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1.
J Clin Endocrinol Metab ; 97(7): E1284-93, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22539591

ABSTRACT

CONTEXT: Childhood adrenocortical tumors (ACT) are rare malignancies, except in southern Brazil, where a higher incidence rate is associated to a high frequency of the founder R337H TP53 mutation. To date, copy number alterations in these tumors have only been analyzed by low-resolution comparative genomic hybridization. OBJECTIVE: We analyzed an international series of 25 childhood ACT using high-resolution single nucleotide polymorphism arrays to: 1) detect focal copy number alterations highlighting candidate driver genes; and 2) compare genetic alterations between Brazilian patients carrying the R337H TP53 mutation and non-Brazilian patients. RESULTS: We identified 16 significantly recurrent chromosomal alterations (q-value < 0.05), the most frequent being -4q34, +9q33-q34, +19p, loss of heterozygosity (LOH) of chromosome 17 and 11p15. Focal amplifications and homozygous deletions comprising well-known oncogenes (MYC, MDM2, PDGFRA, KIT, MCL1, BCL2L1) and tumor suppressors (TP53, RB1, RPH3AL) were identified. In addition, eight focal deletions were detected at 4q34, defining a sharp peak region around the noncoding RNA LINC00290 gene. Although non-Brazilian tumors with a mutated TP53 were similar to Brazilian tumors, those with a wild-type TP53 displayed distinct genomic profiles, with significantly fewer rearrangements (P = 0.019). In particular, three alterations (LOH of chromosome 17, +9q33-q34, and -4q34) were significantly more frequent in TP53-mutated samples. Finally, two of four TP53 wild-type tumors displayed as sole rearrangement a copy-neutral LOH of the imprinted region at 11p15, supporting a major role for this region in ACT development. CONCLUSIONS: Our findings highlight potential driver genes and cellular pathways implicated in childhood ACT and demonstrate the existence of different oncogenic routes in this pathology.


Subject(s)
Adrenal Cortex Neoplasms/genetics , Adrenocortical Adenoma/genetics , Adrenocortical Carcinoma/genetics , Cell Transformation, Neoplastic/genetics , Microarray Analysis , Polymorphism, Single Nucleotide , Adolescent , Adrenal Cortex Neoplasms/complications , Adrenal Cortex Neoplasms/epidemiology , Adrenocortical Adenoma/complications , Adrenocortical Adenoma/epidemiology , Adrenocortical Carcinoma/complications , Adrenocortical Carcinoma/epidemiology , Age of Onset , Child , Child, Preschool , Cohort Studies , Female , Gene Expression Profiling , Genetic Association Studies , Humans , Infant , Infant, Newborn , Male , Polymorphism, Single Nucleotide/physiology , Signal Transduction/genetics
3.
Am J Med Genet A ; 149A(8): 1754-7, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19606480

ABSTRACT

We detailed the story from birth to the age of 5 years 9 months, of the oldest patient reported with a Bohring-Opitz syndrome with the three main diagnostic criteria: characteristic facial appearance, fixed contractures of the upper limbs and severe feeding difficulties. The facial anomalies described in our patient were microcephaly, bitemporal narrowing, "puffy" cheeks, forehead naevus flammeus, hypoplastic orbital ridges, prominent eyes, broad nasal bridge, high arched palate, buccal-alveola frenula and retrognathism. The magnetic resonance imaging (MRI) of the brain showed a hypoplastic corpus callosum and a narrowed upper cervical canal; and the cervical MRI showed a malformation of the atlas consisting in an agenesis of the anterior arch and an anterior slip of the posterior arch. We focused on her neurological and nutritional evolution. Despite the gastrostomy and a Nissen fundoplication at age 7 months, she still had developmental growth delays overall (<3rd centile). At 3 years 9 months of age, she began to put on weight quickly, which seemed to be atypical. Meanwhile she developed epilepsy, which was controlled with specific drugs. Currently, she is 5 years 9 months old and has significant psychomotor retardation, although this disease is often fatal in early childhood, due to obstructive apnea and unexplained bradycardia.


