A mouse model demonstrates a multigenic origin of congenital hypothyroidism

Elena Amendola, Pasquale De Luca, Paolo Emidio Macchia, Daniela Terracciano, Annamaria Rosica, Gennaro Chiappetta, Shioko Kimura, Ahmed Mansouri, Andrea Affuso, Claudio Arra, Vincenzo Macchia, Roberto Di Lauro, Mario De Felice

Research output: Contribution to journalArticlepeer-review


Congenital hypothyroidism with thyroid dysgenesis (TD) is a frequent human condition characterized by elevated levels of TSH in response to reduced thyroid hormone levels. Congenital hypothyroidism is a genetically heterogeneous disease. In the majority of cases studied, no causative mutations have been identified and very often the disease does not show a Mendelian transmission. However, in approximately 5% of cases, it can be a consequence of mutations in genes encoding the TSH receptor or the transcription factors TITF1, FOXE1, or PAX8. We report here that in mouse models, the combination of partial deficiencies in the Titf1 and Pax8 genes results in an overt TD phenotype that is absent in either of the singly deficient, heterozygous mice. The disease is characterized by a small thyroid gland, elevated levels of TSH, reduced thyroglobulin biosynthesis, and high occurrence of hemiagenesis. The observed phenotype is strain specific, and the pattern of transmission indicates that at least two other genes, in addition to Titf1 and Pax8, are necessary to generate the condition. These results show that TD can be of multigenic origin in mice and strongly suggest that a similar pathogenic mechanism may be observed in humans.

Original languageEnglish
Pages (from-to)5038-5047
Number of pages10
Issue number12
Publication statusPublished - Dec 2005

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism


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