Journal
NATURE GENETICS
Volume 44, Issue 12, Pages 1375-1381Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2453
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Funding
- US National Institutes of Health (NIH) [DK15700]
- China Scholarship Council
- National Sciences and Engineering Research Council (NSERC)
- NSERC [341801-07]
- Fonds de la Recherche en Sante du Quebec (FRSQ) Chercheur Boursier Senior Award
- Wellcome Trust [095564, WT077157/Z/05/Z, 084361, 078432, 086545]
- National Institutes of Health Research Cambridge Biomedical Research Centre
- UK Medical Research Council (MRE) [U117570590]
- National Health and Medical Research Council of Australia
- Dutch Growth Research Foundation
- Istituto Auxologico Italian IRCCS [GR-2008-1137632]
- Great Ormond Street Children's Hospital Charity
- Italian Ministry of Health
- MRC [MC_U117570590] Funding Source: UKRI
- Great Ormond Street Hospital Childrens Charity [V1255] Funding Source: researchfish
- Medical Research Council [MC_U117570590] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10198] Funding Source: researchfish
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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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