title: The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGFβ and Activin pathways.
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.
authors.affiliation: Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: García
authors.affiliation: Pediatric Endocrinology and Diabetes, Ramón y Cajal University Hospital, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Barrio
authors.affiliation: Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela, Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: García-Lavandeira
authors.affiliation: Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela, Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain.
authors.forename: Angela R
authors.initials: AR
authors.lastname: Garcia-Rendueles
authors.affiliation: Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain.
authors.forename: Adela
authors.initials: A
authors.lastname: Escudero
authors.affiliation: Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela, Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Díaz-Rodríguez
authors.affiliation: Department of Pediatrics, subdivision of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Darya
authors.initials: D
authors.lastname: Gorbenko Del Blanco
authors.affiliation: Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Fernández
authors.affiliation: Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Yolanda B
authors.initials: YB
authors.lastname: de Rijke
authors.affiliation: Functional and Structural Genomics, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Vallespín
authors.affiliation: Functional and Structural Genomics, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: Nevado
authors.affiliation: Functional and Structural Genomics, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.affiliation: Department of Biosciences, University of Oslo, Oslo, Norway.
authors.forename: Vilborg
authors.initials: V
authors.lastname: Matre
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center Rochester, NY, USA.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Hinkle
authors.affiliation: Department of Pediatrics, subdivision of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Anita C S
authors.initials: AC
authors.lastname: Hokken-Koelega
authors.affiliation: Cell Engineering Laboratory, La Paz Hospital Research Institute IdiPAZ, Madrid, Spain.
authors.forename: María P
authors.initials: MP
authors.lastname: de Miguel
authors.affiliation: Department of Anatomic Pathology, Medical Faculty, University of Santiago de Compostela, Clinical University Hospital, Santiago de Compostela, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Cameselle-Teijeiro
authors.affiliation: Department of Anatomy, Histology and Neuroscience, Autonomous University of Madrid, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Nistal
authors.affiliation: Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela, Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain.
authors.forename: Clara V
authors.initials: CV
authors.lastname: Alvarez
authors.affiliation: Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain.
authors.forename: José C
authors.initials: JC
authors.lastname: Moreno
mesh_terms: D028341:Activins / Q000378:metabolism*; D000818:Animals; D004252:DNA Mutational Analysis; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics / Q000378:metabolism*; D005500:Follow-Up Studies; D017353:Gene Deletion; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics / Q000473:pathology*; D007136:Immunoglobulins / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D051785:Smad Proteins / Q000378:metabolism; D013737:Testis / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D037201:Follicle Stimulating Hormone, beta Subunit; C112314:IGSF1 protein, human; D007136:Immunoglobulins; D008565:Membrane Proteins; D018025:Receptors, Thyrotropin-Releasing Hormone; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D028341:Activins