Nature Genetics
19, 83 - 86 (1998)
doi:10.1038/ng0598-83
PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesisPaolo Emidio Macchia1, Paola Lapi1, Heiko Krude1, 7, Maria Teresa Pirro1, 5, Caterina Missero1, Luca Chiovato2, Abdallah Souabni3, Mariangiola Baserga4, Vittorio Tassi5, Aldo Pinchera2, Gianfranco Fenzi6, Annette Grüters7, Meinrad Busslinger3
& Roberto Di Lauro8
1Stazione Zoologica "A. Dohrn" Napoli, Italy.
2Istituto di Endocrinologia, Università degli Studi di Pisa, Italy.
3Research Institute of Molecular Pathology, Vienna, Austria.
4Cattedra di Pediatria, Facoltá di Medicina e Chirurgia di Catanzaro, Universitá di Reggio Calabria, Italy.
5Divisione ed Unitá di Ricerca di Endocrinologia, Istituto Scientific Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
6Cattedra di Endocrinologia, Universitá degli Studi di Napoli Federico II, Italy.
7Klinik und Poliklinik für Kinderheilkunde, Virchow-Klinikum, Humboldt-Unversität Berlin, Germany.
8e-mail: rdilauro@unina.it Permanent congenital hypothyroidism (CH) is a common disease that occurs in 1 of 3,000−4,000 newborns. Except in rare cases due to hypothalamic or pituitary defects, CH is characterized by elevated levels of thyroid-stimulating hormone (TSH) resulting from reduced thyroid function. When thyroid hormone therapy is not initiated within the first two months of life, CH can cause severe neurological, mental and motor damage1,2. In 80−85% of cases, CH is associated with and presumably is a consequence of thyroid dysgenesis (TD). In these cases, the thyroid gland can be absent (agenesis, 35−40%), ectopically located (30−45%) and/or severely reduced in size (hypoplasia, 5%). Familial cases of TD are rare, even though ectopic or absent thyroid has been occasionally observed in siblings3. The pathogenesis of TD is still largely unknown. Although a genetic component has been suggested, mutations in the gene encoding the receptor for the thyroid-stimulating hormone (TSHR) have been identified in only two cases of TD with hypoplasia4,5. We report mutations in the coding region of PAX8 in two sporadic patients and one familial case of TD. All three point mutations are located in the paired domain of PAX8 and result in severe reduction of the DMA-binding activity of this transcription factor. These genetic alterations implicate PAX8 in the pathogenesis of TD and in normal thyroid development.
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