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Pseudodominant Inheritance of Goitrous Congenital Hypothyroidism Caused by TPO Mutations: Molecular and in Silico Studies

Endocrinology Service and Research Center (J.D., G.V.V.), Sainte-Justine Hospital and Department of Pediatrics, University of Montreal, Montreal, Canada H3T 1C5; Pediatric Endocrinology (N.P., J.P.), Department of Pediatrics, and Department of Pathology (S.B.), Children’s Hospital of Johannes Gutenberg University, D-55101 Mainz, Germany; Department of Pediatrics (J.-M.V.), University Children’s Hospital, University of Bern, CH-3010 Bern, Switzerland; and Interdisciplinary 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

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. E-mail: guy.van-vliet{at}recherche-ste-justine.qc.ca.

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.1978CG; 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.