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.

Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement / 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, H. Zhu, T.M.E. Davis, A.C..S. Hokken-Koelega, D.G. Del Blanco, J.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.D. Den Dunnen, M.G. Wade, M.H. Breuning, R.C. Hennekam, K. Chatterjee, M.T. Dattani, J.M. Wit, D.J. Bernard. - In: NATURE GENETICS. - ISSN 1061-4036. - 44:12(2012 Dec), pp. 1375-1381.

Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement

L. Persani;I. Campi;M. Bonomi;P. Beck-Peccoz;
2012

Abstract

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.
thyrotropin-releasing-hormone; inhibin-protein; stimulation test; diagnosis; pituitary; bioactivity; expression; disorders; thyroxine; children
Settore MED/13 - Endocrinologia
Settore MED/38 - Pediatria Generale e Specialistica
dic-2012
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/274944
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