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1.
Sci Adv ; 5(9): eaax2166, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31579823

RESUMO

RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity-related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.

2.
Am J Med Genet A ; 179(11): 2284-2291, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31403263

RESUMO

Aspartate-glutamate carrier 1 (AGC1) is one of two exchangers within the malate-aspartate shuttle. AGC1 is encoded by the SLC25A12 gene. Three patients with pathogenic variants in SLC25A12 have been reported in the literature. These patients were clinically characterized by neurodevelopmental delay, epilepsy, hypotonia, cerebral atrophy, and hypomyelination; however, there has been discussion in the literature as to whether this hypomyelination is primary or secondary to a neuronal defect. Here we report a 12-year-old patient with variants in SLC25A12 and magnetic resonance imaging (MRI) at multiple ages. Novel compound heterozygous, recessive variants in SLC25A12 were identified: c.1295C>T (p.A432V) and c.1447-2_1447-1delAG. Clinical presentation is characterized by severe intellectual disability, nonambulatory, nonverbal status, hypotonia, epilepsy, spastic quadriplegia, and a happy disposition. The serial neuroimaging findings are notable for cerebral atrophy with white matter involvement, namely, early hypomyelination yet subsequent progression of myelination. The longitudinal MRI findings are most consistent with a leukodystrophy of the leuko-axonopathy category, that is, white matter abnormalities that are most suggestive of mechanisms that result from primary neuronal defects. We present here the first case of a patient with compound heterozygous variants in SLC25A12, including brain MRI findings, in the oldest individual reported to date with this neurogenetic condition.

4.
Genet Med ; 21(9): 2059-2069, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30923367

RESUMO

PURPOSE: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. METHODS: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. RESULTS: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). CONCLUSION: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.

6.
JPEN J Parenter Enteral Nutr ; : 148607117696330, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29187120

RESUMO

BACKGROUND: Administration of high-dose parenteral amino acids (AAs) to premature infants within hours of delivery is currently recommended. This study compared the effect of lower and higher AA administration starting close to birth on short-term growth and neurodevelopmental outcomes at 18-24 months corrected gestational age (CGA). METHODS: Infants <1250 g birth weight (n = 168) were randomly assigned in a blinded fashion to receive parenteral nutrition providing 1-2 g/kg/d AA and advancing daily by 0.5 g/kg/d to a goal of 4 g/kg/d (standard AA) or 3-4 g/kg/d and advancing to 4 g/kg/d by day 1. The primary outcome was neurodevelopmental outcomes measured by the Bayley Scales of Infant and Toddler Development, Third Edition at 18-24 months CGA. Secondary outcomes were growth parameters at 36 weeks CGA among infants surviving to hospital discharge, serum bicarbonate, serum urea nitrogen, creatinine, AA profiles in the first week of life, and incidence of major morbidities and mortality. RESULTS: No differences in neurodevelopmental outcome were detected between the high and low AA groups. Infants in the high AA group had significantly lower mean weight, length, and head circumference percentiles than those in the standard AA group at 36 weeks CGA and at hospital discharge. These differences did not persist after controlling for birth growth parameters, except for head circumference. Infants in the high AA group had higher mean serum urea nitrogen than the standard group on each day throughout the first week. CONCLUSION: Current recommendations for high-dose AA starting at birth are not associated with improved growth or neurodevelopmental outcomes.

