RESUMO
To maintain cellular homeostasis, the endoplasmic reticulum (ER) necessitates a continuous removal of ER fragments via a selective, receptor-mediated, form of autophagy known as ER-phagy. In this issue of The EMBO Journal, Jiang et al (2020) shed light on how the best characterized autophagy receptor FAM134B mediates ER membrane fragmentation, the earliest event during ER-phagy. They propose a dynamic model for FAM134B protein oligomerization and ER membrane scission, which are driven by CAMK2B-mediated phosphorylation of the receptor and are altered in sensory neuropathy.
Assuntos
Autofagia , Proteínas de Membrana , Proteínas de Transporte , Retículo Endoplasmático , HomeostaseRESUMO
Lysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is emerging as a critical regulator of cell homeostasis and function. The recent identification of ER-phagy receptors has shed light on the molecular mechanisms underlining this process. However, the signaling pathways regulating ER-phagy in response to cellular needs are still largely unknown. We found that the nutrient responsive transcription factors TFEB and TFE3-master regulators of lysosomal biogenesis and autophagy-control ER-phagy by inducing the expression of the ER-phagy receptor FAM134B. The TFEB/TFE3-FAM134B axis promotes ER-phagy activation upon prolonged starvation. In addition, this pathway is activated in chondrocytes by FGF signaling, a critical regulator of skeletal growth. FGF signaling induces JNK-dependent proteasomal degradation of the insulin receptor substrate 1 (IRS1), which in turn inhibits the PI3K-PKB/Akt-mTORC1 pathway and promotes TFEB/TFE3 nuclear translocation and enhances FAM134B transcription. Notably, FAM134B is required for protein secretion in chondrocytes, and cartilage growth and bone mineralization in medaka fish. This study identifies a new signaling pathway that allows ER-phagy to respond to both metabolic and developmental cues.
Assuntos
Autofagia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Núcleo Celular/metabolismo , Retículo Endoplasmático/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais , Transporte Ativo do Núcleo Celular , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Núcleo Celular/genética , Retículo Endoplasmático/genética , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas de Membrana/genética , Camundongos , OryziasRESUMO
Autophagy is a cytosolic quality control process that recognizes substrates through receptor-mediated mechanisms. Procollagens, the most abundant gene products in Metazoa, are synthesized in the endoplasmic reticulum (ER), and a fraction that fails to attain the native structure is cleared by autophagy. However, how autophagy selectively recognizes misfolded procollagens in the ER lumen is still unknown. We performed siRNA interference, CRISPR-Cas9 or knockout-mediated gene deletion of candidate autophagy and ER proteins in collagen producing cells. We found that the ER-resident lectin chaperone Calnexin (CANX) and the ER-phagy receptor FAM134B are required for autophagy-mediated quality control of endogenous procollagens. Mechanistically, CANX acts as co-receptor that recognizes ER luminal misfolded procollagens and interacts with the ER-phagy receptor FAM134B. In turn, FAM134B binds the autophagosome membrane-associated protein LC3 and delivers a portion of ER containing both CANX and procollagen to the lysosome for degradation. Thus, a crosstalk between the ER quality control machinery and the autophagy pathway selectively disposes of proteasome-resistant misfolded clients from the ER.
Assuntos
Calnexina/metabolismo , Retículo Endoplasmático/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Pró-Colágeno/metabolismo , Animais , Autofagia , Calnexina/genética , Linhagem Celular , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Oryzias , Dobramento de ProteínaRESUMO
Recombinant human growth hormone (r-hGH) is used as a therapeutic agent for disorders of growth including growth hormone deficiency (GHD) and Turner syndrome (TS). Treatment is costly and current methods to model response are inexact. GHD (n = 71) and TS patients (n = 43) were recruited to study response to r-hGH over 5 years. Analysis was performed using 1219 genetic markers and baseline (pre-treatment) blood transcriptome. Random forest was used to determine predictive value of transcriptomic data associated with growth response. No genetic marker passed the stringency criteria for prediction. However, we identified an identical set of genes in both GHD and TS whose expression could be used to classify therapeutic response to r-hGH with a high accuracy (AUC > 0.9). Combining transcriptomic markers with clinical phenotype was shown to significantly reduce predictive error. This work could be translated into a single genomic test linked to a prediction algorithm to improve clinical management. Trial registration numbers: NCT00256126 and NCT00699855.
Assuntos
Hormônio do Crescimento Humano/uso terapêutico , Transcriptoma/genética , Criança , Feminino , Perfilação da Expressão Gênica/métodos , Marcadores Genéticos/genética , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/genética , Hormônio do Crescimento Humano/deficiência , Humanos , Masculino , Estudos Prospectivos , Resultado do Tratamento , Síndrome de Turner/tratamento farmacológico , Síndrome de Turner/genéticaRESUMO
Response to recombinant human growth hormone (r-hGH) in the first year of therapy has been associated with single-nucleotide polymorphisms (SNPs) in children with GH deficiency (GHD). Associated SNPs were screened for regulatory function using a combination of in silico techniques. Four SNPs in regulatory sequences were selected for the analysis of in vitro transcriptional activity (TA). There was an additive effect of the alleles in the four genes associated with good growth response. For rs3110697 within IGFBP3, rs1045992 in CYP19A1 and rs2888586 in SOS1, the variant associated with better growth response showed higher TA with r-hGH treatment. For rs1024531 in GRB10, a negative regulator of IGF-I signalling and growth, the variant associated with better growth response had a significantly lower TA on r-hGH stimulation. These results indicate that specific SNP variants have effects on TA that provide a rationale for their clinical impact on growth response to r-hGH therapy.
Assuntos
Aromatase/genética , Transtornos do Crescimento/genética , Hormônio do Crescimento/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína SOS1/genética , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Estatura , Criança , Pré-Escolar , Hipersensibilidade a Drogas , Feminino , Proteína Adaptadora GRB10/genética , Estudos de Associação Genética , Transtornos do Crescimento/patologia , Hormônio do Crescimento/deficiência , Terapia de Reposição Hormonal/efeitos adversos , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/efeitos adversos , Humanos , Fator de Crescimento Insulin-Like I/administração & dosagem , Fator de Crescimento Insulin-Like I/efeitos adversos , Fator de Crescimento Insulin-Like I/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Sequências Reguladoras de Ácido Nucleico/genéticaRESUMO
Enzyme replacement therapy (ERT) is the standard of care for several lysosomal storage diseases (LSDs). ERT, however, requires multiple and costly administrations and has limited efficacy. We recently showed that a single high dose administration of adeno-associated viral vector serotype 8 (AAV2/8) is at least as effective as weekly ERT in a mouse model of mucopolysaccharidosis type VI (MPS VI). However, systemic administration of high doses of AAV might result in both cell-mediated immune responses and insertional mutagenesis. Here we evaluated whether the combination of low doses of AAV2/8 with a less frequent (monthly) than canonical (weekly) ERT schedule may be as effective as the single treatments at high doses or frequent regimen. A greater reduction of both urinary glycosaminoglycans, considered a sensitive biomarker of therapeutic efficacy, and storage in the myocardium and heart valves was observed in mice receiving the combined than the single therapies. Importantly, these levels of correction were similar to those we obtained in a previous study following either high doses of AAV2/8 or weekly ERT. Our data show that low-dose gene therapy can be used as a means to rarify ERT administration, thus reducing both the risks and costs associated with either therapies.
