Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis.
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.
Dentice
Monica
M
Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università di Napoli Federico II, Via S. Pansin 5, 80131 Naples, Italy.
Cordeddu
Viviana
V
Rosica
Annamaria
A
Ferrara
Alfonso Massimiliano
AM
Santarpia
Libero
L
Salvatore
Domenico
D
Chiovato
Luca
L
Perri
Anna
A
Moschini
Lidia
L
Fazzini
Cristina
C
Olivieri
Antonella
A
Costa
Pietro
P
Stoppioni
Vera
V
Baserga
Mariangiola
M
De Felice
Mario
M
Sorcini
Mariella
M
Fenzi
Gianfranco
G
Di Lauro
Roberto
R
Tartaglia
Marco
M
Macchia
Paolo Emidio
PE
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*
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