7.
J Inherit Metab Dis ; 40(6): 823-830, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28801758

RESUMO

PRKAG2 encodes the γ2 subunit of AMP-activated protein kinase (AMPK), which is an important regulator of cardiac metabolism. Mutations in PRKAG2 cause a cardiac syndrome comprising ventricular hypertrophy, pre-excitation, and progressive conduction-system disease, which is typically not diagnosed until adolescence or young adulthood. However, significant variability exists in the presentation and outcomes of patients with PRKAG2 mutations, with presentation in infancy being underrecognized. The diagnosis of PRKAG2 can be challenging in infants, and we describe our experience with three patients who were initially suspected to have Pompe disease yet ultimately diagnosed with mutations in PRKAG2. A disease-causing PRKAG2 mutation was identified in each case, with a novel missense mutation described in one patient. We highlight the potential for patients with PRKAG2 mutations to mimic Pompe disease in infancy and the need for confirmatory testing when diagnosing Pompe disease.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Mutação/genética , Pré-Escolar , Feminino , Doença de Depósito de Glicogênio Tipo II/genética , Humanos , Lactente , Recém-Nascido , Masculino
8.
Am J Physiol Heart Circ Physiol ; 313(2): H283-H292, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28550180

RESUMO

PRKAG2 encodes the γ2-subunit isoform of 5'-AMP-activated protein kinase (AMPK), a heterotrimeric enzyme with major roles in the regulation of energy metabolism in response to cellular stress. Mutations in PRKAG2 have been implicated in a unique hypertrophic cardiomyopathy (HCM) characterized by cardiac glycogen overload, ventricular preexcitation, and hypertrophy. We identified a novel, de novo PRKAG2 mutation (K475E) in a neonate with prenatal onset of HCM. We aimed to investigate the cellular impact, signaling pathways involved, and therapeutic options for K475E mutation using cells stably expressing human wild-type (WT) or the K475E mutant. In human embryonic kidney-293 cells, the K475E mutation induced a marked increase in the basal phosphorylation of T172 and AMPK activity, reduced sensitivity to AMP in allosteric activation, and a loss of response to phenformin. In H9c2 cardiomyocytes, the K475E mutation induced inhibition of AMPK and reduced the response to phenformin and increases in the phosphorylation of p70S6 kinase (p70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). Primary fibroblasts from the patient with the K475E mutation also showed marked increases in the phosphorylation of p70S6K and 4E-BP1 compared with those from age-matched, nondiseased controls. Moreover, overexpression of K475E induced hypertrophy in H9c2 cells, which was effectively reversed by treatment with rapamycin. Taken together, we have identified a novel, de novo infantile-onset PRKAG2 mutation causing HCM. Our study suggests the K475E mutation induces alteration in basal AMPK activity and results in a hypertrophy phenotype involving the mechanistic target of rapamycin signaling pathway, which can be reversed with rapamycin.NEW & NOTEWORTHY We identified a novel, de novo PRKAG2 mutation (K475E) in the cystathionine ß-synthase 3 repeat, a region critical for AMP binding but with no previous reported mutation. Our data suggest the mutation affects AMP-activated protein kinase activity, activates cell growth pathways, and results in cardiac hypertrophy, which can be reversed with rapamycin.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Cardiomiopatia Hipertrófica/genética , Mutação de Sentido Incorreto , Miócitos Cardíacos/enzimologia , Transdução de Sinais , Proteínas Quinases Ativadas por AMP/química , Proteínas Quinases Ativadas por AMP/metabolismo , Monofosfato de Adenosina/metabolismo , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/enzimologia , Cardiomiopatia Hipertrófica/fisiopatologia , Proteínas de Transporte/metabolismo , Estudos de Casos e Controles , Análise Mutacional de DNA , Ativação Enzimática , Fibroblastos/enzimologia , Fibroblastos/patologia , Predisposição Genética para Doença , Células HEK293 , Humanos , Recém-Nascido , Modelos Moleculares , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Fenformin/farmacologia , Fenótipo , Fosfoproteínas/metabolismo , Fosforilação , Conformação Proteica , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Transfecção
10.
J Pediatr Endocrinol Metab ; 30(2): 247-251, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-28085675

