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

Yu Sun; Beata Bak; Nadia Schoenmakers; A. S. Paul van Trotsenburg; Wilma Oostdijk; Peter Voshol; Emma Cambridge; Jacqueline K. White; Paul le Tissier; S. Neda Mousavy Gharavy; Juan P. Martinez-Barbera; Wilhelmina H. Stokvis-Brantsma; Thomas Vulsma; Marlies J. Kempers; Luca Persani; Irene Campi; Marco Bonomi; Paolo Beck-Peccoz; Hongdong Zhu; Timothy M. E. Davis; Anita C. S. Hokken-Koelega; Daria Gorbenko del Blanco; Jayanti J. Rangasami; Claudia A. L. Ruivenkamp; Jeroen F. J. Laros; Marjolein Kriek; Sarina G. Kant; Cathy A. J. Bosch; Nienke R. Biermasz; Natasha M. Appelman-Dijkstra; Eleonora P. Corssmit; Guido C. J. Hovens; Alberto M. Pereira; Johan T. den Dunnen; Michael G. Wade; Martijn H. Breuning; Raoul C. Hennekam; Krishna Chatterjee; Mehul T. Dattani; Jan M. Wit; Daniel J. Bernard

doi:https://doi.org/10.1038/ng.2453

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

Yu Sun, Beata Bak, Nadia Schoenmakers, A. S. Paul van Trotsenburg, Wilma Oostdijk, Peter Voshol, Emma Cambridge, Jacqueline K. White, Paul le Tissier, S. Neda Mousavy Gharavy, Juan P. Martinez-Barbera, Wilhelmina H. Stokvis-Brantsma, Thomas Vulsma, Marlies J. Kempers, Luca Persani, Irene Campi, Marco Bonomi, Paolo Beck-Peccoz, Hongdong Zhu, Timothy M. E. DavisAnita C. S. Hokken-Koelega, Daria Gorbenko del Blanco, Jayanti J. Rangasami, Claudia A. L. Ruivenkamp, Jeroen F. J. Laros, Marjolein Kriek, Sarina G. Kant, Cathy A. J. Bosch, Nienke R. Biermasz, Natasha M. Appelman-Dijkstra, Eleonora P. Corssmit, Guido C. J. Hovens, Alberto M. Pereira, Johan T. den Dunnen, Michael G. Wade, Martijn H. Breuning, Raoul C. Hennekam, Krishna Chatterjee, Mehul T. Dattani, Jan M. Wit, Daniel J. Bernard

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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

Original language	English
Pages (from-to)	1375-1381
Journal	Nature Genetics
Volume	44
Issue number	12
DOIs	https://doi.org/10.1038/ng.2453
Publication status	Published - 2012

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Sun, Y., Bak, B., Schoenmakers, N., van Trotsenburg, A. S. P., Oostdijk, W., Voshol, P., Cambridge, E., White, J. K., le Tissier, P., Gharavy, S. N. M., Martinez-Barbera, J. P., Stokvis-Brantsma, W. H., Vulsma, T., Kempers, M. J., Persani, L., Campi, I., Bonomi, M., Beck-Peccoz, P., Zhu, H., ... Bernard, D. J. (2012). Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nature Genetics, 44(12), 1375-1381. https://doi.org/10.1038/ng.2453

@article{1a2691c0778d463eb05384112fe36d72,

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

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",

author = "Yu Sun and Beata Bak and Nadia Schoenmakers and {van Trotsenburg}, {A. S. Paul} and Wilma Oostdijk and Peter Voshol and Emma Cambridge and White, {Jacqueline K.} and {le Tissier}, Paul and Gharavy, {S. Neda Mousavy} and Martinez-Barbera, {Juan P.} and Stokvis-Brantsma, {Wilhelmina H.} and Thomas Vulsma and Kempers, {Marlies J.} and Luca Persani and Irene Campi and Marco Bonomi and Paolo Beck-Peccoz and Hongdong Zhu and Davis, {Timothy M. E.} and Hokken-Koelega, {Anita C. S.} and {del Blanco}, {Daria Gorbenko} and Rangasami, {Jayanti J.} and Ruivenkamp, {Claudia A. L.} and Laros, {Jeroen F. J.} and Marjolein Kriek and Kant, {Sarina G.} and Bosch, {Cathy A. J.} and Biermasz, {Nienke R.} and Appelman-Dijkstra, {Natasha M.} and Corssmit, {Eleonora P.} and Hovens, {Guido C. J.} and Pereira, {Alberto M.} and {den Dunnen}, {Johan T.} and Wade, {Michael G.} and Breuning, {Martijn H.} and Hennekam, {Raoul C.} and Krishna Chatterjee and Dattani, {Mehul T.} and Wit, {Jan M.} and Bernard, {Daniel J.}",

year = "2012",

doi = "https://doi.org/10.1038/ng.2453",

language = "English",

volume = "44",

pages = "1375--1381",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

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Sun, Y, Bak, B, Schoenmakers, N, van Trotsenburg, ASP, Oostdijk, W, Voshol, P, Cambridge, E, White, JK, le Tissier, P, Gharavy, SNM, Martinez-Barbera, JP, Stokvis-Brantsma, WH, Vulsma, T, Kempers, MJ, Persani, L, Campi, I, Bonomi, M, Beck-Peccoz, P, Zhu, H, Davis, TME, Hokken-Koelega, ACS, del Blanco, DG, Rangasami, JJ, Ruivenkamp, CAL, Laros, JFJ, Kriek, M, Kant, SG, Bosch, CAJ, Biermasz, NR, Appelman-Dijkstra, NM, Corssmit, EP, Hovens, GCJ, Pereira, AM, den Dunnen, JT, Wade, MG, Breuning, MH, Hennekam, RC, Chatterjee, K, Dattani, MT, Wit, JM & Bernard, DJ 2012, 'Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement', Nature Genetics, vol. 44, no. 12, pp. 1375-1381. https://doi.org/10.1038/ng.2453

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.

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

Y1 - 2012

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

U2 - https://doi.org/10.1038/ng.2453

DO - https://doi.org/10.1038/ng.2453

M3 - Article

C2 - 23143598

SN - 1061-4036

VL - 44

SP - 1375

EP - 1381

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -