Abstract
Permanent congenital hypothyroidism is the most prevalent inborn endocrine disorder, and principally due to developmental defects leading to absent, ectopic or hypoplastic thyroid gland. Although commonly regarded as sporadic disease, nonsyndromic thyroid hypoplasia has, in rare cases, been attributed to inherited defects in PAX8 and the TSHR gene. The shared clinical picture caused by these defects is a variable degree of thyrotropin resistance (RTSH [MIM 275200]), accompanied in its severe form by thyroid gland hypoplasia. We recently identified six extended kindreds with autosomal dominant RTSH, only one of which was linked to a mutation in the PAX8 candidate gene. Genome wide scans conducted in two of the remaining five families revealed independently significant linkage to chromosome 15q25.3–26.1, with maximum multipoint LOD scores of 8.51 and 4.31. Linkage to this novel locus was replicated (P<0.01) in each of the three remaining kindreds. Fine mapping of key recombinants in the largest family localized the causative gene within a 3 cM/2.9 Mb interval. Thus, we report the first locus for congenital nongoitrous hypothyroidism identified by a genome wide screening approach.
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Acknowledgements
This study was supported by the National Institutes of Health (grants DK17050 and RR00055 to S.R.), the Belgian “Fonds National de la Recherche Scientifique Médicale” and “Fondation Erasme” (to G.V.), the Belgian program on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister’s Office, Science Policy Programming and the Life Science Health program of the European Community (to G.V.). Also supported by grants from FRSM and FNRS (to G.V.). We are indebted to M.-C. Vantyghem, G. Van Vliet, D. Metzger and H. Abdullatif for referring patients and obtaining blood samples from family members, to Cécile Lecoeur for her participation in the linkage analysis, and to Val Sheffield and Graeme Bell for sharing laboratory equipment. Last but not least, we gratefully acknowledge the participation of the families, without whom our investigations would not have been possible.
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Helmut Grasberger Martine Vaxillaire have contributed equally to this work.
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Grasberger, H., Vaxillaire, M., Pannain, S. et al. Identification of a locus for nongoitrous congenital hypothyroidism on chromosome 15q25.3-26.1. Hum Genet 118, 348–355 (2005). https://doi.org/10.1007/s00439-005-0036-6
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DOI: https://doi.org/10.1007/s00439-005-0036-6