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Thais Biude Mendes Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil

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Bruno Heidi Nozima Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil

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Alexandre Budu Enzymology Laboratory, Department of Biophysics, Universidade Federal de São Paulo, São Paulo, Brazil

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Rodrigo Barbosa de Souza Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil

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Marcia Helena Braga Catroxo Laboratory of Electron Microscopy, Center for Research and Development of Animal Health, Instituto Biológico, São Paulo, Brazil

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Rosana Delcelo Department of Pathology, Universidade Federal de São Paulo, São Paulo, Brazil

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Marcos Leoni Gazarini Cell Signaling Laboratory in Plasmodium, Department of Biosciences, Universidade Federal de São Paulo, Santos, São Paulo, Brazil

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Janete Maria Cerutti Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil

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We have identified previously a panel of markers (C1orf24, ITM1 and PVALB) that can help to discriminate benign from malignant thyroid lesions. C1orf24 and ITM1 are specifically helpful for detecting a wide range of thyroid carcinomas, and PVALB is particularly valuable for detecting the benign Hürthle cell adenoma. Although these markers may ultimately help patient care, the current understanding of their biological functions remains largely unknown. In this article, we investigated whether PVALB is critical for the acquisition of Hürthle cell features and explored the molecular mechanism underlying the phenotypic changes. Through ectopic expression of PVALB in thyroid carcinoma cell lines (FTC-133 and WRO), we demonstrated that PVALB sequesters free cytoplasmic Ca2+, which ultimately lowers calcium levels and precludes endoplasmic reticulum (ER) Ca2+ refilling. These results were accompanied by induced expression of PERK, an ER stress marker. Additionally, forced expression of PVALB reduces Ca2+ inflow in the mitochondria, which can in turn cause changes in mitochondria morphology, increase mitochondria number and alter subcellular localization. These findings share striking similarity to those observed in Hürthle cell tumors. Moreover, PVALB inhibits cell growth and induces cell death, most likely through the AKT/GSK-3β. Finally, PVALB expression coincides with Ca2+ deposits in HCA tissues. Our data support the hypothesis that the loss of PVALB plays a role in the pathogenesis of thyroid tumors.

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Paraskevi Xekouki Section on Endocrinology and Genetics, Pediatric Endocrinology Inter‐institute Training Program Building 10, Molecular Neurophysiology and Biophysics Unit, Endocrine Oncology Section, Program on Developmental Endocrinology and Genetics (PDEGEN)

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Michael M Hatch Section on Endocrinology and Genetics, Pediatric Endocrinology Inter‐institute Training Program Building 10, Molecular Neurophysiology and Biophysics Unit, Endocrine Oncology Section, Program on Developmental Endocrinology and Genetics (PDEGEN)

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Lin Lin Section on Endocrinology and Genetics, Pediatric Endocrinology Inter‐institute Training Program Building 10, Molecular Neurophysiology and Biophysics Unit, Endocrine Oncology Section, Program on Developmental Endocrinology and Genetics (PDEGEN)

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De Alexandre Rodrigo Section on Endocrinology and Genetics, Pediatric Endocrinology Inter‐institute Training Program Building 10, Molecular Neurophysiology and Biophysics Unit, Endocrine Oncology Section, Program on Developmental Endocrinology and Genetics (PDEGEN)

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Monalisa Azevedo Section on Endocrinology and Genetics, Pediatric Endocrinology Inter‐institute Training Program Building 10, Molecular Neurophysiology and Biophysics Unit, Endocrine Oncology Section, Program on Developmental Endocrinology and Genetics (PDEGEN)

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Maria de la Luz Sierra Section on Endocrinology and Genetics, Pediatric Endocrinology Inter‐institute Training Program Building 10, Molecular Neurophysiology and Biophysics Unit, Endocrine Oncology Section, Program on Developmental Endocrinology and Genetics (PDEGEN)

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Isaac Levy Section on Endocrinology and Genetics, Pediatric Endocrinology Inter‐institute Training Program Building 10, Molecular Neurophysiology and Biophysics Unit, Endocrine Oncology Section, Program on Developmental Endocrinology and Genetics (PDEGEN)

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Emmanouil Saloustros Section on Endocrinology and Genetics, Pediatric Endocrinology Inter‐institute Training Program Building 10, Molecular Neurophysiology and Biophysics Unit, Endocrine Oncology Section, Program on Developmental Endocrinology and Genetics (PDEGEN)

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Andreas Moraitis Section on Endocrinology and Genetics, Pediatric Endocrinology Inter‐institute Training Program Building 10, Molecular Neurophysiology and Biophysics Unit, Endocrine Oncology Section, Program on Developmental Endocrinology and Genetics (PDEGEN)

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Anelia Horvath Section on Endocrinology and Genetics, Pediatric Endocrinology Inter‐institute Training Program Building 10, Molecular Neurophysiology and Biophysics Unit, Endocrine Oncology Section, Program on Developmental Endocrinology and Genetics (PDEGEN)

