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: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

School of Neurological and Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

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)	1375-81
Number of pages	7
Journal	Nature Genetics
Volume	44
Issue number	12
DOIs	https://doi.org/10.1038/ng.2453
Publication status	Published - Dec 2012

Keywords / Materials (for Non-textual outputs)

Adolescent
Adult
Aged
Animals
Base Sequence
Child
Child, Preschool
Congenital Hypothyroidism
Exome
Ferrous Compounds
Genetic Diseases, X-Linked
Humans
Immunoglobulins
Infant
Male
Membrane Proteins
Mice
Middle Aged
Mutation
Pituitary Gland
Prolactin
Receptors, Thyrotropin-Releasing Hormone
Sequence Analysis, DNA
Syndrome
Testicular Diseases
Testis
Thyrotropin
Triiodothyronine
Young Adult

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10.1038/ng.2453

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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), 1375-81. https://doi.org/10.1038/ng.2453

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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.",

keywords = "Adolescent, Adult, Aged, Animals, Base Sequence, Child, Child, Preschool, Congenital Hypothyroidism, Exome, Ferrous Compounds, Genetic Diseases, X-Linked, Humans, Immunoglobulins, Infant, Male, Membrane Proteins, Mice, Middle Aged, Mutation, Pituitary Gland, Prolactin, Receptors, Thyrotropin-Releasing Hormone, Sequence Analysis, DNA, Syndrome, Testicular Diseases, Testis, Thyrotropin, Triiodothyronine, Young Adult",

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",

month = dec,

doi = "10.1038/ng.2453",

language = "English",

volume = "44",

pages = "1375--81",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "12",

}

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. 1375-81. 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 - 2012/12

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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Animals

KW - Base Sequence

KW - Child

KW - Child, Preschool

KW - Congenital Hypothyroidism

KW - Exome

KW - Ferrous Compounds

KW - Genetic Diseases, X-Linked

KW - Humans

KW - Immunoglobulins

KW - Infant

KW - Male

KW - Membrane Proteins

KW - Mice

KW - Middle Aged

KW - Mutation

KW - Pituitary Gland

KW - Prolactin

KW - Receptors, Thyrotropin-Releasing Hormone

KW - Sequence Analysis, DNA

KW - Syndrome

KW - Testicular Diseases

KW - Testis

KW - Thyrotropin

KW - Triiodothyronine

KW - Young Adult

U2 - 10.1038/ng.2453

DO - 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 -

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

Abstract

Keywords / Materials (for Non-textual outputs)

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