RT Journal Article
T1 The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGFβ and Activin pathways
A1 García, Marta
A1 Barrio, Raquel
A1 García Lavandeira, Montserrat
A1 Rodríguez García-Rendueles, Ángela
A1 Escudero, Adela
A1 Díaz Rodríguez, Esther
A1 Gorbenko del Blanco, Darya
A1 Fernández, Ana
A1 de Rijke, Yolanda B.
A1 Vallespín, Elena
A1 Nevado, Julián
A1 Lapunzina, Pablo
A1 Matre, Vilborg
A1 Hinkle, Patricia M.
A1 Hokken-Koelega, Anita C. S.
A1 Miguel, María P. de
A1 Cameselle Teijeiro, José Manuel
A1 Nistal, Manuel
A1 Álvarez Villamarín, María Clara
A1 Moreno, José C.
AB IGSF1 (Immunoglobulin Superfamily 1) gene defects cause central hypothyroidism and macroorchidism. However, the pathogenic mechanisms of the disease remain unclear. Based on a patient with a full deletion of IGSF1 clinically followed from neonate to adulthood, we investigated a common pituitary origin for hypothyroidism and macroorchidism, and the role of IGSF1 as regulator of pituitary hormone secretion. The patient showed congenital central hypothyroidism with reduced TSH biopotency, over-secretion of FSH at neonatal minipuberty and macroorchidism from 3 years of age. His markedly elevated inhibin B was unable to inhibit FSH secretion, indicating a status of pituitary inhibin B resistance. We show here that IGSF1 is expressed both in thyrotropes and gonadotropes of the pituitary and in Leydig and germ cells in the testes, but at very low levels in Sertoli cells. Furthermore, IGSF1 stimulates transcription of the thyrotropin-releasing hormone receptor (TRHR) by negative modulation of the TGFβ1-Smad signaling pathway, and enhances the synthesis and biopotency of TSH, the hormone secreted by thyrotropes. By contrast, IGSF1 strongly down-regulates the activin-Smad pathway, leading to reduced expression of FSHB, the hormone secreted by gonadotropes. In conclusion, two relevant molecular mechanisms linked to central hypothyroidism and macroorchidism in IGSF1 deficiency are identified, revealing IGSF1 as an important regulator of TGFβ/Activin pathways in the pituitary.
PB Nature Publishing Group
SN 2045-2322
YR 2017
FD 2017
LK http://hdl.handle.net/10347/22398
UL http://hdl.handle.net/10347/22398
LA eng
NO García, M., Barrio, R., García-Lavandeira, M. et al. The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGFβ and Activin pathways. Sci Rep 7, 42937 (2017). https://doi.org/10.1038/srep42937
NO This work was supported in part by the grants from Research funding of the Madrid Autonomous Region ENDOSCREEN S2010/BMD-2396 (to J.C.M.) and the European Regional Development Fund (ERDF-FEDER) and the Spanish Ministry of Economy and Competitiveness SAF2010-19230 (to M.P.M.); and from the Social Funds of the European Community (ERDF-FEDER) and the Spanish Ministry of Economy and Competitiveness BFU2013-46109-R (to C.V.A.), from the Social Funds of the European Community (ERDF-FEDER) and the Xunta de Galicia R2014/050 REDICENT (to C.V.A.); and from Instituto de Salud Carlos III PI15/01501- FEDER (to J.M.C-T.)
DS Minerva
RD 28 abr 2026