Is IGSF1 involved in human pituitary tumor formation?

    1. Constantine A Stratakis1,4
    1. 1Section on Endocrinology and Genetics, 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
      2Group for Advanced Molecular Investigation, Graduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba 80215, Brazil
      3Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada H3G 1Y6
      4Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA
      5The Liggins Institute, University of Auckland, Auckland 1023, New Zealand
      6Taranaki Base Hospital, New Plymouth 4310, New Zealand
      7Auckland City Hospital & Greenlane Clinical Centre, Auckland 1142, New Zealand
      8Department of Neurosurgery, University of Virginia Health Sciences Center, University of Virginia, Charlottesville, Virginia 22904, USA
      9Surgical Neurology Branch, National Institute for Neurological Diseases and Stroke (NINDS), National Institutes of Health, Bethesda, Maryland 20892, USA Departments of
      10Endocrinology and Metabolic Disorders
      11Pediatrics, Leiden University Medical Center, Leiden 2333, The Netherlands
    1. Correspondence should be addressed to C A Stratakis; Email: stratakc{at}


    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.

    • Revision received 17 November 2014
    • Accepted 19 November 2014
    • Made available online as an Accepted Preprint 19 December 2014
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