Tuberous sclerosis with hypothyroidism and precocious puberty

Adhvaryu, Kaitav; Shanbag, Preeti; Vaidya, Mamta

doi:10.1007/bf02724284

Cited by 7 publications

(7 citation statements)

References 6 publications

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“…Our data from the TPO-TSC2KO mice align with the notion that mTORC1 is essential for thyroid proliferation and growth [38] but also indicate that TSH-induced compensation might depend on thyrocyte mTORC1 activity [39,40]. Furthermore, mTORC1 appears to mediate thyrocyte proliferation in adaptive responses to iodine deficiency, as chronic in vivo treatment of mice with the rapalog RAD001 (Everolimus) during goitrogenic conditions abolished the hyperplastic thyrocyte response [32]. However, it's noteworthy that the authors did not observe any effects of rapamycin treatment on thyroid gland growth.…”

Section: Discussionsupporting

confidence: 83%

“…The role of mTOR in thyroid function is clinically relevant. Patients suffering from Tuberous Sclerosis, which involves overactivation of mTORC1 due to mutations in the TSC1/2 genes, often present with thyroid abnormalities [45][46][47][48][49][50][51] . Furthermore, whether mTORC1 controls NIS expression is clinically significant because the loss of NIS expression in thyroid cancer is proposed as the mechanism for refractory response to radioiodine therapy 35 .…”

Section: Introductionmentioning

confidence: 99%

“…In routine chest computed tomography for lung disease assessment, 20% of TSC patients exhibited thyroid nodules, with half of them diagnosed with multiple nodules [30]. Thyroid abnormalities, although less frequent, in TSC encompass papillary and medullary thyroid carcinoma [29, 31], as well as hypothyroidism [32, 33].…”

Section: Introductionmentioning

confidence: 99%

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Defining thein vivorole of mTORC1 in thyrocytes by studying the TSC2 conditional knockout mouse model

Rossetti,

Lourençoni,

Peçanha

et al. 2023

Preprint

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The serine-threonine protein kinase mechanistic target of rapamycin complex 1 (mTORC1) plays a pivotal role in regulating cellular metabolism, growth, and proliferation. The thyroid gland is a frequent site of abnormal epithelial cell growth and proliferation that can lead to thyroid dysfunction. In the thyroid gland, the PI3K-Akt-mTOR pathway is abnormally overactive in tumors and has been linked to increased aggressiveness in thyroid cancer. However, our understanding of mTORC1’s role in thyrocytes is primarily based onin vitrostudies, leaving itsin vivofunction unclear. To bridge this knowledge gap, we developed a novel mouse model of mTOR gain of function specifically in thyrocytes by crossing the mouse with thyroperoxidase (TPO)-driven cre recombinase expression with the Tuberous Sclerosis Complex 2 (TSC2)-floxed mouse. TSC2 acts as an intracellular inhibitor of mTORC1 and its conditional disruption leads to overactivation of mTOR activity. In TPO-TSC2KOmice, thyroid glands exhibited 70-80% less TSC2 protein and mRNA levels. Concomitantly, the TSC2 knockout in thyrocytes led to increased protein expression of mTORC1 target pS6 and decreased expression of mTORC2 target Akt phosphorylated in serine 473. Thyroid gland size was bigger in the TPO-TSC2KOmice as early as 1-month of age and continued to grow throughout life in both genders. Microscopic examination revealed significant heterogeneity among thyroid follicles in the TPO-TSC2KOmice, and their thyroids present larger follicles, colloid and epithelium. Overactivation of mTORC1 resulted in increased thyrocyte proliferation, as indicated by Ki67 staining, and elevated Cyclin D3 levels. Chronic mTOR overactivation suppressed mRNA expression of key genes involved in thyroid hormone biosynthesis such as thyroglobulin, thyroperoxidase and sodium-iodide symporter in both male and female mice. As a result, TPO-TSC2KOmice exhibited slight hypothyroidism with 20% less plasma thyroxine and 2-fold increase in TSH levels. Systemic treatment with rapamycin, an mTORC1 inhibitor, prevented thyroid mass expansion and gene expression alterations in TPO-TSC2KOmice. Finally, TPO-TSC2KOmice aged 12 months or older developed aberrant thyroid conditions including follicular hyperplasia, inflammation and thyroid tumors. In summary, our study demonstrates that mTORC1 gain of function specifically in thyrocytes leads to alterations in follicle morphology and impairs thyroid gland function.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

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Defining thein vivorole of mTORC1 in thyrocytes by studying the TSC2 conditional knockout mouse model

Rossetti,

Lourençoni,

Peçanha

et al. 2023

Preprint

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show abstract

“…Only a few studies have previously reported abnormalities of the thyroid gland in TSC patients. 27,54 Paediatric and adult TSC patients were also shown to have developed visual impairment more frequently than in the Comparator cohort, another manifestation that has been explored less often in TSC. Such manifestations may be under-reported in real clinical practice due to psychiatric complications (e.g.…”

Section: Discussionmentioning

confidence: 99%

The clinical profile of tuberous sclerosis complex (TSC) in the United Kingdom: A retrospective cohort study in the Clinical Practice Research Datalink (CPRD)

Kingswood

Bolton

Crawford

et al. 2016

European Journal of Paediatric Neurology

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“…Another cause of precocious puberty is tuberous sclerosis. Both gonadotropin-dependent and gonadotropin-independent mechanisms have been involved [115,238].…”

Section: Precocious Pubertymentioning

confidence: 99%

Perspectives in Pediatric Pathology, Chapter 15. Macrorchidism as the Expression of Several Congenital and Acquired Pathologies

et al. 2016

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Tuberous sclerosis with hypothyroidism and precocious puberty

Cited by 7 publications

References 6 publications

Defining thein vivorole of mTORC1 in thyrocytes by studying the TSC2 conditional knockout mouse model

Defining thein vivorole of mTORC1 in thyrocytes by studying the TSC2 conditional knockout mouse model

The clinical profile of tuberous sclerosis complex (TSC) in the United Kingdom: A retrospective cohort study in the Clinical Practice Research Datalink (CPRD)

Perspectives in Pediatric Pathology, Chapter 15. Macrorchidism as the Expression of Several Congenital and Acquired Pathologies

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