic BAG5 variants recently linked to dilated cardiomyopathy (DCM) prompt further investigation into phenotypic, mutational, and pathomechanistic aspects. We explored the clinical and molecular characteristics of DCM associated with BAG5 variants, uncovering the consistently severe manifestations of the disease and its impact on the endoplasmic reticulum (ER) stress response. The analysis involved three siblings affected by DCM and arrhythmia, along with their four unaffected siblings, their unaffected father, and their mother who exhibited arrhythmia. The parents were consanguineous. Exome and Sanger sequencing identified a novel BAG5 variant, c.444_445delGA (p.Lys149AsnfsTer6), homozygous in affected siblings and heterozygous in parents and unaffected siblings. We generated heterozygous and homozygous Bag5 point mutant knock-in (KI) mice and evaluated cardiac pathophysiology under stress conditions, including tunicamycin (TN) administration. Bag5-/- mice displayed no abnormalities up to 12 months old and showed no anomalies during an exercise stress test. However, following TN injection, Bag5-/- mice exhibited significantly reduced left ventricular fractional shortening (LVFS) and ejection fraction (LVEF). Their cardiac tissues exhibited a notable increase in apoptotic cells, despite non-distinctive changes in CHOP and GRP78 levels. Interestingly, only Bag5 KI male mice demonstrated arrhythmia, which was more pronounced in Bag5-/- than in Bag5+/-males. Here, our study reveals a novel BAG5 mutation causing DCM by impairing the ER stress response, with observed sex-specific arrhythmia differences.
Asunto(s)
Arritmias Cardíacas , Cardiomiopatía Dilatada , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico , Animales , Cardiomiopatía Dilatada/genética , Estrés del Retículo Endoplásmico/genética , Humanos , Arritmias Cardíacas/genética , Masculino , Femenino , Ratones , Linaje , Ratones Noqueados , Adulto , Apoptosis/genética , MutaciónRESUMEN
Mutations in KCNQ2 encoding for voltage-gated K channel subunits underlying the neuronal M-current have been associated with infantile-onset epileptic disorders. The clinical spectrum ranges from self-limited neonatal seizures to epileptic encephalopathy and delayed development. Mutations in KCNQ2 could be either gain- or loss-of-function which require different therapeutic approaches. To better understand genotype-phenotype correlation, more reports of patients and their mutations with elucidated molecular mechanism are needed. We studied 104 patients with infantile-onset pharmacoresistant epilepsy who underwent exome or genome sequencing. Nine patients with neonatal-onset seizures from unrelated families were found to harbor pathogenic or likely pathogenic variants in the KCNQ2 gene. The p.(N258K) was recently reported, and p. (G279D) has never been previously reported. Functional effect of p.(N258K) and p.(G279D) has never been previously studied. The cellular localization study demonstrated that the surface membrane expression of Kv7.2 carrying either variant was decreased. Whole-cell patch-clamp analyses revealed that both variants significantly impaired Kv7.2 M-current amplitude and density, conductance depolarizing shift in voltage dependence of activation, membrane resistance, and membrane time constant (Tau), indicating a loss-of-function in both the homotetrameric and heterotetrameric with Kv7.3 channels. In addition, both variants exerted dominant-negative effects in heterotetrameric with Kv7.3 channels. This study expands the mutational spectrum of KCNQ2- related epilepsy and their functional consequences provide insights into their pathomechanism.
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Epilepsia Generalizada , Epilepsia , Enfermedades del Recién Nacido , Recién Nacido , Humanos , Epilepsia/genética , Mutación Missense , Mutación , Convulsiones/genética , Canal de Potasio KCNQ2/genéticaRESUMEN
Pathogenic variants in SMARCA4 cause Coffin-Siris syndrome (CSS) while those in SMAD6 lead to aortic valve disease and other dysmorphisms. We identified a 6-year-old Thai boy with features of CSS alongside unusual manifestations including, very severe coarctation of the aorta (CoA) requiring coarctectomy in the neonatal period and bilateral radioulnar synostoses. Trio exome sequencing revealed that the patient harbored two de novo variants, a missense c.2475G > T, p.(Trp825Cys) in SMARCA4 and a nonsense c.652C > T, p.(Gln218Ter) in SMAD6. Both of which have never been previously reported. The clinical presentations in our patient are a result of the combinational features of each genetic variant: the SMARCA4 p.(Trp825Cys) variant leads to facial features of Coffin Siris syndrome and Dandy-Walker malformation, while the SMAD6 p.(Gln218Ter) variant underlies radioulnar synostosis. Interestingly, the severity of CoA in the proband is beyond the phenotypic spectra of each genetic variant and may be a result of the synergistic effects of both variants. Here, we report a child with variants in SMARCA4 or SMAD6 with combined features of each plus a severe CoA, possibly due to an additive effect of each variant.
