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



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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Figure 1: IGSF1 mutations identified in individuals with central hypothyroidism.
Figure 2: IGSF1 is expressed in anterior pituitary gland.
Figure 3: Alterations in IGSF1 impair its plasma membrane trafficking.
Figure 4: Igsf1Δex1 mice have several characteristics of central hypothyroidism.

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The authors thank X.-H. Liao from the Refetoff laboratory (The University of Chicago, supported by US National Institutes of Health (NIH) grant DK15700) for measuring T4, T3, FT4I and TSH in mice, P. Scheiffele for the antibody to IGSF1 CTD and S. Kimmins (McGill University) and P. Bisschop (Academic Medical Center, University of Amsterdam) for human testis and pituitary RNA, respectively. We also thank H. Bikker, J.C. Moreno, A. Escudero, E. Aten, M. Losekoot, E. Endert, J.W.A. Smit, R.van Rijn and E.L. van Persijn-van Meerten for technical support and advice. We thank F.J. de Jong and Y. de Rijke for measuring serum inhibin B and AMH and for providing age references. We thank S. Tran and X. Zhou for assistance with collection of mouse serum samples. We acknowledge the help of N. Zwaveling, J. Gosen, E.J. Schroor, L.C.G. de Graaff and G. Radetti in providing clinical data. We acknowledge The Eastern Region Sequencing and Informatics Hub (see URLs), who undertook sequencing and preliminary bioinformatics analyses of data from the UK families. We thank the subjects and their families for participating. Our work was supported in part by a grant from the China Scholarship Council (to Y.S.); a National Sciences and Engineering Research Council (NSERC) Doctoral Research Award (to B.B.), NSERC Discovery Grant 341801-07 and a Fonds de la Recherche en Santé du Québec (FRSQ) Chercheur Boursier Senior Award (to D.J.B.); grants from the Wellcome Trust (095564 to N.S. and K.C.; WT077157/Z/05/Z to E.C. and J.K.W.; 084361, 078432 and 086545 to J.P.M.-B.), the National Institutes of Health Research Cambridge Biomedical Research Centre (to N.S. and K.C.) and the UK Medical Research Council (MRC; U117570590 to P.l.T.); a National Health and Medical Research Council of Australia Practitioner Fellowship (to T.M.E.D.); the Dutch Growth Research Foundation (D.G.D.B.); the Young Investigator grant of the Italian Ministry of Health and Istituto Auxologico Italiano IRCCS (GR-2008-1137632 to M.B.); and the Great Ormond Street Children's Hospital Charity (to M.T.D.).

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Authors and Affiliations



Y.S., J.T.d.D., M.K., N.S. and K.C. developed the exome sequencing protocol. A.S.P.v.T., W.O., S.G.K., N.R.B., N.M.A.-D., A.M.P., M.H.B., R.C.H., M.T.D., N.S., L.P., I.C., M.B., P.B.-P., H.Z., T.M.E.D., K.C., A.C.S.H.-K., D.G.D.B. and J.M.W. designed the clinical research studies. Y.S., J.F.J.L. and N.S. performed bioinformatics analyses, mutational analysis and genotyping. B.B. generated the vectors expressing mutant IGSF1 and performed all associated biochemical analyses; maintained the mouse colony, collected all mouse tissues and plasma, and analyzed pituitary gene expression; and prepared figures. D.J.B. generated the mouse model, supervised all in vitro and mouse work and participated in data collection and construction of the figures. P.V. and M.G.W. contributed to mouse phenotyping. E.C., J.K.W. and M.G.W. performed mouse T4 measurements. P.l.T. performed measurements of pituitary TSH and prolactin content. S.N.M.G. and J.P.M.-B. carried out the IGSF1 expression studies in mouse and human embryos. C.A.L.R. and C.A.J.B. performed and analyzed the microarray and hybridization experiments. A.S.P.v.T., W.O., W.H.S.-B., T.V., M.J.K., L.P., I.C., M.B., P.B.-P., H.Z., T.M.E.D., A.C.S.H.-K., D.G.D.B., J.J.R., S.G.K., N.R.B., N.M.A.-D., A.M.P., G.C.J.H., E.P.C., M.H.B., R.C.H., A.C.S.H.-K. and M.T.D. contributed to clinical evaluations and the delineation of the subject phenotypes. Y.S., B.B., N.S., A.S.P.v.T., K.C., M.T.D., R.C.H., D.J.B. and J.M.W. prepared the manuscript. D.J.B., J.M.W., K.C. and M.T.D. conceived and supervised the study.

Corresponding authors

Correspondence to Krishna Chatterjee, Mehul T Dattani, Jan M Wit or Daniel J Bernard.

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The authors declare no competing financial interests.

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Sun, Y., Bak, B., Schoenmakers, N. et al. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nat Genet 44, 1375–1381 (2012).

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