Congenital isolated central hypothyroidism: Novel mutations and their functional implications

Boelen, Anita; Trotsenburg, A S Paul van; Fliers, Eric

doi:10.1016/b978-0-12-820107-7.00010-0

Cited by 6 publications

(8 citation statements)

References 49 publications

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“…The second step involves IGSF1, a protein expressed in squirrel hypothalamic neurons and astrocytes. IGSF1 dysfunction is strongly linked with congenital central hypothyroidism in humans, and this phenotype is recapitulated in mouse models [41][42][43][44][45] .…”

Section: Discussionmentioning

confidence: 98%

“…Next, we assessed the level of expression of the immunoglobulin superfamily member 1 (Igsf1). Loss of function mutations in IGSF1 causes central hypothyroidism in humans and mice [41][42][43][44][45] . Igsf1 was expressed in neurons and astrocytes of squirrel ARC, and the level of expression significantly decreased in both groups during IBA (Extended Data Fig.…”

Section: Hibernating Animals Demonstrate Central Hypothyroidismmentioning

confidence: 99%

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Hypothalamic hormone deficiency enables physiological anorexia

Pra

Platt

Feketa

et al. 2023

Preprint

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Mammalian hibernators survive prolonged periods of cold and resource scarcity by temporarily modulating normal physiological functions, but the mechanisms underlying these adaptations are poorly understood. The hibernation cycle of thirteen-lined ground squirrels lasts for 5-7 months and comprises weeks of hypometabolic, hypothermic torpor interspersed with 24-48-hour periods of an active-like interbout arousal (IBA) state. We show that ground squirrels, who endure the entire hibernation season without food, have negligible hunger drive during IBAs. These squirrels exhibit reversible inhibition of the hypothalamic feeding center, such that hypothalamic arcuate nucleus neurons exhibit reduced sensitivity to the orexigenic and anorexigenic effects of ghrelin and leptin, respectively. However, hypothalamic infusion of thyroid hormone during an IBA is sufficient to rescue hibernation anorexia. Our results reveal that thyroid hormone deficiency underlies hibernation anorexia and demonstrate the functional flexibility of the hypothalamic feeding center.

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Section: Discussionmentioning

confidence: 98%

Section: Hibernating Animals Demonstrate Central Hypothyroidismmentioning

confidence: 99%

Hypothalamic hormone deficiency enables physiological anorexia

Pra

Platt

Feketa

et al. 2023

Preprint

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“…It has been established that leptin, such as insulin, stimulates TRH release by activating POMC-expressing neurons [ 368 ] and inhibiting AgRP/NPY-expressing neurons [ 369 ]. The weakening of hypothalamic insulin and leptin signaling as a result of inactivation of IRS4, which couples the insulin and leptin receptors with PI3K, leads to a decrease in TRH production and central hypothyroidism [ 373 ]. Thus, in hypothyroid patients with DM and MS, as well as in the correction of thyroid hormone deficiency induced by insufficient TRH secretion, the use of INI may be useful.…”

Section: Intranasal Insulin and The Gonadal And Thyroid Systemsmentioning

confidence: 99%

Hot Spots for the Use of Intranasal Insulin: Cerebral Ischemia, Brain Injury, Diabetes Mellitus, Endocrine Disorders and Postoperative Delirium

Zorina

Derkach

2023

IJMS

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A decrease in the activity of the insulin signaling system of the brain, due to both central insulin resistance and insulin deficiency, leads to neurodegeneration and impaired regulation of appetite, metabolism, endocrine functions. This is due to the neuroprotective properties of brain insulin and its leading role in maintaining glucose homeostasis in the brain, as well as in the regulation of the brain signaling network responsible for the functioning of the nervous, endocrine, and other systems. One of the approaches to restore the activity of the insulin system of the brain is the use of intranasally administered insulin (INI). Currently, INI is being considered as a promising drug to treat Alzheimer’s disease and mild cognitive impairment. The clinical application of INI is being developed for the treatment of other neurodegenerative diseases and improve cognitive abilities in stress, overwork, and depression. At the same time, much attention has recently been paid to the prospects of using INI for the treatment of cerebral ischemia, traumatic brain injuries, and postoperative delirium (after anesthesia), as well as diabetes mellitus and its complications, including dysfunctions in the gonadal and thyroid axes. This review is devoted to the prospects and current trends in the use of INI for the treatment of these diseases, which, although differing in etiology and pathogenesis, are characterized by impaired insulin signaling in the brain.

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“…In CCH, thyroid hormone levels are low to low-normal without the expected increases in thyrotropin (TSH), implicating defects in the brain and/or pituitary gland. TSH deficiency can occur in isolation or in the context of combined pituitary hormone deficiency ( 1 , 2 ). Isolated CCH has thus far been associated with mutations in five genes in humans: TSHB , TRHR , IGSF1 , TBL1X , and IRS4 ( 2 , 3 , 4 , 5 , 6 , 7 , 8 ).…”

Section: Introductionmentioning

confidence: 99%

“…TSH deficiency can occur in isolation or in the context of combined pituitary hormone deficiency ( 1 , 2 ). Isolated CCH has thus far been associated with mutations in five genes in humans: TSHB , TRHR , IGSF1 , TBL1X , and IRS4 ( 2 , 3 , 4 , 5 , 6 , 7 , 8 ). TSHB encodes the beta subunit of TSH, TSHβ, and loss of function mutations in the gene prevent production of the dimeric hormone, leading to profound hypothyroidism ( 8 , 9 ).…”

Section: Introductionmentioning

confidence: 99%

The hypothalamic–pituitary–thyroid axis is intact in male Irs4 knockout mice

Brûlé,

Zhou,

Wang

et al. 2024

European Thyroid Journal

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Objective: Loss of function mutations in the insulin receptor substrate 4 (IRS4) gene cause a rare form of X-linked congenital central hypothyroidism in boys and men. Affected individuals show decreased thyroid-stimulation hormone (TSH) secretion. Members of the IRS family canonically act as scaffold proteins between tyrosine kinase receptors and downstream effectors. How loss of IRS4 affects TSH synthesis or secretion is unresolved. We therefore assessed IRS4’s role in the hypothalamic-pituitary-thyroid axis of Irs4 knockout mice. Methods: We generated two global Irs4 knockout mouse lines harboring either two or four base-pair deletions that result in frameshifts and loss of most of the IRS4 protein. Results: Under normal laboratory conditions, Irs4 knockout males did not exhibit impairments in pituitary expression of TSH subunit genes (Tshb or Cga) or in the thyrotropin-releasing hormone (TRH) receptor. Additionally, their serum thyroid hormone, T3 (triiodothyronine) and T4 (thyroxine), and hypothalamic Trh expression levels were normal. When Irs4 knockouts were rendered hypothyroid with a low-iodine diet supplemented with propylthiouracil (PTU) for 3 weeks, their serum TSH increased similarly to wild-type males. Conclusions: Overall, Irs4 knockout mice do not exhibit central hypothyroidism or otherwise appear to phenocopy IRS4 deficient patients. Compensation by another IRS protein may explain euthyroidism in these animals.

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Congenital isolated central hypothyroidism: Novel mutations and their functional implications

Cited by 6 publications

References 49 publications

Hypothalamic hormone deficiency enables physiological anorexia

Hypothalamic hormone deficiency enables physiological anorexia

Hot Spots for the Use of Intranasal Insulin: Cerebral Ischemia, Brain Injury, Diabetes Mellitus, Endocrine Disorders and Postoperative Delirium

The hypothalamic–pituitary–thyroid axis is intact in male Irs4 knockout mice

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