Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Using exome and candidate gene sequencing, we identified 8 distinct mutations and 2 deletions in IGSF1 in males from 11 unrelated families with central hypothyroidism, testicular enlargement and variably low prolactin concentrations. IGSF1 is a membrane glycoprotein that is highly expressed in the anterior pituitary gland, and the identified mutations impair its trafficking to the cell surface in heterologous cells. Igsf1-deficient male mice show diminished pituitary and serum thyroid-stimulating hormone (TSH) concentrations, reduced pituitary thyrotropin-releasing hormone (TRH) receptor expression, decreased triiodothyronine concentrations and increased body mass. Collectively, our observations delineate a new X-linked disorder in which loss-of-function mutations in IGSF1 cause central hypothyroidism, likely secondary to an associated impairment in pituitary TRH signaling.
|Titolo:||Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement|
|Parole Chiave:||thyrotropin-releasing-hormone; inhibin-protein; stimulation test; diagnosis; pituitary; bioactivity; expression; disorders; thyroxine; children|
|Settore Scientifico Disciplinare:||Settore MED/13 - Endocrinologia|
Settore MED/38 - Pediatria Generale e Specialistica
|Data di pubblicazione:||dic-2012|
|Digital Object Identifier (DOI):||10.1038/ng.2453|
|Appare nelle tipologie:||01 - Articolo su periodico|