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, Johnny Deladoëy 1Endocrinology Service and Research Center (J.D., G.V.V.), Sainte-Justine Hospital and Department of Pediatrics, University of Montreal, Montreal, Canada H3T 1C5 Search for other works by this author on: Oxford Academic Nicole Pfarr 2Pediatric Endocrinology (N.P., J.P.), Children’s Hospital of Johannes Gutenberg University, D-55101 Mainz, Germany Search for other works by this author on: Oxford Academic Jean-Marc Vuissoz 4Department of Pediatrics (J.-M.V.), University Children’s Hospital, University of Bern, CH-3010 Bern, Switzerland Search for other works by this author on: Oxford Academic Jasmine Parma 2Pediatric Endocrinology (N.P., J.P.), Children’s Hospital of Johannes Gutenberg University, D-55101 Mainz, Germany 5Interdisciplinary Research Institute for Human and Molecular Biology (J.P., G.V.), Faculty of Medicine, and Department of Genetics, Erasme Hospital, Free University of Brussels, B-1070 Brussels, Belgium Search for other works by this author on: Oxford Academic Gilbert Vassart 5Interdisciplinary Research Institute for Human and Molecular Biology (J.P., G.V.), Faculty of Medicine, and Department of Genetics, Erasme Hospital, Free University of Brussels, B-1070 Brussels, Belgium Search for other works by this author on: Oxford Academic Stefan Biesterfeld 3Department of Pediatrics, and Department of Pathology (S.B.), Children’s Hospital of Johannes Gutenberg University, D-55101 Mainz, Germany Search for other works by this author on: Oxford Academic Joachim Pohlenz 2Pediatric Endocrinology (N.P., J.P.), Children’s Hospital of Johannes Gutenberg University, D-55101 Mainz, Germany Search for other works by this author on: Oxford Academic Guy Van Vliet 1Endocrinology Service and Research Center (J.D., G.V.V.), Sainte-Justine Hospital and Department of Pediatrics, University of Montreal, Montreal, Canada H3T 1C5 *Address all correspondence and requests for reprints to: Guy Van Vliet, M.D., Hôpital Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, Québec, Canada H3T 1C5. Search for other works by this author on: Oxford Academic
The Journal of Clinical Endocrinology & Metabolism, Volume 93, Issue 2, 1 February 2008, Pages 627–633, https://doi.org/10.1210/jc.2007-2276
Published:
01 February 2008
Article history
Received:
10 October 2007
Accepted:
13 November 2007
Published:
01 February 2008
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Johnny Deladoëy, Nicole Pfarr, Jean-Marc Vuissoz, Jasmine Parma, Gilbert Vassart, Stefan Biesterfeld, Joachim Pohlenz, Guy Van Vliet, Pseudodominant Inheritance of Goitrous Congenital Hypothyroidism Caused by TPO Mutations: Molecular and in Silico Studies, The Journal of Clinical Endocrinology & Metabolism, Volume 93, Issue 2, 1 February 2008, Pages 627–633, https://doi.org/10.1210/jc.2007-2276
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Abstract
Context and Objective: Most cases of goitrous congenital hypothyroidism (CH) from thyroid dyshormonogenesis 1) follow a recessive mode of inheritance and 2) are due to mutations in the thyroid peroxidase gene (TPO). We report the genetic mechanism underlying the apparently dominant inheritance of goitrous CH in a nonconsanguineous family of French Canadian origin.
Design, Setting, and Participants: Two brothers identified by newborn TSH screening had severe hypothyroidism and a goiter with increased 99mTc uptake. The mother was euthyroid, but the father and two paternal uncles had also been diagnosed with goitrous CH. After having excluded PAX8 gene mutations, we hypothesized that the underlying defect could be TPO mutations.
Results: Both compound heterozygous siblings had inherited a mutant TPO allele carried by their mother (c.1496delC; p.Pro499Argfs2X), and from their father, one brother had inherited a missense mutation (c.1978C→G; p.Gln660Glu) and the other an insertion (c.1955insT; p.Phe653Valfs15X). The thyroid gland of one uncle who is a compound heterozygote for TPO mutations (p.Phe653Valfs15X/p.Gln660Glu) was removed because of concurrent multiple endocrine neoplasia type 2A. Immunohistochemistry revealed normal TPO staining, implying that Gln660Glu TPO is expressed properly. Modeling of this mutant in silico suggests that its three-dimensional structure is conserved, whereas the electrostatic binding energy between the Gln660Glu TPO and its heme group becomes repulsive.
Conclusion: We report a pedigree presenting with pseudodominant goitrous CH due to segregation of three different TPO mutations. Although goitrous CH generally follows a recessive mode of inheritance, the high frequency of TPO mutations carriers may lead to pseudodominant inheritance.
Copyright © 2008 by The Endocrine Society
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