Molecular genetics of congenital hypothyroidism

doi:10.1016/S0959-437X(99)80043-4

Current Opinion in Genetics & Development

Volume 9, Issue 3, June 1999, Pages 289-294

https://doi.org/10.1016/S0959-437X(99)80043-4 Get rights and content

Congenital thyroid gland defects — resulting in reduced production of the hormones triiodothyronine (T3) and thyroxine (T4) — can be a consequence of either reduced or absent thyroid tissue (thyroid dysgenesis) or, less frequently, of impairment in the biochemical mechanisms responsible for hormone biosynthesis (thyroid dyshormonogenesis). Recent studies have revealed how mutations in the genes encoding either transcription factors or the thyroid stimulating hormone receptor cause, in humans or in mouse models, thyroid dysgenesis. This demonstrates, for the first time, the heritability of this condition. New genes responsible for thyroid dyshormonogenesis have also been discovered.

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Cited by (32)

Positive correlation of thyroid hormones and serum copper in children with congenital hypothyroidism
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Citation Excerpt :
This has become most evident in congenital hypothyroidism (CH). If left untreated, CH will cause severe growth impairment, neurocognitive defects, hypotonia, bradycardia and other systemic disturbances [2–4]. Despite the strong phenotype of CH, however, the molecular mechanisms underlying these TH-dependent developmental defects have remained largely enigmatic.
Thyroid hormones are of central relevance for growth and development. However, the underlying molecular mechanisms are still not fully understood. Recent studies in humans and mice have demonstrated that serum levels of selenium (Se) and copper (Cu) are positively affected by thyroid hormones. Given the importance of these trace elements for many biochemical processes, we tested whether this interaction is found in children at risk for hypothyroidism, potentially providing a novel factor contributing to the disturbed development observed in congenital hypothyroidism (CH). We conducted a cross-sectional analysis of 84 children diagnosed with CH displaying a wide range of thyroid hormone concentrations. Serum Se and Cu concentrations were measured by total reflection X-ray fluorescence. Data for thyrotropin (TSH) were available in all, thyroxine (T4) and free thyroxine (fT4) in the majority and triiodothyronine (T3) in 29 of the children. Spearman rank analyzes were performed. Cu and thyroid hormones showed a strong positive correlation (Cu/T4, rho = 0.5241, P = 0.0003; Cu/T3, rho = 0.6003, P = 0.0006). Unlike in adults, no associations were found between Se and any of the thyroid hormones. Our data highlight that serum Cu and thyroid hormones are strongly associated already in early postnatal life. Severely hypothyroid children are thus at risk of developing a Cu deficiency if not adequately nourished or supplemented. This finding needs to be verified in larger groups of children in order not to miss an easily-avoidable risk factor for poor development.
Thyroid gland development and function in the zebrafish model
2009, Molecular and Cellular Endocrinology
Thyroid development has been intensively studied in the mouse, where it closely recapitulates the human situation. Despite the lack of a compact thyroid gland, the zebrafish thyroid tissue originates from the pharyngeal endoderm and the main genes involved in its patterning and early development are conserved between zebrafish and mammals. In recent years, the zebrafish has become a powerful model not only for the developmental biology studies, but also for large-scale genetic analyses and drug screenings, mostly thanks to the ease with which its embryos can be manipulated and to its translucent body, which allows in vivo imaging. In this review we will provide an overview of the current knowledge of thyroid gland origin and differentiation in the zebrafish. Moreover, we will consider the action of thyroid hormones and some aspects related to endocrine disruptors.
An integrated regulatory network controlling survival and migration in thyroid organogenesis
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The thyroid gland originates from the ventral floor of the foregut as a thickening of the endodermal cell layer. The molecular mechanisms underlying the early steps of thyroid morphogenesis are not known. Gene targeting experiments have contributed to the identification of several transcription factors, in general playing a role in the proliferation, survival, and migration of the thyroid cell precursors. The experiments reported here analyze the expression of the transcription factors Titf1, Hhex, Pax8, and Foxe1 in the thyroid primordium of null mutants of each of them. We found that most of these transcription factors are linked in an integrated regulatory network, each of them controlling the presence of other members of the network. The expression of Foxe1 is regulated in an intriguing fashion as it is strongly dependent on the presence of Pax8 in thyroid precursor cells, while the expression of the same gene in the pharyngeal endoderm surrounding the primordium is dependent on Sonic hedgehog (Shh)-derived signaling. Moreover, by the generation of mouse mutants expressing Foxe1 exclusively in the thyroid primordium, we provide a better understanding of the role of Foxe1 in these cells in order to acquire the competence to migrate into the underlying mesenchyme. In conclusion, we provide the first evidence of gene expression programs, controlled by a hierarchy of transcription factors expressed in the thyroid presumptive gut domain and directing the progression of thyroid morphogenesis.
Endocrine disorders in the neonate
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Defining normative sonographic measurements of neonatal thyroid volumes: Results of 165 healthy neonates from a single center in Northwest Malaysia
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^*: Present address, University of Chicago, Dept. of Medicine — Thyroid Study Unit, MC3090 Room M369, 5841 S. Maryland Ave., Chicago, Illinois 60637, USA.

View full text

Molecular genetics of congenital hypothyroidism

Genomics

Science

Hum Mol Genet

Hum Mol Genet

Genes Dev

Cell

Dev Biol

Epidemiology of congenital hypothyroidism

Exp Clin Endocrinol Diabetes

Screening for congenital hypothyroidism-effectiveness and clinical outcome

Bailliere Clin Paediatr

The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain

Development

Inherited disorders of the thyroid system

Inborn errors of thyroid hormone biosynthesis

Exp Clin Endocrinol Diabetes

Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity

EMBO J

The expression of TTF-2 is consistent with a dual role in thyroid differentiation

EMBO J

Pax-8, a murine paired box gene expressed in the developing excretory system and thyroid gland

Development

The thyrotropin receptor and the regulation of thyrocyte function and growth

Endocr Rev

The T/ebp null mouse, thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary

Genes Dev

Mutations in the gene for thyroid transcription factor-1 (TTF-1) are not a frequent cause of congenital hypothyroidism (CH) with thyroid dysgenesis

Thyroid

A bsence of mutations in TTF-1 gene in patients with thyroid dysgenesis

Thyroid

Deletion of thyroid transcription factor-1 gene in an infant with neonatal thyroid dysfunction and respiratory failure

N Engl J Med

A mouse model for hereditary thyroid dysgenesis and cleft palate

Nat Genet

Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia

Nat Genet

Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9

Nat Genet

Follicular cells of the thyroid gland require Pax8 gene function

Nat Genet