Assuntos
Terapia Combinada/métodos , Terapia de Reposição de Enzimas/métodos , Terapia Genética/métodos , Doenças por Armazenamento dos Lisossomos/terapia , Animais , Dependovirus/genética , Modelos Animais de Doenças , Vetores Genéticos/administração & dosagem , Glicosaminoglicanos/urina , Humanos , Doenças por Armazenamento dos Lisossomos/urina , Camundongos , Resultado do TratamentoRESUMO
BACKGROUND: Controversial data exist on the possibility that inhaled corticosteroids (ICs) affect growth in children with mild-to-moderate asthma. We assessed whether ICs affect growth and final height (FH) in asthmatic children compared to controls. METHODS: A retrospective study was conducted on 113 asthmatic children compared with 66 control children. Asthmatic children presented with mild-to-moderate asthma and had exclusive ICs. Anthropometric data of four specific time-points were collected for both groups (pre-puberty, onset and late puberty, and FH) and converted to standard deviation scores (SDS). Growth trajectories were assessed as follows: (i) in puberty, using peak height velocity (PHV) and pubertal height gain SDS (PHG-SDS); (ii) until FH achievement, using FH-SDS and FH gain SDS (FHG-SDS). Repeated measurement analysis was performed across longitudinal study visits. A general linear model (GLM) was performed in asthmatic group evaluating the effect of corticosteroid type, treatment duration, and cumulative dose on FH corrected for multiple variables. RESULTS: At pre-puberty, height and weight SDS were similar between the groups (p > 0.05). Height SDS progressively declined over the study period in asthmatic patients from pre-puberty to FH (p-trend < 0.05), whereas it did not change over time in controls (p-trend > 0.05), in both boys and girls. Asthmatic children had exclusive ICs [budesonide (n = 36) vs. fluticasone (n = 43) vs. mometasone (n = 34)] for a mean period of 6.25 ± 1.20 years and a mean cumulative dose of 560.07 ± 76.02 mg. They showed decreased PHG-SDS and lower PHV compared to controls (all p < 0.05). FH-SDS and FHG-SDS were significantly reduced in asthmatic group compared to controls. FH in asthmatic patients was 2.5 ± 2.89 cm lower in boys and 2.0 ± 2.03 cm lower in girls than controls. The GLM showed that FH achievement was dependent on the type of ICs, duration of the treatment, and cumulative dose (p < 0.05). CONCLUSIONS: ICs affect pubertal growth determining reduced final height in asthmatic children compared to controls, in a dose- and duration-dependent manner.
Assuntos
Corticosteroides/efeitos adversos , Antiasmáticos/efeitos adversos , Asma/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Maturidade Sexual , Corticosteroides/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/complicações , Estatura/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Criança , Pré-Escolar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Crescimento/efeitos dos fármacos , Humanos , Itália , Masculino , Estudos Retrospectivos , Maturidade Sexual/efeitos dos fármacosRESUMO
Protein biogenesis within the endoplasmic reticulum (ER) is crucial for organismal function. Errors during protein folding necessitate the removal of faulty products. ER-associated protein degradation and ER-phagy target misfolded proteins for proteasomal and lysosomal degradation. The mechanisms initiating ER-phagy in response to ER proteostasis defects are not well understood. By studying mouse primary cells and patient samples as a model of ER storage disorders (ERSDs), we show that accumulation of faulty products within the ER triggers a response involving SESTRIN2, a nutrient sensor controlling mTORC1 signaling. SESTRIN2 induction by XBP1 inhibits mTORC1's phosphorylation of TFEB/TFE3, allowing these transcription factors to enter the nucleus and upregulate the ER-phagy receptor FAM134B along with lysosomal genes. This response promotes ER-phagy of misfolded proteins via FAM134B-Calnexin complex. Pharmacological induction of FAM134B improves clearance of misfolded proteins in ERSDs. Our study identifies the interplay between nutrient signaling and ER quality control, suggesting therapeutic strategies for ERSDs.
Assuntos
Retículo Endoplasmático , Alvo Mecanístico do Complexo 1 de Rapamicina , Dobramento de Proteína , Proteína 1 de Ligação a X-Box , Animais , Retículo Endoplasmático/metabolismo , Humanos , Camundongos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteína 1 de Ligação a X-Box/metabolismo , Proteína 1 de Ligação a X-Box/genética , Transdução de Sinais , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Lisossomos/metabolismo , Estresse do Retículo Endoplasmático , Sestrinas/metabolismo , Sestrinas/genética , Fosforilação , Proteostase , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix BásicosRESUMO
UNLABELLED: Hypophosphatasia is characterized by deficiency of serum alkaline phosphatase with defective bone and teeth mineralization. We report on an 11-month-old boy who developed a complex clinical picture characterized by bulging anterior fontanelle, growth failure, nephrocalcinosis and impaired bone mineralization during high-dose calcium and vitamin D supplementation. This therapy had been started 5 months earlier for a presumed diagnosis of nutritional rickets established on the grounds of isolated widened anterior fontanelle. However, laboratory investigations revealed reduced alkaline phosphatase levels associated with hypercalcemia, hypercalciuria, low PTH and normal 25-hydroxy vitamin D levels. Genetic testing detected a compound heterozygote for the novel mutation (c.262G>A) and the described mutation (c.920C>T) in the ALPL gene. CONCLUSION: High calcium and vitamin D supplementation should not be started in the presence of isolated signs of nutritional rickets without assessing calcium-phosphate metabolism. In fact, in rare bone-mineralizing disorders, this combined therapy might induce severe clinical complications.
