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Missense Mutation in the Transcription Factor NKX2–5: A Novel Molecular Event in the Pathogenesis of Thyroid Dysgenesis

Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica (M.D., A.M.F., D.S., G.F., P.E.M.) and Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano (L.S., R.D.L.), Università degli Studi di Napoli Federico II, 80131 Naples, Italy; Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità (V.C., C.F., A.O., M.S., M.T.), 00161 Rome, Italy; Stazione Zoologica A. Dohrn, CEINGE (A.R., M.D.F., R.D.L.), 80145 Naples, Italy; Fondazione S. Maugieri, IRCCS (L.C.), 27100 Pavia, Italy; Dipartimento di Endocrinologia e Metabolismo, Ortopedia e Traumatologia, Medicina del Lavoro, Università di Pisa (A.P.), 56124 Pisa, Italy; Istituto di Puericoltura, Università La Sapienza (L.M., P.C.), 00185 Rome, Italy; Centro Screening Neonatale, Ospedale Santa Croce (V.S.), 61132 Fano, Italy; and Dipartimento di Medicina Sperimentale, Università degli Studi della Magna Grecia (M.B.), Catanzaro, Italy

Address all correspondence and requests for reprints to: Dr. Paolo E. Macchia, Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università di Napoli Federico II, Via S. Pansin, 5, 80131 Naples, Italy. E-mail: pmacchia{at}unina.it.

Abstract

Context: Congenital hypothyroidism (CH) is a common endocrine disorder with an incidence of 1:3000–4000 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 evidence supports the view that the genetics of TD are complex, possibly with a polygenic/multifactorial basis. A higher prevalence of congenital heart disease has been documented in children with CH than in the general population. Such an association suggests a possible pathogenic role of genes involved in both heart and thyroid development. NKX2–5 encodes a homeodomain-containing transcription factor with a major role in heart development, and mutations affecting this gene have been reported in individuals with congenital heart disease.

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: Our results suggest a previously unknown role of NKX2–5 in the pathogenesis of TD.

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