Subject(s)
Abnormalities, Multiple/pathology , Cervical Vertebrae/pathology , Child , Child, Preschool , Female , Growth and Development , Hand Deformities, Congenital/complications , Hand Deformities, Congenital/pathology , Humans , Infant , Infant, Newborn , Magnetic Resonance Imaging , Syndrome
4.
Hum Reprod ; 23(8): 1708-18, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18503055

ABSTRACT

BACKGROUND: Since fetal exposure to anti-androgenic and/or estrogenic compounds has adverse effect on animal reproduction, such exposure could be harmful to human fetus. Data are scarce on cryptorchidism and human exposure to endocrine disruptors. METHODS: We performed a prospective case-control study to assess the incidence of cryptorchidism and fetal exposure to selected chemicals in the Nice area. One hundred and fifty-one cord bloods (67 cryptorchid, 84 tightly matched controls) and 125 colostrums (56 for cryptorchid and 69 for controls) were screened for xenobiotics, including anti-androgenic dichloro-diphenyl-trichloro-ethylene (DDE), polychlorinated biphenyls (PCBs), and dibutylphthalate (and metabolite monobutylphthalate, mBP). RESULTS: Median concentrations in colostrum were higher, although not statistically significantly, in cryptorchid versus controls. Cryptorchid boys were more likely to be classified in the most contaminated groups in colostrum for DDE, Sigma PCBs and the composite score PCB + DDE. The same trend, but again not statistically significantly was observed for mBP. Odds ratio for cryptorchidism was increased for the highest score of Sigma PCB, with a trend only for DDE and Sigma PCB + DDE versus the lowest score of those components. CONCLUSIONS: Our results support an association between congenital cryptorchidism and fetal exposure to PCBs and possibly DDE. Higher concentrations in milk could be a marker of higher exposure or for an impaired detoxification pattern in genetically predisposed individuals.


Subject(s)
Colostrum/chemistry , Cryptorchidism/chemically induced , Dichlorodiphenyl Dichloroethylene/adverse effects , Maternal Exposure/adverse effects , Polychlorinated Biphenyls/adverse effects , Adolescent , Adult , Africa South of the Sahara/ethnology , Case-Control Studies , Female , Fetal Blood/chemistry , Humans , Infant, Newborn , Male , Milk, Human/chemistry , Prospective Studies , White People
5.
Diabetes ; 57(5): 1216-26, 2008 May.
Article in English | MEDLINE | ID: mdl-18174527

ABSTRACT

OBJECTIVE: Oxidative stress is associated with insulin resistance and is thought to contribute to progression toward type 2 diabetes. Oxidation induces cellular damages through increased amounts of reactive aldehydes from lipid peroxidation. The aim of our study was to investigate 1) the effect of the major lipid peroxidation end product, 4-hydroxynonenal (HNE), on insulin signaling in 3T3-L1 adipocytes, and 2) whether fatty aldehyde dehydrogenase (FALDH), which detoxifies HNE, protects cells and improves insulin action under oxidative stress conditions. RESEARCH DESIGN AND METHODS: 3T3-L1 adipocytes were exposed to HNE and/or infected with control adenovirus or adenovirus expressing FALDH. RESULTS: Treatment of 3T3-L1 adipocytes with HNE at nontoxic concentrations leads to a pronounced decrease in insulin receptor substrate (IRS)-1/-2 proteins and in insulin-induced IRS and insulin receptor beta (IR beta) tyrosine phosphorylation. Remarkably, we detect increased binding of HNE to IRS-1/-2-generating HNE-IRS adducts, which likely impair IRS function and favor their degradation. Phosphatidylinositol 3-kinase and protein kinase B activities are also downregulated upon HNE treatment, resulting in blunted metabolic responses. Moreover, FALDH, by reducing adduct formation, partially restores HNE-generated decrease in insulin-induced IRS-1 tyrosine phosphorylation and metabolic responses. Moreover, rosiglitazone could have an antioxidant effect because it blocks the noxious HNE action on IRS-1 by increasing FALDH gene expression. Collectively, our data show that FALDH improves insulin action in HNE-treated 3T3-L1 adipocytes. CONCLUSION: Oxidative stress induced by reactive aldehydes, such as HNE, is implicated in the development of insulin resistance in 3T3-L1 adipocytes, which is alleviated by FALDH. Hence, detoxifying enzymes could play a crucial role in blocking progression of insulin resistance to diabetes.