RESUMO

BACKGROUND: Glycogen storage disease (GSD) type IX and growth hormone (GH) deficiency cause ketotic hypoglycemia via different mechanisms and are not known to be associated. We describe a patient presenting with severe ketotic hypoglycemia found to have both GSD IX and isolated GH deficiency. CASE PRESENTATION: A 3-year-and-11-month-old boy with a history of prematurity, autism, developmental delay, seizures, and feeding difficulty was admitted for poor weight gain and symptomatic hypoglycemia. He was nondysmorphic, with a height of 93.8 cm (2%, -1.97 SDS), and has no hepatomegaly. He developed symptomatic hypoglycemia, with a serum glucose level of 37 mg/dL after 14 h of fasting challenge. Critical sample showed a GH of 0.24 ng/mL. GH provocative stimulation testing was done with a peak GH of 2.8 ng/mL. Brain magnetic resonance imaging showed a hypoplastic pituitary gland. Given the clinical symptoms, suspicion for mitochondrial disease was high. Dual Genome Panel by Massively Parallel Sequencing revealed a hemizygous variant c.721A>G (p1241V) in the X-linked PHKA2 gene, a causative gene for GSD IX. Red blood cell PhK enzyme activity testing was low, supporting the diagnosis. CONCLUSIONS: Given the patient's developmental delays that were not explained by GH deficiency alone, further investigation showed two unrelated conditions resulting in deranged metabolic adaptation to fasting leading to severe hypoglycemia.


Assuntos
Doença de Depósito de Glicogênio/diagnóstico , Transtornos do Crescimento/diagnóstico , Hormônio do Crescimento Humano/deficiência , Hipoglicemia/diagnóstico , Pré-Escolar , Diagnóstico Diferencial , Doença de Depósito de Glicogênio/complicações , Transtornos do Crescimento/complicações , Humanos , Hipoglicemia/complicações , Masculino , Prognóstico
11.
J Pediatr Endocrinol Metab ; 29(11): 1319-1324, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27718492

RESUMO

Kearns-Sayre syndrome (KSS) is characterized by external ophthalmoplegia, retinal pigmentation and cardiac conduction defects due to mitochondrial DNA (mtDNA) deletions. Short stature and growth hormone (GH) deficiency have been reported in KSS, but data on GH treatment is limited. We describe the clinical presentation, phenotype evolution, and response to GH in a patient with KSS and report data on eight additional KSS patients from the KIGS database. Our patient with KSS and GH deficiency achieved a final adult height at -0.8 SDS. In the KIGS database GH treatment resulted in mean improvement in height from -3.9 to -2.9 SDS in patients with KSS. Two patients did not show growth improvement. Our data shows improvement in height SDS in our patient and mixed results in eight additional patients from the KIGS database after treatment with GH. Heterogeneity in responsiveness may relate to presence of GH deficiency or severity of underlying mitochondrial dysfunction.


Assuntos
Transtornos do Crescimento/prevenção & controle , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/uso terapêutico , Síndrome de Kearns-Sayre/tratamento farmacológico , Estatura , Criança , Registros Eletrônicos de Saúde , Feminino , Transtornos do Crescimento/etiologia , Terapia de Reposição Hormonal/efeitos adversos , Hormônio do Crescimento Humano/efeitos adversos , Hormônio do Crescimento Humano/deficiência , Humanos , Síndrome de Kearns-Sayre/fisiopatologia , Medicina de Precisão , Resultado do Tratamento
12.
NPJ Genom Med ; 1: 16016, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-29263815

RESUMO

Targeted next-generation sequencing (NGS) identified a novel loss of function mutation in GARS, a gene linked to Charcot-Marie-Tooth disease (CMT), in a paediatric acute lymphoblastic leukaemia patient with severe chemotherapy-induced peripheral neuropathy (CIPN) due to vincristine. The patient was clinically asymptomatic, and lacked a family history of neuropathy. The effect of the mutation was modelled in a zebrafish knockdown system that recapitulated the symptoms of the patient both prior to and after treatment with vincristine. Confocal microscopy of pre- and post-synaptic markers revealed that the GARS knockdown results in changes to peripheral motor neurons, acetylcholine receptors and their co-localisation in neuromuscular junctions (NMJs), whereas a sensitive and reproducible stimulus-response assay demonstrated that the changes correlating with the GARS mutation in themselves fail to produce peripheral neuropathy symptoms. However, with vincristine treatment the GARS knockdown exacerbates decreased stimulus response and NMJ lesions. We propose that there is substantial benefit in the use of a targeted NGS screen of cancer patients who are to be treated with microtubule targeting agents for deleterious mutations in CMT linked genes, and for the screening in zebrafish of reagents that might inhibit CIPN.

