IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction.
Joustra, Sjoerd D
Schneider, Harald J
Kosilek, Robert P
Kroon, Herman M
Le Tissier, Paul
Duncan Bassett, JH
Williams, Graham R
Wit, Jan M
Biermasz, Nienke R
Bernard, Daniel J
The Journal of clinical endocrinology and metabolism
Oxford University Press
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Joustra, S. D., Roelfsema, F., van Trotsenburg, A. P., Schneider, H. J., Kosilek, R. P., Kroon, H. M., Logan, J. G., et al. (2020). IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction.. The Journal of clinical endocrinology and metabolism, 105 (3)https://doi.org/10.1210/clinem/dgz093
ABSTRACT 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 growth hormone (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 seven 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 2-3 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.
Animals, Humans, Mice, Growth Hormone, Intercellular Signaling Peptides and Proteins, Insulin-Like Growth Factor I, Immunoglobulins, Membrane Proteins, Neurosecretion, Adult, Aged, Aged, 80 and over, Middle Aged, Male, Somatotrophs
: We acknowledge support from the Wellcome Trust to NS (100585/Z/12/A), GRW and JHDB (Strategic Award 101123/Z/13/A; Joint Investigator Awards 110140/Z/15/Z and 110141/Z/15/Z) and The National Institute for Health Research Biomedical Research Centre Cambridge (MG, NS). The Disease Model Core is supported by the UK MRC Metabolic Diseases Unit [MC_UU_00014/5] and the Wellcome Trust Major Award [208363/Z/17/Z]). PLT was funded by the UK MRC (U117562207). The Core biochemical Assay Laboratory is supported by MRC Metabolic Diseases Unit [MC_UU_00014/5]. DJB was supported by grants from the Canadian Institutes of Health Research (MOP-133557) and the Natural Sciences and Engineering Research Council of Canada (2015-05178).
Wellcome Trust (100585/Z/12/Z)
Wellcome Trust (208363/Z/17/Z)
External DOI: https://doi.org/10.1210/clinem/dgz093
This record's URL: https://www.repository.cam.ac.uk/handle/1810/297051
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