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Anomalías Múltiples , Coartación Aórtica , Deformidades Congénitas de la Mano , Discapacidad Intelectual , Micrognatismo , Niño , Humanos , Recién Nacido , Masculino , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Coartación Aórtica/genética , ADN Helicasas , Cara/anomalías , Deformidades Congénitas de la Mano/genética , Deformidades Congénitas de la Mano/patología , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Micrognatismo/genética , Micrognatismo/patología , Cuello/anomalías , Proteínas Nucleares/genética , Radio (Anatomía)/anomalías , Proteína smad6 , Sinostosis , Factores de Transcripción/genética , Cúbito/anomalíasRESUMEN
The ability of propionate, a short-chain fatty acid produced from the fermentation of non-digestible carbohydrates in the colon, to stimulate the release of anorectic gut hormones, such as glucagon like peptide-1 (GLP-1), is an attractive approach to enhance appetite regulation, weight management, and glycemic control. Propionate induces GLP-1 release via its G protein-coupled receptor (GPCR), free fatty acid receptor 2 (FFA2), a GPCR that activates Gαi and Gαq/11. However, how pleiotropic GPCR signaling mechanisms in the gut regulates appetite is poorly understood. Here, we identify propionate-mediated G protein signaling is spatially directed within the cell whereby FFA2 is targeted to very early endosomes. Furthermore, propionate activates a Gαi/p38 signaling pathway, which requires receptor internalization and is essential for propionate-induced GLP-1 release in enteroendocrine cells and colonic crypts. Our study reveals that intestinal metabolites engage membrane trafficking pathways and that receptor internalization could orchestrate complex GPCR pathways within the gut.
RESUMEN
Agonist-induced phosphorylation of G protein-coupled receptors (GPCRs) is a key determinant for their interaction with ß-arrestins (ßarrs) and subsequent functional responses. Therefore, it is important to decipher the contribution and interplay of different receptor phosphorylation sites in governing ßarr interaction and functional outcomes. Here, we find that several phosphorylation sites in the human vasopressin receptor (V2R), positioned either individually or in clusters, differentially contribute to ßarr recruitment, trafficking, and ERK1/2 activation. Even a single phosphorylation site in V2R, suitably positioned to cross-talk with a key residue in ßarrs, has a decisive contribution in ßarr recruitment, and its mutation results in strong G-protein bias. Molecular dynamics simulation provides mechanistic insights into the pivotal role of this key phosphorylation site in governing the stability of ßarr interaction and regulating the interdomain rotation in ßarrs. Our findings uncover important structural aspects to better understand the framework of GPCR-ßarr interaction and biased signaling.
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The pivotal and diverse roles G protein-coupled receptors (GPCRs) play in physiology are matched by the increasingly complex signal systems they activate. Over the past decade, our models of GPCR signaling systems also include a vital role of location in controlling GPCR signaling, whereby plasma membrane, clathrin-associated structures and a diverse endomembrane network provide highly specialized signal platforms for this superfamily of receptors. The aim of this review is to highlight the recent developments in this fast-evolving field, with particular emphasis on endocrine-relevant GPCRs. We will also highlight studies that address the possibility of therapeutic intervention and how this fundamental cell biology can be translated to physiology/pathophysiology and therapeutic interventions.
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Sistema Endocrino/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Animales , Proteínas Portadoras/metabolismo , Membrana Celular/metabolismo , Clatrina/metabolismo , Endosomas/metabolismo , Hormonas/metabolismo , Humanos , Transducción de Señal/efectos de los fármacosAsunto(s)
Ictiosis , Mutación Missense , Humanos , Ictiosis/genética , Alopecia/genética , Síndrome , Metaloendopeptidasas/genéticaRESUMEN
Brown adipose tissue (BAT) activation stimulates energy expenditure in human adults, which makes it an attractive target to combat obesity and related disorders. Recent studies demonstrated a role for G protein-coupled receptor 120 (GPR120) in BAT thermogenesis. Here, we investigated the therapeutic potential of GPR120 agonism and addressed GPR120-mediated signaling in BAT We found that activation of GPR120 by the selective agonist TUG-891 acutely increases fat oxidation and reduces body weight and fat mass in C57Bl/6J mice. These effects coincided with decreased brown adipocyte lipid content and increased nutrient uptake by BAT, confirming increased BAT activity. Consistent with these observations, GPR120 deficiency reduced expression of genes involved in nutrient handling in BAT Stimulation of brown adipocytes in vitro with TUG-891 acutely induced O2 consumption, through GPR120-dependent and GPR120-independent mechanisms. TUG-891 not only stimulated GPR120 signaling resulting in intracellular calcium release, mitochondrial depolarization, and mitochondrial fission, but also activated UCP1. Collectively, these data suggest that activation of brown adipocytes with the GPR120 agonist TUG-891 is a promising strategy to increase lipid combustion and reduce obesity.