Assuntos
Fosfatase Alcalina/deficiência , Fontanelas Cranianas/patologia , Erros de Diagnóstico , Hipofosfatasia/diagnóstico , Raquitismo/diagnóstico , Fosfatase Alcalina/genética , Cálcio/uso terapêutico , Diagnóstico Tardio , Humanos , Lactente , Masculino , Erros de Medicação , Mutação/genética , Raquitismo/tratamento farmacológico , Vitamina D/uso terapêuticoRESUMO
Protein misfolding occurring in the endoplasmic reticulum (ER) might eventually lead to aggregation and cellular distress, and is a primary pathogenic mechanism in multiple human disorders. Mammals have developed evolutionary-conserved quality control mechanisms at the level of the ER. The best characterized is the ER-associated degradation (ERAD) pathway, through which misfolded proteins translocate from the ER to the cytosol and are subsequently proteasomally degraded. However, increasing evidence indicates that additional quality control mechanisms apply for misfolded ER clients that are not eligible for ERAD. This review focuses on the alternative, ERAD-independent, mechanisms of clearance of misfolded polypeptides from the ER. These processes, collectively referred to as ER-to-lysosome-associated degradation, involve ER-phagy, microautophagy or vesicular transport. The identification of the underlying molecular mechanisms is particularly important for developing new therapeutic approaches for human diseases associated with protein aggregate formation.
Assuntos
Retículo Endoplasmático/metabolismo , Lisossomos/metabolismo , Animais , Autofagia , Doença , HumanosRESUMO
The lysosome is a catabolic organelle devoted to the degradation of cellular components, such as protein complexes and whole or portion of organelles that reach the lysosomes through (macro)autophagy. The lysosomes also function as signaling organelles by controlling the activity of key metabolic kinases, such as the mechanistic target of Rapamycin complex 1 (mTORC1). Lysosome dysfunction has dramatic consequences on cellular homeostasis and causes lysosomal storage disorders (LSDs). Here we review the recently proposed mechanisms by which impairment of lysosome/autophagy pathway affects extracellular matrix formation and skeletal development and growth. In particular, we will highlight the role of autophagy as a collagen quality control pathway in collagen-producing cells. An impairment of autophagy, such as the one observed in LSDs, leads to a collagen proteostatic defects and can explain, at least in part, the skeletal phenotypes characterizing patients with lysosomal storage disorders.
Assuntos
Colágeno/metabolismo , Matriz Extracelular/metabolismo , Doenças por Armazenamento dos Lisossomos/metabolismo , Animais , Autofagia , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fenótipo , ProteostaseRESUMO
BACKGROUND: The effect of gene expression data on diagnosis remains limited. Here, we show how diagnosis and classification of growth hormone deficiency (GHD) can be achieved from a single blood sample using a combination of transcriptomics and random forest analysis. METHODS: Prepubertal treatment-naive children with GHD (n = 98) were enrolled from the PREDICT study, and controls (n = 26) were acquired from online data sets. Whole blood gene expression was correlated with peak growth hormone (GH) using rank regression and a random forest algorithm tested for prediction of the presence of GHD and in classification of GHD as severe (peak GH <4 µg/l) and nonsevere (peak ≥4 µg/l). Performance was assessed using area under the receiver operating characteristic curve (AUC-ROC). RESULTS: Rank regression identified 347 probe sets in which gene expression correlated with peak GH concentrations (r = ± 0.28, P < 0.01). These 347 probe sets yielded an AUC-ROC of 0.95 for prediction of GHD status versus controls and an AUC-ROC of 0.93 for prediction of GHD severity. CONCLUSION: This study demonstrates highly accurate diagnosis and disease classification for GHD using a combination of transcriptomics and random forest analysis. TRIAL REGISTRATION: NCT00256126 and NCT00699855. FUNDING: Merck and the National Institute for Health Research (CL-2012-06-005).
