2. Academic Validation
  3. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement

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

  • Nat Genet. 2012 Dec;44(12):1375-81. doi: 10.1038/ng.2453.
Yu Sun 1,  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
Affiliations

Affiliation

  • 1 Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
PMID: 23143598 DOI: 10.1038/ng.2453
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.

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