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Tejido Adiposo Pardo/metabolismo , Compuestos de Bifenilo/farmacología , Mitocondrias/metabolismo , Fenilpropionatos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Adipocitos Marrones/citología , Adipocitos Marrones/efectos de los fármacos , Adipocitos Marrones/metabolismo , Adipocitos Blancos/citología , Adipocitos Blancos/efectos de los fármacos , Adipocitos Blancos/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Adiposidad/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Respiración de la Célula/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Lípidos , Masculino , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Modelos Biológicos , Oxidación-Reducción , Consumo de Oxígeno/efectos de los fármacos , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/metabolismo , Proteína Desacopladora 1/metabolismoRESUMEN
BACKGROUND: NICE Guidelines for prevention of diabetes include identifying people at risk followed by cost-effective intervention if necessary. Based on assessment of risk via a questionnaire and/or blood test the intervention may comprise a brief discussion of risk factors and preventive advice or referral to intensive lifestyle intervention. DESIGN AND SETTING: In this cross-sectional study 59 subjects recruited from local GP practices were invited by letter to attend a screening for a diabetes prevention study. METHOD: Following a telephone screening during which subjects were asked whether they had been informed if they were at high-risk of type 2 diabetes, eligible subjects completed a Risk Perception Survey for Developing Diabetes (RPS-DD), a validated diabetes risk score and underwent an oral glucose tolerance test (OGTT) at a medical screening. RESULTS: As measured by the Diabetes UK Risk Score, 44.1% were at high risk, 42.4% moderate risk and 13.6% at increased risk. 42% of patients had been informed they were at high-risk by a health professional. Those who had been informed of their risk had significantly higher perceived risk scores (p<0.001), higher knowledge scores (p<0.001) and decreased optimism scores (p=0.004), but were not more aware that diet (p=0.42) and weight management (p=0.57) can play a role in preventing diabetes. CONCLUSIONS: People at high-risk of diabetes are not being informed of their risk status as recommended by NICE guidelines. There is scope for education for health professionals and the public.
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Diabetes Mellitus Tipo 2/prevención & control , Medicina General/métodos , Adhesión a Directriz , Educación del Paciente como Asunto , Pautas de la Práctica en Medicina , Prevención Primaria/métodos , Conducta de Reducción del Riesgo , Anciano , Estudios de Cohortes , Estudios Transversales , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Dieta/efectos adversos , Ejercicio Físico , Medicina General/normas , Prueba de Tolerancia a la Glucosa , Adhesión a Directriz/normas , Conocimientos, Actitudes y Práctica en Salud , Humanos , Masculino , Persona de Mediana Edad , Educación del Paciente como Asunto/normas , Percepción , Guías de Práctica Clínica como Asunto , Pautas de la Práctica en Medicina/normas , Valor Predictivo de las Pruebas , Prevención Primaria/normas , Medición de Riesgo , Factores de Riesgo , Conducta Sedentaria , Encuestas y Cuestionarios , Resultado del Tratamiento , Reino Unido/epidemiologíaRESUMEN
Chronic hyperglycemia induces non-enzymatic protein glycation, which plays an important role in the development of diabetic complications. Immense efforts have been made to determine effective antiglycation compounds from natural products. Pomelo has shown beneficial effects for human health. The objective of this study was to determine the antiglycation effect of pomelo extract against fructose-mediated protein oxidation and glycation. Our results showed that the pomelo extract (0.25 - 2.00 mg/mL) significantly inhibited the overall formation of advanced glycation end products (AGEs) in a concentration-dependent manner. The pomelo extract markedly decreased the level of fructosamine, which is directly associated with reduction in formation of AGEs and N (ε)-(carboxymethyl)lysine (CML). In addition, the pomelo extract inhibited protein oxidation through its ability to prevent the loss of thiol groups and reduced protein carbonyl formation. We characterized the active components in the pomelo extract by using high-performance liquid chromatography (HPLC), which showed that the pomelo extract contained naringin (11.90 ± 0.21 mg/g dried extract), hesperidin (12.04 ± 0.12 mg/g dried extract), neohesperidin (25.4 ± 0.12 mg/g dried extract), and naringenin (9.20 ± 0.19 mg/g dried extract). Our findings could provide a new insight into the antiglycation properties of the extract of the naturally occurring fruit pomelo for preventing AGE-mediated diabetic complications.
RESUMEN
Pomelo (Citrus grandis L. Osbeck) is a native fruit of great economic importance in Southeast Asia. To provide experimental evidence for the antioxidant and antihyperlipidemic properties of pomelo, 6 cultivars, including Kao-Yai (KY), Thong-dee (TD), Kao-Tangkwa (KT), Kao-Numpueng (KN), Ta-Koi (TK), and Tubtim Siam (TS) were evaluated. KY had the highest phenolic content, and the strongest 1,1-diphenyl-2-pireyhydrazyl radical scavenging capacity and hydroxyl radical scavenging activity. From the high-performance liquid chromatography analysis, naringin and naringenin were the major flavonoids in the KT and TK cultivars. Six pomelo cultivars had antihyperlipidemic activities including the inhibition of pancreatic lipase and cholesterol esterase, as well as cholesterol micelle formation and bile acid binding. Hierarchical clustering analysis showed that the 6 cultivars were separated into 2 classifications. In addition, the total phenolics of the pomelo cultivars were significantly correlated with ferric reducing antioxidant power and Trolox equivalent antioxidant capacity. The results suggest that pomelo provides significant health benefits and may be used for developing functional foods.