13.
Orphanet J Rare Dis ; 10: 131, 2015 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-26446585

RESUMO

BACKGROUND: Enzyme replacement therapy (ERT) with laronidase, (recombinant human α-L-iduronidase; Aldurazyme) is the primary treatment option for patients with attenuated mucopolysaccharidosis type I (MPS I). This study examined the effect of early ERT on clinical manifestations. METHODS: This multinational, retrospective case series abstracted data from records of 20 patients with Hurler-Scheie syndrome within nine sibships that included older siblings treated with laronidase after the development of significant clinical symptoms, and younger siblings treated before significant symptomatology. Median age at diagnosis was 5.6 and 0.5 years for older and younger siblings, respectively. Median age at ERT initiation was 7.9 and 1.9 years for older and younger siblings, respectively. RESULTS: Improvement or stabilization of somatic signs and symptoms was more notable in younger siblings. Organomegaly present at onset of ERT improved in the majority of both older and younger siblings. Analysis of physician-rated symptom severity demonstrated that cardiac, musculoskeletal, and cognitive symptoms, when absent or mild in younger siblings at ERT initiation, generally did not develop or progress. The majority of older siblings had height/length Z-scores greater than two standard deviations below the mean (less than -2) at both time points. In general, Z-scores for younger siblings were closer to the sex- and age-matched means at follow-up. CONCLUSIONS: These findings suggest early initiation of laronidase, prior to the onset of symptoms in patients with attenuated MPS I, can slow or prevent the development of severe clinical manifestations.


Assuntos
Iduronidase/uso terapêutico , Mucopolissacaridose I/diagnóstico por imagem , Mucopolissacaridose I/tratamento farmacológico , Irmãos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Internacionalidade , Masculino , Mucopolissacaridose I/genética , Radiografia , Estudos Retrospectivos , Resultado do Tratamento
15.
Pediatr Dev Pathol ; 17(6): 474-7, 2014 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25075748

RESUMO

Galactosialidosis (GS) is a rare autosomal recessive lysosomal storage disease caused by a combined deficiency of lysosomal ß-galactosidase and neuraminidase as a result of a genetic defect in the protective protein/cathepsin A gene. We report a case of unsuspected fetal galactosialidosis presenting as severe intrauterine growth restriction and oligohydramnios prenatally and as hyperinsulinemic hypoglycemia in the immediate postnatal period. Placental pathology examination showed striking vacuolations of the villous syncytiotrophoblast, extravillous trophoblast, and villous Hofbauer cells. Electron microscopy revealed numerous membrane-bound electron-lucent lysosomes, mainly within the syncytiotrophoblast. The characteristic histologic and ultrastructural placental findings prompted biochemical and molecular genetic testing for fetal storage disease. Enzyme activity of ß-galactosidase was decreased in leukocytes and fibroblasts. Sialic acid content was elevated. Molecular genetic studies revealed 3 variants--c.108, 110delGCT(L37del), c.1045T>A (C349S), and c.1321C>T(R441C)--of the cathepsin A gene, the latter 2 of which have not been previously reported. These findings are consistent with galactosialidosis. We emphasize the importance of following the accepted practice guideline for the examination of the placenta in discovering unsuspected fetal metabolic disorders.


