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A Novel SLC5A5 Variant Reveals the Crucial Role of Kinesin Light Chain 2 in Thyroid Hormonogenesis
A Novel SLC5A5 Variant Reveals the Crucial Role of Kinesin Light Chain 2 in Thyroid Hormonogenesis
- Source :
- J Clin Endocrinol Metab
- Publication Year :
- 2021
- Publisher :
- The Endocrine Society, 2021.
-
Abstract
- Context Iodide transport defect (ITD) (Online Mendelian Inheritance in Man No. 274400) is an uncommon cause of dyshormonogenic congenital hypothyroidism due to loss-of-function variants in the SLC5A5 gene, which encodes the sodium/iodide symporter (NIS), causing deficient iodide accumulation in thyroid follicular cells. Objective This work aims to determine the molecular basis of a patient’s ITD clinical phenotype. Methods The propositus was diagnosed with dyshormonogenic congenital hypothyroidism with minimal 99mTc-pertechnetate accumulation in a eutopic thyroid gland. The propositus SLC5A5 gene was sequenced. Functional in vitro characterization of the novel NIS variant was performed. Results Sanger sequencing revealed a novel homozygous missense p.G561E NIS variant. Mechanistically, the G561E substitution reduces iodide uptake, because targeting of G561E NIS to the plasma membrane is reduced. Biochemical analyses revealed that G561E impairs the recognition of an adjacent tryptophan-acidic motif by the kinesin-1 subunit kinesin light chain 2 (KLC2), interfering with NIS maturation beyond the endoplasmic reticulum, and reducing iodide accumulation. Structural bioinformatic analysis suggests that G561E shifts the equilibrium of the unstructured tryptophan-acidic motif toward a more structured conformation unrecognizable to KLC2. Consistently, knockdown of Klc2 causes defective NIS maturation and consequently decreases iodide accumulation in rat thyroid cells. Morpholino knockdown of klc2 reduces thyroid hormone synthesis in zebrafish larvae leading to a hypothyroid state as revealed by expression profiling of key genes related to the hypothalamic-pituitary-thyroid axis. Conclusion We report a novel NIS pathogenic variant associated with dyshormonogenic congenital hypothyroidism. Detailed molecular characterization of G561E NIS uncovered the significance of KLC2 in thyroid physiology.
- Subjects :
- Male
Sodium-iodide symporter
Thyroid Hormones
medicine.medical_specialty
Endocrinology, Diabetes and Metabolism
Clinical Biochemistry
Mutation, Missense
Thyroid Gland
Kinesins
Context (language use)
Biochemistry
Endocrinology
Internal medicine
Congenital Hypothyroidism
medicine
Animals
Humans
Missense mutation
health care economics and organizations
Clinical Research Articles
Gene knockdown
Symporters
Chemistry
Biochemistry (medical)
Thyroid
Infant, Newborn
Iodides
medicine.disease
Molecular biology
Rats
Congenital hypothyroidism
Gene expression profiling
Phenotype
medicine.anatomical_structure
Symporter
Microtubule-Associated Proteins
Metabolism, Inborn Errors
Subjects
Details
- ISSN :
- 19457197 and 0021972X
- Volume :
- 106
- Database :
- OpenAIRE
- Journal :
- The Journal of Clinical Endocrinology & Metabolism
- Accession number :
- edsair.doi.dedup.....9172eddb540ebed457d1fba818d3f123
- Full Text :
- https://doi.org/10.1210/clinem/dgab283