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Autosomal Dominant Transmission of Congenital Thyroid Hypoplasia Due to Loss-of-Function Mutation of PAX8¹

Institut de Recherche Interdisciplinaire en Biologie Humaine et Nucléaire, Faculté de Médecine (C.V., L.D., B.R., S.C., G.V.), Université Libre de Bruxelles, B-1070 Brussels; Department of Medical Genetics, Erasme Hospital, Faculté de Médecine (C.R., M.A., J.P., G.V.), Université Libre de Bruxelles, B-1070 Brussels; Department of Pediatric Endocrinology, Hôpital Universitaire des Enfants Reine Fabiola (C.H.), Université Libre de Bruxelles, B-1020 Brussels; and Department of Pediatrics, Cliniques Universitaires Saint Luc (P.M.), Université Catholique de Louvain, B-1200 Bruxelles, Belgium

Address correspondence and requests for reprints to: Gilbert Vassart, Institut de Recherche Interdisciplinaire en Biologie Humaine et Nucléaire, Free University of Brussels, 808 route de Lennik, B-1070 Brussels, Belgium. E-mail: gvassart{at}ulb.ac.be

Congenital hypothyroidism (CH) is a relatively frequent and potentially severe disease. It is classically subdivided into: 1) thyroid dysgenesis (TD), a defect in the organogenesis of the gland leading to hypoplastic, ectopic, or absent thyroid gland; or 2) thyroid dyshormonogenesis, a defect in one of the biochemical mechanisms responsible for thyroid hormone synthesis. Most cases of TD are sporadic, although familial occurrences have occasionally been described. Recently, several genes have been implicated in a small proportion of TD, but, in the majority of the cases, the etiology remains unknown. PAX8 is a transcription factor involved in thyroid development. So far, three loss-of-function mutations of PAX8 have been described, two in sporadic cases and one in familial thyroid hypoplasia. Here, we describe a novel mutation of PAX8 causing autosomal dominant transmission of CH with thyroid hypoplasia. The mutation consists of the substitution of a tyrosine for cysteine 57 in the paired domain of PAX8. When tested in cotransfection experiments with a thyroid peroxidasse promoter construct, the mutant allele was unable to exert its normal transactivation effect on transcription. Our results give further evidence that, contrary to the situation in knockout mice, haplo-insufficiency of PAX8 is a cause of CH in humans.

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