Subject(s)
Adipocytes/physiology , Aldehyde Dehydrogenase/metabolism , Aldehydes/pharmacology , Insulin/physiology , Oxidative Stress/drug effects , Signal Transduction/physiology , 3T3 Cells , Adipocytes/cytology , Adipocytes/drug effects , Aldehyde Dehydrogenase/genetics , Animals , Biological Transport/drug effects , Cell Differentiation , Cells, Cultured , Deoxyglucose/metabolism , Mice , Phosphatidylinositol 3-Kinases/metabolism , Polymerase Chain Reaction , Proto-Oncogene Proteins c-akt/metabolism , Recombinant Proteins/metabolism
6.
J Clin Endocrinol Metab ; 92(8): 3253-60, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17566092

ABSTRACT

CONTEXT: Childhood adrenocortical tumors (ACTs) have a fetal adrenal phenotype and overexpress steroidogenic factor-1 (SF-1). Nephroblastoma overexpressed (NOV)/cysteine-rich protein 61/connective tissue growth factor/nephroblastoma overexpressed gene-3 mRNA is significantly down-regulated in childhood ACTs. OBJECTIVE: The objective of the study was to measure NOV protein levels in childhood ACTs and characterize NOV expression regulation and biological function in human adrenocortical cells. DESIGN AND SETTING: Protein extracts from ACT and normal adrenal cortex samples, human adrenocortical carcinoma H295R, primary adrenocortical tumors and fetal adrenal cultures, tissue culture supernatants, and cell lysates from H295R cells overexpressing SF-1 in an inducible fashion were used. MAIN OUTCOME MEASURES: NOV protein levels were measured by enzyme-linked immunoassay and immunoblot. Transient transfection assays were used to study the activity of NOV promoter. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling, caspase assays, and flow cytometry were used to assess the proapoptotic activity of NOV on cells in culture. RESULTS: NOV mRNA and protein expression is lower in childhood ACTs than in normal adrenal cortex. No significant difference was observed between adenomas and carcinomas. SF-1 overexpression down-regulates NOV at the transcriptional level. NOV has a selective proapoptotic activity toward human adrenocortical cells. The C-terminal domain of NOV is responsible for its proapoptotic effect. NOV protein is expressed in DAX-1-positive human fetal adrenal cells. CONCLUSIONS: NOV is a selective proapoptotic factor for human adrenocortical cells. Reduced expression of NOV in ACTs may play an important role in the process of childhood ACT tumorigenesis, accounting at least in part for the defect of apoptotic regression of the fetal adrenal that has been proposed to be responsible for tumor formation.


Subject(s)
Adenoma/metabolism , Adrenal Cortex Neoplasms/metabolism , Adrenal Cortex/cytology , Apoptosis/genetics , Apoptosis/physiology , Carcinoma/metabolism , Gene Expression Regulation, Neoplastic/genetics , Immediate-Early Proteins/genetics , Intercellular Signaling Peptides and Proteins/genetics , Adenoma/genetics , Adenoma/pathology , Adrenal Cortex/physiology , Adrenal Cortex Neoplasms/genetics , Adrenal Cortex Neoplasms/pathology , Carcinoma/genetics , Carcinoma/pathology , Caspases/metabolism , Cell Line, Tumor , Child , Connective Tissue Growth Factor , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Down-Regulation/genetics , Down-Regulation/physiology , Enzyme Activation/physiology , Flow Cytometry , Fluorescent Antibody Technique , Gene Expression Regulation, Neoplastic/physiology , Homeodomain Proteins/biosynthesis , Homeodomain Proteins/genetics , Humans , Immediate-Early Proteins/biosynthesis , Immunoblotting , Intercellular Signaling Peptides and Proteins/biosynthesis , Luciferases/biosynthesis , Luciferases/genetics , Nephroblastoma Overexpressed Protein , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Neoplasm/biosynthesis , RNA, Neoplasm/genetics , Receptors, Cytoplasmic and Nuclear/biosynthesis , Receptors, Cytoplasmic and Nuclear/genetics , Reverse Transcriptase Polymerase Chain Reaction , Steroidogenic Factor 1 , Transcription Factors/biosynthesis , Transcription Factors/genetics , Transfection
7.
Eur J Endocrinol ; 155(1): 47-52, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16793949