Assuntos
Catepsina A/genética , Doenças por Armazenamento dos Lisossomos/genética , Mutação , Trofoblastos/ultraestrutura , Vacúolos/ultraestrutura , Adulto , Biópsia , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Humanos , Recém-Nascido , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças por Armazenamento dos Lisossomos/enzimologia , Microscopia Eletrônica , Fenótipo
16.
Genet Med ; 14(9): 800-10, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22538254

RESUMO

PURPOSE: Enzyme replacement therapy with alglucosidase alfa for infantile Pompe disease has improved survival creating new management challenges. We describe an emerging phenotype in a retrospective review of long-term survivors. METHODS: Inclusion criteria included ventilator-free status and age ≤6 months at treatment initiation, and survival to age ≥5 years. Clinical outcome measures included invasive ventilator-free survival and parameters for cardiac, pulmonary, musculoskeletal, gross motor, and ambulatory status; growth; speech, hearing, and swallowing; and gastrointestinal and nutritional status. RESULTS: Eleven of 17 patients met study criteria. All were cross-reactive immunologic material-positive, alive, and invasive ventilator-free at most recent assessment, with a median age of 8.0 years (range: 5.4-12.0 years). All had marked improvements in cardiac parameters. Commonly present were gross motor weakness, motor speech deficits, sensorineural and/or conductive hearing loss, osteopenia, gastroesophageal reflux, and dysphagia with aspiration risk. Seven of 11 patients were independently ambulatory and four required the use of assistive ambulatory devices. All long-term survivors had low or undetectable anti-alglucosidase alfa antibody titers. CONCLUSION: Long-term survivors exhibited sustained improvements in cardiac parameters and gross motor function. Residual muscle weakness, hearing loss, risk for arrhythmias, hypernasal speech, dysphagia with risk for aspiration, and osteopenia were commonly observed findings.


Assuntos
Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/patologia , Sobreviventes , alfa-Glucosidases/administração & dosagem , Autoanticorpos/sangue , Doenças Ósseas Metabólicas/patologia , Criança , Pré-Escolar , Deglutição , Transtornos de Deglutição/patologia , Feminino , Refluxo Gastroesofágico/patologia , Doença de Depósito de Glicogênio Tipo II/sangue , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Perda Auditiva/patologia , Humanos , Masculino , Debilidade Muscular/patologia , Fenótipo , Estudos Retrospectivos , Distúrbios da Fala/patologia , Resultado do Tratamento , alfa-Glucosidases/sangue
18.
J Pediatr ; 158(4): 538-42, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21232766

RESUMO

OBJECTIVE: To test the hypothesis that very low birth weight (VLBW) and extremely low birth weight (ELBW) infants have an increased incidence of congenital hypothyroidism (CH) with a delayed thyroid-stimulating hormone (TSH) elevation and that the outcomes of these infants are similar to control infants. STUDY DESIGN: Retrospective analysis of newborn thyroid screening data for 92 800 live births in Rhode Island to identify CH with a delayed TSH elevation. Developmental, growth, and endocrine outcomes of the index cases were assessed at 18 months corrected age. RESULTS: CH with a delayed TSH elevation occurred in 1 in 58 ELBW, 1 in 95 VLBW, and 1 in 30 329 infants weighing ≥1500 grams (P < .0001). The incidence of head circumference <10(th) percentile was higher in VLBW infants with CH associated with a delayed TSH elevation (P < .05), and the mean head circumferences, weights, lengths, and developmental scores were similar to matched control infants. Three infants received short-term levothyroxine replacement. CONCLUSIONS: The incidence of CH with a delayed TSH elevation was higher in ELBW and VLBW infants compared with infants weighing ≥1500 grams. The outcomes of these infants were comparable with matched control infants.


