Loss-of-funcation mutations in IGSFI cause an X-linked syndrome of central hypothyroidism and testicular englargement

Y. Sun, B. Bak, N. Schoenmakers, A.S.P. Van Trotsenburg, W. Oostdijk, P. Voshol, E. Cambridge, J.K. White, P. Le Tissier, S.N.M. Gharavy, J.P. Martinez-Barbera, W.H. Stokvis-Brantsma, T. Vulsma, M.J. Kempers, L. Persani, I. Campi, M. Bonomi, P. Beck-Peccoz, Hongdong Zhu, Timothy DavisA.C.S. Hokken-Koelega, D.G. Del Blanco, J. Rangasami, C.A.L. Ruivenkamp, J.F.J. Laros, M. Kriek, S.G. Kant, C.A.J. Bosch, N.R. Biermasz, N.M. Appelman-Dijkstra, E.P. Corssmit, G.C.J. Hovens, A.M. Pereira, J.T. Den Dunnen, M.G. Wade, M.H. Breuning, R.C. Hennekam, K. Chatterjee, M.T. Dattani, M.J. Wit, D.J. Bernard

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    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.
    Original languageEnglish
    Pages (from-to)1375-1383
    JournalNature Genetics
    Issue number12
    Early online date11 Nov 2012
    Publication statusPublished - 1 Dec 2012


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