ABSTRACT

OBJECTIVE: Clinical features associated with microdeletion of chromosome 22q11 (del(22)(q11)) are highly variable. Increased awareness of this condition is needed among specialists such as endocrinologists to reduce diagnostic delay and improve clinical care. The purpose of this study was to describe the phenotype of patients with del(22)(q11), focusing on parathyroid gland dysfunction. DESIGN AND METHODS: Charts of 19 patients, including one kindred of three, known to have del(22)(q11) diagnosed by fluorescence in situ hybridization (FISH) were reviewed from the register of the department of Medical Genetics. Major clinical features including hypoparathyroidism phenotype were collected. RESULTS: Parathyroid dysfunction was present in 8 out of 16 patients (50%). Six patients were diagnosed with overt hypoparathyroidism. Hypocalcemia manifested as laryngeal stridor within the first days of life (n = 3), seizures in infancy (n = 1) and adolescence (n = 2). The connection between hypoparathyroidism and diagnosis of del(22)(q11) was belated at the median age of 18 years. One patient had presented with transient neonatal hypoparathyroidism, and one patient had latent hypoparathyroidism. Within the kindred family, the phenotype variability including that of parathyroid dysfunction was as marked as between unrelated individuals. Standard karyotype failed to detect the deletion in 15 out of 19 cases. CONCLUSIONS: Abnormal parathyroid function in the del(22)(q11) ranges from severe neonatal hypocalcemia to latent hypoparathyroidism. Del(22)(q11) should be considered as a potential cause of hypocalcemia even in young adult. When suspected, the diagnosis requires investigation by FISH. Furthermore, long-term calcemia follow-up is needed in normocalcemic patients with del(22)(q11) because of the possible evolution to hypocalcemic hypoparathyroidism.


Subject(s)
Chromosomes, Human, Pair 22/genetics , Gene Deletion , Parathyroid Diseases/genetics , Adolescent , Adult , Female , Humans , Hypocalcemia/blood , Hypocalcemia/etiology , Hypoparathyroidism/etiology , Hypoparathyroidism/genetics , In Situ Hybridization, Fluorescence , Karyotyping , Male , Middle Aged , Parathyroid Diseases/blood , Parathyroid Diseases/physiopathology , Parathyroid Hormone/blood , Phenotype , Retrospective Studies , Seizures/etiology , Seizures/genetics
8.
J Biol Chem ; 279(8): 6261-70, 2004 Feb 20.
Article in English | MEDLINE | ID: mdl-14638678

ABSTRACT

Phosphatidylinositol 3-kinase signaling regulates the expression of several genes involved in lipid and glucose homeostasis; deregulation of these genes may contribute to insulin resistance and progression toward type 2 diabetes. By employing RNA arbitrarily primed-PCR to search for novel phosphatidylinositol 3-kinase-regulated genes in response to insulin in isolated rat adipocytes, we identified fatty aldehyde dehydrogenase (FALDH), a key component of the detoxification pathway of aldehydes arising from lipid peroxidation events. Among these latter events are oxidative stresses associated with insulin resistance and diabetes. Upon insulin injection, FALDH mRNA expression increased in rat liver and white adipose tissue and was impaired in two models of insulin-resistant mice, db/db and high fat diet mice. FALDH mRNA levels were 4-fold decreased in streptozotocin-treated rats, suggesting that FALDH deregulation occurs both in hyperinsulinemic insulin-resistant state and hypoinsulinemic type 1 diabetes models. Moreover, insulin treatment increases FALDH activity in hepatocytes, and expression of FALDH was augmented during adipocyte differentiation. Considering the detoxifying role of FALDH, its deregulation in insulin-resistant and type 1 diabetic models may contribute to the lipid-derived oxidative stress. To assess the role of FALDH in the detoxification of oxidized lipid species, we evaluated the production of reactive oxygen species in normal versus FALDH-overexpressing adipocytes. Ectopic expression of FALDH significantly decreased reactive oxygen species production in cells treated by 4-hydroxynonenal, the major lipid peroxidation product, suggesting that FALDH protects against oxidative stress associated with lipid peroxidation. Taken together, our observations illustrate the importance of FALDH in insulin action and its deregulation in states associated with altered insulin signaling.


Subject(s)
Aldehyde Oxidoreductases/physiology , Gene Expression Regulation, Enzymologic , Insulin/metabolism , Adenoviridae/genetics , Adipocytes/metabolism , Adipose Tissue/metabolism , Aldehyde Oxidoreductases/chemistry , Aldehydes/pharmacology , Animals , Blotting, Northern , Blotting, Western , Cell Differentiation , Culture Techniques , Cysteine Proteinase Inhibitors/pharmacology , Diabetes Mellitus, Experimental/enzymology , Hepatocytes/metabolism , Humans , Insulin Resistance , Lipid Metabolism , Lipid Peroxidation , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Models, Biological , Oxidative Stress , Oxygen/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Polymerase Chain Reaction , RNA/chemistry , RNA, Messenger/metabolism , Rats , Rats, Wistar , Reactive Oxygen Species , Signal Transduction , Streptozocin/pharmacology , Tissue Distribution
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