Assuntos
Hipotireoidismo Congênito/sangue , Hipotireoidismo Congênito/epidemiologia , Recém-Nascido de muito Baixo Peso , Tireotropina/sangue , Hipotireoidismo Congênito/terapia , Feminino , Humanos , Incidência , Lactente , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro , Recém-Nascido de muito Baixo Peso/sangue , Masculino , Triagem Neonatal , Tiroxina/sangue , Resultado do Tratamento
19.
Radiology ; 256(3): 744-50, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20634430

RESUMO

PURPOSE: To evaluate the effect of in utero exposure to a single dose of water-soluble intravenous iodinated contrast medium on thyroid function at birth. MATERIALS AND METHODS: This study was approved by the institutional review board, with waiver of consent, and was HIPAA compliant. Maternal and newborn records were retrospectively reviewed. All pregnant women who underwent multidetector pulmonary computed tomographic angiography because they were suspected of having pulmonary embolism between 2004 and 2008 and newborns resulting from the index pregnancy were included. In all examinations, iohexol was used as the contrast agent. Dose and amount of contrast agent and gestational age at the time of administration of the contrast agent were collected, and thyroxine (T(4)) and thyroid-stimulating hormone (TSH) levels were measured at birth. A total of 344 maternal and 343 newborn records were reviewed. A descriptive analysis was performed, and means, standard deviations, and confidence intervals were reported. RESULTS: Mean gestational age at the time of administration of the contrast material was 27.8 weeks +/- 7.4. The mean dose of total iodine administered was 45,000 mg/L +/- 7321. All newborns had a normal T(4) level at birth; only one newborn had a transiently abnormal TSH level at birth, which normalized at day 6 of life. This newborn was born to a mother who had many drug exposures during pregnancy. CONCLUSION: A single, high-dose in utero exposure to water-soluble, low-osmolar, iodinated intravenous products, such as iohexol, is unlikely to have a clinically important effect on thyroid function at birth.


Assuntos
Meios de Contraste/efeitos adversos , Iohexol/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Glândula Tireoide/efeitos dos fármacos , Adulto , Meios de Contraste/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Recém-Nascido , Iohexol/administração & dosagem , Gravidez , Resultado da Gravidez , Embolia Pulmonar/diagnóstico por imagem , Estudos Retrospectivos , Testes de Função Tireóidea , Glândula Tireoide/embriologia , Tireotropina/sangue , Tomografia Computadorizada por Raios X
20.
Am J Physiol Endocrinol Metab ; 299(2): E325-34, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20530736

RESUMO

The ATDC5 cell line exhibits a multistep process of chondrogenic differentiation analogous to that observed during endochondral bone formation. Previous investigators have induced ATDC5 cells to differentiate by exposing them to insulin at high concentrations. We have observed spontaneous differentiation of ATDC5 cells maintained in ascorbic acid-containing alpha-MEM. A comparison of the differentiation events in response to high-dose insulin vs. ascorbic acid showed similar expression patterns of key genes, including collagen II, Runx2, Sox9, Indian hedgehog, and collagen X. We took advantage of the action of ascorbic acid to examine signaling events associated with differentiation. In contrast to high-dose insulin, which downregulates both IGF-I and insulin receptors, there were only minimal changes in the abundance of these receptors during ascorbic acid-induced differentiation. Furthermore, ascorbic acid exposure was associated with ERK activation, and ERK inhibition attenuated ascorbic acid-induced differentiation. This was in contrast to the inhibitory effect of ERK activation during IGF-I-induced differentiation. Inhibition of collagen formation with a proline analog markedly attenuated the differentiating effect of ascorbic acid on ATDC5 cells. When plates were conditioned with ATDC5 cells exposed to ascorbic acid, ATDC5 cells were able to differentiate in the absence of ascorbic acid. Our results indicate that matrix formation early in the differentiation process is essential for ascorbic acid-induced ATDC5 differentiation. We conclude that ascorbic acid can promote the differentiation of ATDC5 cells by promoting the formation of collagenous matrix and that matrix formation mediates activation of the ERK signaling pathway, which promotes the differentiation program.


Assuntos
Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Diferenciação Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Animais , Western Blotting , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Colágeno/biossíntese , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Insulina/fisiologia , Fator de Crescimento Insulin-Like I/fisiologia , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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