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This version published online on January 17, 2006
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1350
A more recent version of this article appeared on April 1, 2006
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Submitted on June 16, 2005
Accepted on January 5, 2006

Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis

MONICA DENTICE, VIVIANA CORDEDDU, ANNAMARIA ROSICA, ALFONSO MASSIMILIANO FERRARA, LIBERO SANTARPIA, DOMENICO SALVATORE, LUCA CHIOVATO, ANNA PERRI, LIDIA MOSCHINI, CRISTINA FAZZINI, ANTONELLA OLIVIERI, PIETRO COSTA, VERA STOPPIONI, MARIANGIOLA BASERGA, MARIO DE FELICE, MARIELLA SORCINI, GIANFRANCO FENZI, ROBERTO DI LAURO, MARCO TARTAGLIA, and PAOLO EMIDIO MACCHIA*

Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università degli Studi di Napoli "Federico II", Via S. Pansini 5, 80131 Napoli, Italy (M.D., A.M.F., D.S., G.F., P.E.M.); Dipartimento di Biologia e Patologia Cellulare e Molecolare "L. Califano", Università degli Studi di Napoli "Federico II", Via S. Pansini 5, 80131 Naples, Italy (L.S., R.D.L.); Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, V.le Regina Elena 299, 00161 - Roma, Italy (V.C., C.F., A.O., M.S., M.T.); Stazione Zoologica A. Dohrn, at CEINGE via Comunale Margherita 482, 80145 Napoli, Italy (A.R., M.D.F., R.D.L.); Fondazione S. Maugieri, IRCCS, Località Cravino Via Ferrata 8, 27100 Pavia, Italy (L.C.); Dipartimento di Endocrinologia e Metabolismo, Ortopedia e Traumatologia, Medicina del Lavoro, Università di Pisa, Via Paradisa, 2 Cisanello 56124 Pisa, Italy (A.P.); Istituto di Puericoltura, Università "La Sapienza", Via dei Sardi 58, 00185 Rome, Italy (L.M., P.C.); Centro Screening Neonatale, Ospedale Santa Croce, Via A. Tazzoli 15, 61132 Fano, Italy (V.S.); Dipartimento di Medicina Sperimentale, Università degli Studi della Magna Grecia, Viale Pio X, Catanzaro, Italy (M.B.)

* To whom correspondence should be addressed. E-mail: pmacchia{at}unina.it.

Context. Congenital hypothyroidism (CH) is a common endocrine disorder with an incidence of 1:3-4000 at birth. In 80-85% of cases, CH is caused by defects in thyroid organogenesis, resulting in absent, ectopically located and/or severely reduced gland (thyroid dysgenesis, TD). Mutations in genes controlling thyroid development have demonstrated that, in a few cases, TD is a Mendelian trait. However, accumulating evidences support the view that the genetics of TD is complex, possibly with a polygenic/multifactorial basis.

A higher prevalence of congenital heart disease (CHD) has been documented in children with CH than in general population. Such association suggests a possible pathogenic role of genes involved in both heart and thyroid development.

NKX2-5 encodes a homeodomain-containing transcription factor with major role in heart development, and mutations affecting this gene have been reported in individuals with CHD.

Objective. In the present work we investigated the possible involvement of NKX2-5 mutations in TD.

Results. Our results indicate that Nkx2-5-/- embryos exhibit thyroid bud hypoplasia, providing evidence that NKX2-5 plays a role in thyroid organogenesis, and that NKX2-5 mutations contribute to TD.

NKX2-5 mutational screening in 241 patients with TD allowed the identification of three heterozygous missense changes (R25C, A119S and R161P) in four patients with TD. Functional characterization of the three mutations demonstrated reduced DNA binding and/or transactivation properties with a dominant negative effect on wild-type NKX2-5.

Conclusion. On the whole, our results suggest a previously unknown role of NKX2-5 in the pathogenesis of TD.
Key words: Thyroid dysgenesis • Congenital hypothyroidism • Transcription factor




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