ArticleEndocrinology2015
A mouse model suggests two mechanisms for thyroid alterations in infantile cystinosis: decreased thyroglobulin synthesis due to endoplasmic reticulum stress/unfolded protein response and impaired lysosomal processing.
Article in Endocrinology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 43 citations in OpenAlex.
- The HEAT Repeat Protein MROH1 Deficiency Leads to Reduced Circulating Thyroid Hormone Levels in Mice.Endocrinology, diabetes & metabolism · 2026Article
- Cystinosin/Ers1 functions in redox homeostasis in the early secretory pathway.bioRxiv : the preprint server for biology · 2026Article
- A different approach to cystinosis: ultrasound, doppler, and shear wave elastography findings of thyroid gland.Orphanet journal of rare diseases · 2023Article
- Genistein improves renal disease in a mouse model of nephropathic cystinosis: a comparison study with cysteamine.Human molecular genetics · 2023Article
- [Cystinosis: From the gene identification to the first gene therapy clinical trial].Medecine sciences : M/S · 2023Review
- Cystinosis: Status of research and treatment in India and the world.Journal of biosciences · 2023Article
- Programmed Cell Death in Cystinosis.Cells · 2022Review
- Nephropathic Cystinosis: Pathogenic Roles of Inflammation and Potential for New Therapies.Cells · 2022Review
- Cystinosis induced byZhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2021Article
- Review
- Bartter syndrome and hypothyroidism masquerading cystinosis in a 3-year-old girl: rare manifestation of a rare disease.BMJ case reports · 2021Article
- Cysteamine-bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis.EMBO molecular medicine · 2021Article
- Protective effects of selenium and zinc against potassium dichromate-induced thyroid disruption, oxidative stress, and DNA damage in pregnant Wistar rats.Environmental science and pollution research international · 2021Article
- Resveratrol Alleviates the Inhibitory Effect of Tunicamycin-Induced Endoplasmic Reticulum Stress on Expression of Genes Involved in Thyroid Hormone Synthesis in FRTL-5 Thyrocytes.International journal of molecular sciences · 2021Article
- Mice Hypomorphic forThyroid : official journal of the American Thyroid Association · 2021Article
- Inherited disorders of lysosomal membrane transporters.Biochimica et biophysica acta. Biomembranes · 2020Review
- Class III PI3K Vps34 Controls Thyroid Hormone Production by Regulating Thyroglobulin Iodination, Lysosomal Proteolysis, and Tissue Homeostasis.Thyroid : official journal of the American Thyroid Association · 2020Article
- Management of bone disease in cystinosis: Statement from an international conference.Journal of inherited metabolic disease · 2019Article
- Interaction between galectin-3 and cystinosin uncovers a pathogenic role of inflammation in kidney involvement of cystinosis.Kidney international · 2019Article
- The role of thyroglobulin in thyroid hormonogenesis.Nature reviews. Endocrinology · 2019Review
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
Thyroid hormones are released from thyroglobulin (Tg) in lysosomes, which are impaired in infantile/nephropathic cystinosis. Cystinosis is a lysosomal cystine storage disease due to defective cystine exporter, cystinosin. Cystinotic children develop subclinical and then overt hypothyroidism. Why hypothyroidism is the most frequent and earliest endocrine complication of cystinosis is unknown. We here defined early alterations in Ctns(-/-) mice thyroid and identified subcellular and molecular mechanisms. At 9 months, T4 and T3 plasma levels were normal and TSH was moderately increased (∼4-fold). By histology, hyperplasia and hypertrophy of most follicles preceded colloid exhaustion. Increased immunolabeling for thyrocyte proliferation and apoptotic shedding indicated accelerated cell turnover. Electron microscopy revealed endoplasmic reticulum (ER) dilation, apical lamellipodia indicating macropinocytic colloid uptake, and lysosomal cystine crystals. Tg accumulation in dilated ER contrasted with mRNA down-regulation. Increased expression of ER chaperones, glucose-regulated protein of 78 kDa and protein disulfide isomerase, associated with alternative X-box binding protein-1 splicing, revealed unfolded protein response (UPR) activation by ER stress. Decreased Tg mRNA and ER stress suggested reduced Tg synthesis. Coordinated increase of UPR markers, activating transcription factor-4 and C/EBP homologous protein, linked ER stress to apoptosis. Hormonogenic cathepsins were not altered, but lysosome-associated membrane protein-1 immunolabeling disclosed enlarged vesicles containing iodo-Tg and impaired lysosomal fusion. Isopycnic fractionation showed iodo-Tg accumulation in denser lysosomes, suggesting defective lysosomal processing and hormone release. In conclusion, Ctns(-/-) mice showed the following alterations: 1) compensated primary hypothyroidism and accelerated thyrocyte turnover; 2) impaired Tg production linked to ER stress/UPR response; and 3) altered endolysosomal trafficking and iodo-Tg processing. The Ctns(-/-) thyroid is useful to study disease progression and evaluate novel therapies.
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