ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2018) 15 3.1 | DOI: 10.1530/ey.15.3.1

ESPEYB15 3 Thyroid Thyroid development (2 abstracts)

3.1 GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation

Kang HS , Kumar D , Liao G , Lichti-Kaiser K , Gerrish K , Liao XH , Refetoff S , Jothi R & Jetten AM


Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences (NIEHS), NIH, Research Triangle Park, North Carolina, USA


To read the full abstract: J Clin Invest 2017;127:4326-4337

Mutations in the Krüppel-like zinc finger transcription factor GLI-similar 3 (GLIS3) have first been associated with a syndrome combining two rare genetic endocrine diseases, namely neonatal diabetes and congenital hypothyroidism (OMIM #610199)1. Since then, 12 patients have been reported so far with a broad spectrum of a multi-organ disease including growth delay, renal cystic dysplasia, liver fibrosis, congenital glaucoma and osteopenia, besides neonatal diabetes and congenital hypothyroidism. In a large cohort of Chinese patients with congenital hypothyroidism without further multi-organ disease, the prevalence of GLIS3 mutations was 0.3%2. The role of GLIS3 has been extensively described for beta cell differentiation. However, the role of GLIS3 for thyroid follicular cell differentiation and function remained unknown.

Here, Kang et al. elucidated the critical role of GLIS3 for thyroid growth and function by extensive description and functional studies in a murine model. First, they showed that GLIS3 has a key role for murine postnatal thyroid follicular cell proliferation, acting mainly through AKT1 independent activation of the mTORC1 signaling pathway. However, and in contrast to the human phenotypes ranging from thyroid agenesis to thyroid gland in situ, they found no effect of GLIS3 deficiency on embryonic thyroid development in their model, an aspect that will need further attention. Second, they showed that GLIS3 directly binds to promotors of several genes encoding proteins of the thyroid hormone biosynthesis machinery and upregulates their transcription. The most important upregulation was observed for the sodium/iodide symporter (Nis) gene, which has been shown to be the limiting step for onset of thyroid hormone synthesis in the human embryonic thyroid.

In summary, these results extend our knowledge on the complex intracellular TSH-receptor signaling and identified the transcription factor GLIS3 a key regulator of TSH mediated thyroid hormone synthesis and proliferation.

1. Senée V, Chelala C, Duchatelet F, Feng D, Blanc H, Cossec JC, Charon C, Nicolino M, Boileau P, Cavener DR, Bougnères P, Taha D, Julier C. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet 2006;38;682-687.

2. Fu C, Luo S, Long X, Li Y, She S, Hu X, Mo M, Wang Z, Chen Y, He C, Su J, Zhang Y, Lin F, Xie B, Li Q, Chen S. Mutation screening of the GLIS3 gene in a cohort of 592 Chinese patients with congenital hypothyroidism. Clin Chim Acta 2018;476:38-43.

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