Thyroid Transcription Factors and Congenital Hypothyroidism

THYROID TRANSCRIPTION FACTORS AND CONGENITAL HYPOTHYROIDISM

Introduction
Primary congenital hypothyroidism (CH) is the most frequent endocrine-metabolic disease in infancy, with an incidence of about 1/3-4000 newborns. In about 85% of the cases, CH is caused by an alteration in the morphogenesis of the thyroid (thyroid dysgenesis, TD) (2). In 5-16% of cases TD it is associated with other major birth defects, mostly cardiac (Table 1) (3).
Most of the critical events in thyroid morphogenesis take place in the first 60 days of gestation in man or the first 15 days in mice. For this reason, thyroid developmental abnormalities result from morphogenetic errors during this period.
The regulation of formation, migration and proliferation of the thyroid gland are still largely unknown. Several genes, including those encoding thyroid specific transcription factors (TITF1, TITF2, PAX8), thyrotropin (TSH) and its receptor (TSHR), and/or other genes, have been demonstrated to play a role (1). Alterations in any of these genes can be responsible for thyroid dysgenesis.
Mutations in the genes involved in thyroid development give rise to animal models with TD, and mutations in the same genes have been identified also in a small number of patients with congenital hypothyroidism associated with TD.

In this review we will briefly describe the role of thyroid transcription factors and their involvement in the pathogenesis of TD.

NKX2-1/TITF1
NKX2-1, also known as TITF1 (Thyroid Transcription Factor–1) is a homeodomain transcription factor that was initially identified in a rat thyroid cell as a nuclear protein able to bind to specific sequences in the Tg promoter. TITF1 belongs to the Nkx2 class of transcription factors and is encoded by a gene, located on chromosome 14q13 (Table 1). The gene is formed by at least 3 exons and encodes for 42 kDa protein that is phosphorylated. During human development, the gene is expressed in the ventral diencephalon and in the telencephalon; in the lung bud and in the thyroid primordium (1, 4).
Studies in mice demonstrated that Titf1 is required for the survival and subsequent differentiation of the cells.

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Interesting... this is not a rare disorder. If an endocrinologist who mainly treats children cannot recognize this in adults, how will s/he recognize it in the young persons in his/her care?