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E Kebebew Section on Endocrinology and Genetics, Pediatric Endocrinology Inter‐institute Training Program Building 10, Molecular Neurophysiology and Biophysics Unit, Endocrine Oncology Section, Program on Developmental Endocrinology and Genetics (PDEGEN)

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Dax A Hoffman Section on Endocrinology and Genetics, Pediatric Endocrinology Inter‐institute Training Program Building 10, Molecular Neurophysiology and Biophysics Unit, Endocrine Oncology Section, Program on Developmental Endocrinology and Genetics (PDEGEN)

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Constantine A Stratakis Section on Endocrinology and Genetics, Pediatric Endocrinology Inter‐institute Training Program Building 10, Molecular Neurophysiology and Biophysics Unit, Endocrine Oncology Section, Program on Developmental Endocrinology and Genetics (PDEGEN)
Section on Endocrinology and Genetics, Pediatric Endocrinology Inter‐institute Training Program Building 10, Molecular Neurophysiology and Biophysics Unit, Endocrine Oncology Section, Program on Developmental Endocrinology and Genetics (PDEGEN)

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KCNJ5 mutations were recently described in primary hyperaldosteronism (PH or Conn's syndrome). The frequency of these mutations in PH and the way KCNJ5 defects cause disease remain unknown. A total of 53 patients with PH have been seen at the National Institutes of Health over the last 12 years. Their peripheral and tumor DNAs (the latter from 16 that were operated) were screened for KCNJ5 mutations; functional studies on the identified defects were performed after transient transfection. Only two mutations were identified, and both in the tumor DNA only. There were no germline sequencing defects in any of the patients except for known synonymous variants of the KCNJ5 gene. One mutation was the previously described c.G451C alteration; the other was a novel one in the same codon: c.G451A; both lead to the same amino acid substitution (G151R) in the KCNJ5 protein. Functional studies confirmed previous findings that both mutations caused loss of channel selectivity and a positive shift in the reversal potential. In conclusion, the KCNJ5 protein was strongly expressed in the zona glomerulosa of normal adrenal glands but showed variable expression in the aldosterone-producing adenomas with and without mutation. The rate of KCNJ5 mutations among patients with PH and/or their tumors is substantially lower than what was previously reported. The G151R amino acid substitution appears to be the most frequent one so far detected in PH, despite additional nucleotide changes. The mutation causes loss of this potassium channel's selectivity and may assist in the design of new therapies for PH.

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Rodrigo B de Alexandre Section on Endocrinology and Genetics, School of Health and Biosciences, Department of Pharmacology and Physiology, Laboratory of Genomics and Molecular Biology, Department of Pathology, Department of Statistics, Program on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter‐institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA
Section on Endocrinology and Genetics, School of Health and Biosciences, Department of Pharmacology and Physiology, Laboratory of Genomics and Molecular Biology, Department of Pathology, Department of Statistics, Program on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter‐institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA

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Anelia D Horvath Section on Endocrinology and Genetics, School of Health and Biosciences, Department of Pharmacology and Physiology, Laboratory of Genomics and Molecular Biology, Department of Pathology, Department of Statistics, Program on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter‐institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA
Section on Endocrinology and Genetics, School of Health and Biosciences, Department of Pharmacology and Physiology, Laboratory of Genomics and Molecular Biology, Department of Pathology, Department of Statistics, Program on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter‐institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA

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Eva Szarek Section on Endocrinology and Genetics, School of Health and Biosciences, Department of Pharmacology and Physiology, Laboratory of Genomics and Molecular Biology, Department of Pathology, Department of Statistics, Program on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter‐institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA

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Allison D Manning Section on Endocrinology and Genetics, School of Health and Biosciences, Department of Pharmacology and Physiology, Laboratory of Genomics and Molecular Biology, Department of Pathology, Department of Statistics, Program on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter‐institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA

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Leticia F Leal Section on Endocrinology and Genetics, School of Health and Biosciences, Department of Pharmacology and Physiology, Laboratory of Genomics and Molecular Biology, Department of Pathology, Department of Statistics, Program on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter‐institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA

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Fabio Kardauke Section on Endocrinology and Genetics, School of Health and Biosciences, Department of Pharmacology and Physiology, Laboratory of Genomics and Molecular Biology, Department of Pathology, Department of Statistics, Program on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter‐institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA

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Jonathan A Epstein Section on Endocrinology and Genetics, School of Health and Biosciences, Department of Pharmacology and Physiology, Laboratory of Genomics and Molecular Biology, Department of Pathology, Department of Statistics, Program on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter‐institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA

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Dirce M Carraro Section on Endocrinology and Genetics, School of Health and Biosciences, Department of Pharmacology and Physiology, Laboratory of Genomics and Molecular Biology, Department of Pathology, Department of Statistics, Program on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter‐institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA

