IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction

Sjoerd D Joustra, Ferdinand Roelfsema, A S Paul van Trotsenburg, Harald J Schneider, Robert P Kosilek, Herman M Kroon, John G Logan, Natalie C Butterfield, Xiang Zhou, Chirine Toufaily, Beata Bak, Marc-Olivier Turgeon, Emilie Brûlé, Frederik J Steyn, Mark Gurnell, Olympia Koulouri, Paul Le Tissier, Pierre Fontanaud, J H Duncan Bassett, Graham R WilliamsWilma Oostdijk, Jan M Wit, Alberto M Pereira, Nienke R Biermasz, Daniel J Bernard, Nadia Schoenmakers

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

CONTEXT: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition.

OBJECTIVE: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function.

PATIENTS, DESIGN, AND SETTING: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting.

MAIN OUTCOME MEASURES: We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates.

RESULTS: IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels.

CONCLUSIONS: We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.

Original languageEnglish
JournalThe Journal of Clinical Endocrinology & Metabolism (JCEM)
Issue number3
Early online date25 Oct 2019
Publication statusPublished - 1 Mar 2020

Keywords / Materials (for Non-textual outputs)

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Growth Hormone/biosynthesis
  • Humans
  • Immunoglobulins/deficiency
  • Insulin-Like Growth Factor I/analysis
  • Intercellular Signaling Peptides and Proteins/deficiency
  • Male
  • Membrane Proteins/deficiency
  • Mice
  • Middle Aged
  • Neurosecretion/physiology
  • Somatotrophs/physiology


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