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, Paolo Emidio Macchia

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1428-1433
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Issue number4
Publication statusPublished - Apr 2006

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism


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