Assuntos
Perfilação da Expressão Gênica , Transtornos do Crescimento/diagnóstico , Hormônio do Crescimento Humano/deficiência , Aprendizado de Máquina , Adolescente , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Conjuntos de Dados como Assunto , Feminino , Redes Reguladoras de Genes , Transtornos do Crescimento/sangue , Transtornos do Crescimento/genética , Voluntários Saudáveis , Hormônio do Crescimento Humano/sangue , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Análise de Componente Principal , Curva ROC , Índice de Gravidade de Doença , Transcriptoma/genéticaRESUMO
The mammalian target of rapamycin complex 1 (mTORC1) kinase promotes cell growth by activating biosynthetic pathways and suppressing catabolic pathways, particularly that of macroautophagy. A prerequisite for mTORC1 activation is its translocation to the lysosomal surface. Deregulation of mTORC1 has been associated with the pathogenesis of several diseases, but its role in skeletal disorders is largely unknown. Here, we show that enhanced mTORC1 signaling arrests bone growth in lysosomal storage disorders (LSDs). We found that lysosomal dysfunction induces a constitutive lysosomal association and consequent activation of mTORC1 in chondrocytes, the cells devoted to bone elongation. mTORC1 hyperphosphorylates the protein UV radiation resistance-associated gene (UVRAG), reducing the activity of the associated Beclin 1-Vps34 complex and thereby inhibiting phosphoinositide production. Limiting phosphoinositide production leads to a blockage of the autophagy flux in LSD chondrocytes. As a consequence, LSD chondrocytes fail to properly secrete collagens, the main components of the cartilage extracellular matrix. In mouse models of LSD, normalization of mTORC1 signaling or stimulation of the Beclin 1-Vps34-UVRAG complex rescued the autophagy flux, restored collagen levels in cartilage, and ameliorated the bone phenotype. Taken together, these data unveil a role for mTORC1 and autophagy in the pathogenesis of skeletal disorders and suggest potential therapeutic approaches for the treatment of LSDs.
Assuntos
Autofagia , Desenvolvimento Ósseo , Doenças por Armazenamento dos Lisossomos/metabolismo , Complexos Multiproteicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Condrócitos/metabolismo , Condrócitos/patologia , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Knockout , Complexos Multiproteicos/genética , Fosfatidilinositóis/genética , Fosfatidilinositóis/metabolismo , Fosforilação/genética , Fosforilação/efeitos da radiação , Serina-Treonina Quinases TOR/genética , Raios UltravioletaRESUMO
BRCA2 encodes a protein with a fundamental role in homologous recombination that is essential for normal development. Carrier status of mutations in BRCA2 is associated with familial breast and ovarian cancer, while bi-allelic BRCA2 mutations can cause Fanconi anemia (FA), a cancer predisposition syndrome with cellular cross-linker hypersensitivity. Cancers associated with BRCA2 mutations can acquire chemo-resistance on relapse. We modeled acquired cross-linker resistance with an FA-derived BRCA2-mutated acute myeloid leukemia (AML) platform. Associated with acquired cross-linker resistance was the expression of a functional BRCA2 protein variant lacking exon 5 and exon 7 (BRCA2ΔE5+7), implying a role for BRCA2 splicing for acquired chemo-resistance. Integrated network analysis of transcriptomic and proteomic differences for phenotyping of BRCA2 disruption infers impact on transcription and chromatin remodeling in addition to the DNA damage response. The striking overlap with transcriptional profiles of FA patient hematopoiesis and BRCA mutation associated ovarian cancer helps define and explicate the 'BRCAness' profile.
Assuntos
Processamento Alternativo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Resistencia a Medicamentos Antineoplásicos , Genes BRCA2 , Mutação , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Dano ao DNA , Éxons , Anemia de Fanconi/tratamento farmacológico , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Íntrons , Células K562 , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , Recidiva Local de Neoplasia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Fenótipo , Splicing de RNA , Transcrição GênicaRESUMO
Juvenile idiopathic arthritis (JIA) is a clinically diverse and genetically complex autoimmune disease. Currently, there is very limited understanding of the potential underlying mechanisms that result in the range of phenotypes which constitute JIA.The elucidation of the functional relevance of genetic associations with phenotypic traits is a fundamental problem that hampers the translation of genetic observations to plausible medical interventions. Genome wide association studies, and subsequent fine-mapping studies in JIA patients, have identified many genetic variants associated with disease. Such approaches rely on 'tag' single nucleotide polymorphisms (SNPs). The associated SNPs are rarely functional variants, so the extrapolation of genetic association data to the identification of biologically meaningful findings can be a protracted undertaking. Integrative genomics aims to bridge the gap between genotype and phenotype.Systems biology, principally through network analysis, is emerging as a valuable way to identify biological pathways of relevance to complex genetic diseases. This review aims to highlight recent findings in systems biology related to JIA in an attempt to assist in the understanding of JIA pathogenesis and therapeutic target identification.
