The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGF\u03b2 and Activin pathways

Marta García,María P De Miguel,Adela Escudero,Elena Vallespín,Montserrat García-Lavandeira,Julián Nevado,Darya Gorbenko Del Blanco,Patricia M Hinkle,Raquel Barrio,Clara V Álvarez ,Manuel Nistal,Angela R Garcia-Rendueles,Yolanda B De Rijke,Esther Díaz‐Rodriguez ,Ana Patricia Fernández ,Pablo Lapunzina,Vilborg Matre,Anita Hokken-Koelega ,José Cameselle-Teijeiro ,José Moreno

doi:10.1038/srep42937

Abstract

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.

Highlights

Central Congenital Hypothyroidism (CCH) is a group of hypothalamic-pituitary disorders leading to deficient thyrotropin (TSH) secretion and low thyroid hormone (T4 and T3) synthesis from an otherwise normal thyroid gland[1,2]
The typical testicular enlargement can be apparently absent in some IGSF1-deficient patients[12,13] while a variable presence of partial deficiency of growth hormone (GH) and prolactin was reported in a few others[4,11]
Neither the inhibitory DSmad[2] nor the constitutively active ALK4 receptor altered IGSF1 stimulation of thyrotropin-releasing hormone receptor (TRHR) promoter (Supplemental Fig. 6). These results indicate that IGSF1 action on the human TRHR is independent of activin A and must be mediated by an alternative signaling cascade

Summary

Introduction

Central Congenital Hypothyroidism (CCH) is a group of hypothalamic-pituitary disorders leading to deficient thyrotropin (TSH) secretion and low thyroid hormone (T4 and T3) synthesis from an otherwise normal thyroid gland[1,2]. In 2009, we described the clinical association of familial isolated central hypothyroidism and testicular enlargement, suggesting a genetic nature of the disorder[3] Such combined (hypophyseal-testicular) phenotype was linked to defects in the IGSF1 gene in male adolescents and adults[4]. The molecular function and implications of IGSF1 on gonadal and thyroid hormone axes remain to be elucidated Knowing such mechanisms will be valuable to explain the large phenotypic variability of patients with IGSF1 defects and to define the physiological pathways disrupted in the disorder[4,11]. IGSF1 potentiates transcription of the human thyrotropin-releasing hormone receptor (TRHR) promoter by repressing the TGFβ1-Smad pathway, a signal which is negatively modulating TRHR expression. This work unravels a crucial role of IGSF1 as an important regulator of TGFβsuperfamily pathways in the pituitary

Methods

Results

Conclusion