TY - JOUR
T1 - Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement
AU - Sun, Yu
AU - Bak, Beata
AU - Schoenmakers, Nadia
AU - Van Trotsenburg, A. S Paul
AU - Oostdijk, Wilma
AU - Voshol, Peter
AU - Cambridge, Emma
AU - White, Jacqueline K.
AU - Le Tissier, Paul
AU - Gharavy, S. Neda Mousavy
AU - Martinez-Barbera, Juan P.
AU - Stokvis-Brantsma, Wilhelmina H.
AU - Vulsma, Thomas
AU - Kempers, Marlies J.
AU - Persani, Luca
AU - Campi, Irene
AU - Bonomi, Marco
AU - Beck-Peccoz, Paolo
AU - Zhu, Hongdong
AU - Davis, Timothy M E
AU - Hokken-Koelega, Anita C S
AU - Del Blanco, Daria Gorbenko
AU - Rangasami, Jayanti J.
AU - Ruivenkamp, Claudia A L
AU - Laros, Jeroen F J
AU - Kriek, Marjolein
AU - Kant, Sarina G.
AU - Bosch, Cathy A J
AU - Biermasz, Nienke R.
AU - Appelman-Dijkstra, Natasha M.
AU - Corssmit, Eleonora P.
AU - Hovens, Guido C J
AU - Pereira, Alberto M.
AU - Den Dunnen, Johan T D
AU - Wade, Michael G.
AU - Breuning, Martijn H.
AU - Hennekam, Raoul C.
AU - Chatterjee, Krishna
AU - Dattani, Mehul T.
AU - Wit, Jan M.
AU - Bernard, Daniel J.
PY - 2012/12
Y1 - 2012/12
N2 - 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.
AB - 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.
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U2 - 10.1038/ng.2453
DO - 10.1038/ng.2453
M3 - Article
C2 - 23143598
AN - SCOPUS:84870524024
VL - 44
SP - 1375
EP - 1381
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 12
ER -