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.
| Original language | English |
|---|---|
| Pages (from-to) | 1428-1433 |
| Number of pages | 6 |
| Journal | Journal of Clinical Endocrinology and Metabolism |
| Volume | 91 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 2006 |
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ASJC Scopus subject areas
- Biochemistry
- Endocrinology, Diabetes and Metabolism
Cite this
Missense mutation in the transcription factor NKX2-5 : A novel molecular event in the pathogenesis of thyroid dysgenesis. / Dentice, Monica; Cordeddu, Viviana; Rosica, Annamaria; Ferrara, Alfonso Massimiliano; Santarpia, Libero; Salvatore, Domenico; Chiovato, Luca; Perri, Anna; Moschini, Lidia; Fazzini, Cristina; Olivieri, Antonella; Costa, Pietro; Stoppioni, Vera; Baserga, Mariangiola; De Felice, Mario; Sorcini, Mariella; Fenzi, Gianfranco; Di Lauro, Roberto; Tartaglia, Marco; Macchia, Paolo Emidio.
In: Journal of Clinical Endocrinology and Metabolism, Vol. 91, No. 4, 04.2006, p. 1428-1433.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Missense mutation in the transcription factor NKX2-5
T2 - A novel molecular event in the pathogenesis of thyroid dysgenesis
AU - Dentice, Monica
AU - Cordeddu, Viviana
AU - Rosica, Annamaria
AU - Ferrara, Alfonso Massimiliano
AU - Santarpia, Libero
AU - Salvatore, Domenico
AU - Chiovato, Luca
AU - Perri, Anna
AU - Moschini, Lidia
AU - Fazzini, Cristina
AU - Olivieri, Antonella
AU - Costa, Pietro
AU - Stoppioni, Vera
AU - Baserga, Mariangiola
AU - De Felice, Mario
AU - Sorcini, Mariella
AU - Fenzi, Gianfranco
AU - Di Lauro, Roberto
AU - Tartaglia, Marco
AU - Macchia, Paolo Emidio
PY - 2006/4
Y1 - 2006/4
N2 - 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.
AB - 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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U2 - 10.1210/jc.2005-1350
DO - 10.1210/jc.2005-1350
M3 - Article
VL - 91
SP - 1428
EP - 1433
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 4
ER -