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Fernando A Soares Section on Endocrinology and Genetics, School of Health and Biosciences, Department of Pharmacology and Physiology, Laboratory of Genomics and Molecular Biology, Department of Pathology, Department of Statistics, Program on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter‐institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA

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Tatiyana V Apanasovich Section on Endocrinology and Genetics, School of Health and Biosciences, Department of Pharmacology and Physiology, Laboratory of Genomics and Molecular Biology, Department of Pathology, Department of Statistics, Program on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter‐institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA

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Constantine A Stratakis Section on Endocrinology and Genetics, School of Health and Biosciences, Department of Pharmacology and Physiology, Laboratory of Genomics and Molecular Biology, Department of Pathology, Department of Statistics, Program on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter‐institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA

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Fabio R Faucz Section on Endocrinology and Genetics, School of Health and Biosciences, Department of Pharmacology and Physiology, Laboratory of Genomics and Molecular Biology, Department of Pathology, Department of Statistics, Program on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter‐institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA
Section on Endocrinology and Genetics, School of Health and Biosciences, Department of Pharmacology and Physiology, Laboratory of Genomics and Molecular Biology, Department of Pathology, Department of Statistics, Program on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter‐institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA

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We hypothesized that mutations that inactivate phosphodiesterase (PDE) activity and lead to increased cAMP and cyclic guanosine monophosphate levels may be associated with prostate cancer (PCa). We sequenced the entire PDE coding sequences in the DNA of 16 biopsy samples from PCa patients. Novel mutations were confirmed in the somatic or germline state by Sanger sequencing. Data were then compared to the 1000 Genome Project. PDE, CREB and pCREB protein expression was also studied in all samples, in both normal and abnormal tissue, by immunofluorescence. We identified three previously described PDE sequence variants that were significantly more frequent in PCa. Four novel sequence variations, one each in the PDE4B, PDE6C, PDE7B and PDE10A genes, respectively, were also found in the PCa samples. Interestingly, PDE10A and PDE4B novel variants that were present in 19 and 6% of the patients were found in the tumor tissue only. In patients carrying PDE defects, there was pCREB accumulation (P<0.001), and an increase of the pCREB:CREB ratio (patients 0.97±0.03; controls 0.52±0.03; P-value <0.001) by immunohistochemical analysis. We conclude that PDE sequence variants may play a role in the predisposition and/or progression to PCa at the germline and/or somatic state respectively.

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Fabio R Faucz Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA
Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Anelia D Horvath Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Monalisa F Azevedo Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Isaac Levy Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Beata Bak Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Ying Wang Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Paraskevi Xekouki Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Eva Szarek Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Evgenia Gourgari Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA
Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Allison D Manning Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Rodrigo Bertollo de Alexandre Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA
Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Emmanouil Saloustros Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Giampaolo Trivellin Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Maya Lodish Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Paul Hofman Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Yvonne C Anderson Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA
Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Ian Holdaway Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Edward Oldfield Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Prashant Chittiboina Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Maria Nesterova Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Nienke R Biermasz Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Jan M Wit Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Daniel J Bernard Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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Constantine A Stratakis Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA
Section on Endocrinology and Genetics, Group for Advanced Molecular Investigation, Department of Pharmacology and Therapeutics, Pediatric Endocrinology Inter-institute Training Program, The Liggins Institute, Taranaki Base Hospital, Auckland City Hospital & Greenlane Clinical Centre, Department of Neurosurgery, Surgical Neurology Branch, Endocrinology and Metabolic Disorders, Pediatrics, Program on Developmental Endocrinology and Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USA

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IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary. Pathogenic mutations in the IGSF1 gene (on Xq26.2) are associated with X-linked central hypothyroidism and testicular enlargement in males. In this study, we tested the hypothesis that IGSF1 is involved in the development of pituitary tumors, especially those that produce growth hormone (GH). IGSF1 was sequenced in 21 patients with gigantism or acromegaly and 92 healthy individuals. Expression studies with a candidate pathogenic IGSF1 variant were carried out in transfected cells and immunohistochemistry for IGSF1 was performed in the sections of GH-producing adenomas, familial somatomammotroph hyperplasia, and in normal pituitary. We identified the sequence variant p.N604T, which in silico analysis suggested could affect IGSF1 function, in two male patients and one female with somatomammotroph hyperplasia from the same family. Of 60 female controls, two carried the same variant and seven were heterozygous for other variants. Immunohistochemistry showed increased IGSF1 staining in the GH-producing tumor from the patient with the IGSF1 p.N604T variant compared with a GH-producing adenoma from a patient negative for any IGSF1 variants and with normal control pituitary tissue. The IGSF1 gene appears polymorphic in the general population. A potentially pathogenic variant identified in the germline of three patients with gigantism from the same family (segregating with the disease) was also detected in two healthy female controls. Variations in IGSF1 expression in pituitary tissue in patients with or without IGSF1 germline mutations point to the need for further studies of IGSF1 action in pituitary adenoma formation.

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