Assuntos
Artrite Juvenil/genética , Redes Reguladoras de Genes , Redes e Vias Metabólicas , Mapas de Interação de Proteínas , Artrite Juvenil/metabolismo , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Biologia de SistemasRESUMO
BACKGROUND: Cardiovascular (CV) risk factors have been identified in adults with untreated growth hormone deficiency (GHD). Existing evidence suggests that the development of the atheromatous plaque begins early in childhood. Previous reports have shown that GHD children are prone to increased CV risks including impaired cardiac function, dyslipidemia and abnormalities in body composition. Recent studies in epigenetics and metabolomics have defined specific fingerprints that might be associated with an increased risk of CV disease. AIM: The aim of this review is to point out the most significant biochemical and clinical predictive markers of CV disease in prepubertal children and to evaluate the effect of recombinant human growth hormone therapy on most of these alterations. The novel findings in epigenetics and metabolomics are also reviewed, with a particular focus on translating them into clinical practice.
Assuntos
Aterosclerose/sangue , Epigênese Genética , Hormônio do Crescimento Humano/deficiência , Placa Aterosclerótica/sangue , Adulto , Aterosclerose/genética , Biomarcadores/sangue , Criança , Pré-Escolar , Epigenômica , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Metabolômica , Placa Aterosclerótica/genética , Fatores de RiscoRESUMO
OBJECTIVE: To measure cerebral regional oxygen saturation (CrSO2), renal regional oxygenation saturation (RrSO2) and mesenteric tissue regional oxygen saturation (MrSO2) during immediate transition and continuously for the first 9 hours of age. Fractional tissue oxygen extraction of the brain (CtFOE), kidneys (RtFOE), splanchnic tissue (MtFOE) were also assessed. STUDY DESIGN: Prospective, observational study of 61 term infants, delivered by elective caesarean section. Using near-infrared spectroscopy, changes in CrSO2, RrSO2, MrSO2 and changes in CtFOE, RtFOE and MtFOE were measured all through the first 9 hours of life. All the episodes of feeding during this period were recorded. RESULTS: Mean CrSO2 increased quickly to 7 minutes, with no further changes. On the other hand, mean RrSO2 and mean MrSO2 increased for 10 minutes and thereafter they remained on their newly reached level. RrSO2 and MrSO2 were significantly lower at 3-4-5-6-7 minutes of life compared to the CrSO2 (p<0.05). RtFOE and MtFOE were significantly higher at 3-4-5-6-7 minutes of life compared to the CtFOE (p<0.05). During feeding, CrSO2, RrSO2 and MrSO2 did not significantly change. CONCLUSIONS: During early adaptive period, oxygen delivery is preserved to 'vital' organs, like brain, at the expense of kidneys and splanchnic tissue. Term infants can provide for the increasing metabolic activity of the intestinal tract during feeding periods without compromising oxygenation.
Assuntos
Encéfalo/metabolismo , Rim/metabolismo , Mesentério/metabolismo , Oxigênio/metabolismo , Biomarcadores/metabolismo , Cesárea , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Estudos Prospectivos , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
Lamellar ichthyosis is a rare congenital disorder characterized by collodion membrane at birth and facial anomalies (eclabium and ectropion). The major underlying genetic defect is in TGM1, with mutations of this gene found in 50% of patients. An early diagnosis is fundamental in view of establishing a specific treatment due to the severity of the disease. We report a case of severe lamellar ichthyosis and arthrogryposis, without the typical facial presentation, negative for TGM1 mutations. The clinical improvement was achieved only after treatment with oral retinoids, highlighting the importance of early diagnosis and prompt administration of a specific therapy.