title: Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  Our results suggest a previously unknown role of NKX2-5 in the pathogenesis of TD.
authors.affiliation: Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università di Napoli Federico II, Via S. Pansin 5, 80131 Naples, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Dentice
authors.forename: Viviana
authors.initials: V
authors.lastname: Cordeddu
authors.forename: Annamaria
authors.initials: A
authors.lastname: Rosica
authors.forename: Alfonso Massimiliano
authors.initials: AM
authors.lastname: Ferrara
authors.forename: Libero
authors.initials: L
authors.lastname: Santarpia
authors.forename: Domenico
authors.initials: D
authors.lastname: Salvatore
authors.forename: Luca
authors.initials: L
authors.lastname: Chiovato
authors.forename: Anna
authors.initials: A
authors.lastname: Perri
authors.forename: Lidia
authors.initials: L
authors.lastname: Moschini
authors.forename: Cristina
authors.initials: C
authors.lastname: Fazzini
authors.forename: Antonella
authors.initials: A
authors.lastname: Olivieri
authors.forename: Pietro
authors.initials: P
authors.lastname: Costa
authors.forename: Vera
authors.initials: V
authors.lastname: Stoppioni
authors.forename: Mariangiola
authors.initials: M
authors.lastname: Baserga
authors.forename: Mario
authors.initials: M
authors.lastname: De Felice
authors.forename: Mariella
authors.initials: M
authors.lastname: Sorcini
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Fenzi
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Lauro
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: Paolo Emidio
authors.initials: PE
authors.lastname: Macchia
mesh_terms: D003409:Congenital Hypothyroidism / Q000235:genetics*; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007453:Iodide Peroxidase / Q000378:metabolism; D020125:Mutation, Missense / Q000502:physiology*; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013954:Thyroglobulin / Q000378:metabolism; D013961:Thyroid Gland / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; D004247:DNA; D013954:Thyroglobulin; D007453:Iodide Peroxidase