The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGFβ and Activin pathways

• DOI: 10.1038/srep42937
• Publication Date: 2017-03-06T11:12:41Z
• Authors: Marta García; Raquel Barrio; Montserrat García...; Angela R. Garcia-...; Adela Escudero; Esther Díaz-Rodrí...; Darya Gorbenko De...; Ana Fernández; Yolanda B. de Rijke; Elena Vallespín; Julián Nevado; Pablo Lapunzina; Vilborg Matre; Patricia M. Hinkle; Anita C. S. Hokke...; María P. de Miguel; José Manuel Cames...; Manuel Nistal; Clara V. Alvarez; José C. Moreno
• Keywords: Thyrotropic cell

Abstract IGSF1 (Immunoglobulin Superfamily 1) gene defects cause central hypothyroidism and macroorchidism. However, the pathogenic mechanisms of disease remain unclear. Based on a patient with full deletion clinically followed from neonate to adulthood, we investigated common pituitary origin for macroorchidism, role as regulator hormone secretion. The showed congenital reduced TSH biopotency, over-secretion FSH at neonatal minipuberty macroorchidism 3 years age. His markedly elevated inhibin B was unable inhibit secretion, indicating status resistance. We show here that is expressed both in thyrotropes gonadotropes Leydig germ cells testes, but very low levels Sertoli cells. Furthermore, stimulates transcription thyrotropin-releasing receptor ( TRHR ) by negative modulation TGFβ1-Smad signaling pathway, enhances synthesis biopotency TSH, secreted thyrotropes. By contrast, strongly down-regulates activin-Smad leading expression FSHB, gonadotropes. In conclusion, two relevant molecular linked deficiency are identified, revealing an important TGFβ/Activin pathways pituitary.