TY - JOUR
T1 - IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction
AU - Joustra, Sjoerd D.
AU - Roelfsema, Ferdinand
AU - van Trotsenburg, A. S. Paul
AU - Schneider, Harald J.
AU - Kosilek, Robert P.
AU - Kroon, Herman M.
AU - Logan, John G.
AU - Butterfield, Natalie C.
AU - Zhou, Xiang
AU - Toufaily, Chirine
AU - Bak, Beata
AU - Turgeon, Marc-Olivier
AU - Brûlé, Emilie
AU - Steyn, Frederik J.
AU - Gurnell, Mark
AU - Koulouri, Olympia
AU - le Tissier, Paul
AU - Fontanaud, Pierre
AU - Duncan Bassett, J. H.
AU - Williams, Graham R.
AU - Oostdijk, Wilma
AU - Wit, Jan M.
AU - Pereira, Alberto M.
AU - Biermasz, Nienke R.
AU - Bernard, Daniel J.
AU - Schoenmakers, Nadia
PY - 2020/1/8
Y1 - 2020/1/8
N2 - 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.
AB - 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.
KW - IGSF1
KW - congenital hypopituitarism
KW - growth hormone
KW - pituitary
UR - http://www.scopus.com/inward/record.url?scp=85078685946&partnerID=8YFLogxK
U2 - https://doi.org/10.1210/clinem/dgz093
DO - https://doi.org/10.1210/clinem/dgz093
M3 - Article
C2 - 31650157
SN - 0021-972X
VL - 105
JO - Journal of clinical endocrinology and metabolism
JF - Journal of clinical endocrinology and metabolism
IS - 3
M1 - dgz093
ER -