Curating the gnomAD database: Report of novel variants in the thyrogobulin gene using in silico bioinformatics algorithms

Pio, Mauricio Gomes; Siffo, Sofía; Scheps, Karen G.; Molina, Maricel F.; Adrover, Ezequiela; Abelleyro, Miguel Martín; Rivolta, Carina M.; Targovnik, Héctor M.

doi:10.1016/j.mce.2021.111359

Cited by 9 publications

(9 citation statements)

References 127 publications

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“…5A). The classical T 4 formation site couples the donor DIT 149 with the acceptor DIT 24 [38-40]; while the classical T 3 formation site couples an MIT 2766 of a TG monomer with the DIT 2766 on the opposite monomer of the TG dimer [41] (Fig. 5A).…”

Section: Discussionmentioning

confidence: 99%

“…However, both the p.Arg787* and p.Glu1854* mutants still harbor the acceptor tyrosine 24 and the donor tyrosine 149 but delete the C-terminal hormonogenic domain. As a consequence, transcripts containing nonsense codons are rapidly degraded in the cytoplasm by the Nonsense-Mediated mRNA Decay (NMD) surveillance mechanism, preventing the accumulation of truncated proteins that are potentially toxic to the cell [42,43].…”

Section: Discussionmentioning

confidence: 99%

“…The N-terminal and central region of the monomeric TG preprotein is composed of three different cysteine-rich repeat motifs called TG type 1, TG type 2 and TG type 3, whereas the región C-terminal is integrated by a non-repeat cholinesterase-like (ChEL) domain [8][9][10][11][12][13]. Recently, the 3-dimensional atomic structure of human an bovine TG has been reported [14][15][16][17] To date, more than two hundred and ninety deleterious variants in the human TG gene (loss-of-function variants or missense variants involving wild-type cysteine residues and the ChEL domain) have been reported associated to thyroid diseases, mainly to CH [18][19][20][21][22][23][24]. Several studies show that structurally defective TG mutants become trapped in the endoplasmic reticulum (ER), causing thyrocyte ER stress [25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

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The p.Pro2232Leu variant in the ChEL domain of thyroglobulin gene causes intracellular transport disorder and congenital hypothyroidism

et al. 2022

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Thyroglobulin (TG), the predominant glycoprotein of the thyroid gland, functions as matrix protein in thyroid hormonegenesis. TG de ciency results in thyroid dyshormonogenesis. These variants produce a heterogeneous spectrum of congenital goitre, with an autosomal recessive mode of inheritance. The purpose of this study was to identify and functionally characterize new variants in the TG gene in order to increase the understanding of the molecular mechanisms responsible for thyroid dyshormonogenesis. A total of four patients from two non-consanguineous families with marked alteration of TG synthesis were studied.The two families were previously analysed in our laboratory, only one deleterious allele, in each one, was detected after sequencing the TG gene (c.2359C > T [p.Arg787*], c.5560G > T [p.Glu1854*]). These ndings were con rmed in the present studies by Next-Generation Sequencing. The single nucleotide coding variants of the TG gene were then analyzed to predict the possible variant causing the disease. The p.Pro2232Leu (c.6695C > T), identi ed in both families, showing a low frequency population in gnomAD v2.1.1 database and protein homology, amino acid prediction, and 3D modeling analysis predict a potential pathogenic effect of this variant. We also transiently express p.Pro2232Leu in a full-length rat TG cDNA clone and con rmed that this point variant was su cient to cause intracellular retention of mutant TG in HEK293T cells. Consequently, each family carried a compound heterozygous for p.Arg787*/p.Pro2232Leu or p.Glu1854*/p.Pro2232Leu variants.In conclusion, our results con rm the pathophysiological importance of altered TG folding as a consequence of missense variants located in the ChEL domain of TG.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The p.Pro2232Leu variant in the ChEL domain of thyroglobulin gene causes intracellular transport disorder and congenital hypothyroidism

et al. 2022

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“…We note that one group has estimated the genetic frequency in the general human population of presumed likely pathogenic variants of TG (heterozygosity) at 1:320 people [ 44 ], and a second group has similarly estimated this frequency at 1:217 people [ 45 ]. Either way, the occurrence of individuals expressing misfolded Tg protein from at least one allele is likely to be rather common.…”

Section: Tg Folding and Tg Mutations That Trigger Misfoldingmentioning

confidence: 99%

Defective Thyroglobulin: Cell Biology of Disease

Zhang

Young

Morishita

et al. 2022

IJMS

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The primary functional units of the thyroid gland are follicles of various sizes comprised of a monolayer of epithelial cells (thyrocytes) surrounding an apical extracellular cavity known as the follicle lumen. In the normal thyroid gland, the follicle lumen is filled with secreted protein (referred to as colloid), comprised nearly exclusively of thyroglobulin with a half-life ranging from days to weeks. At the cellular boundary of the follicle lumen, secreted thyroglobulin becomes iodinated, resulting from the coordinated activities of enzymes localized to the thyrocyte apical plasma membrane. Thyroglobulin appearance in evolution is essentially synchronous with the appearance of the follicular architecture of the vertebrate thyroid gland. Thyroglobulin is the most highly expressed thyroid gene and represents the most abundantly expressed thyroid protein. Wildtype thyroglobulin protein is a large and complex glycoprotein that folds in the endoplasmic reticulum, leading to homodimerization and export via the classical secretory pathway to the follicle lumen. However, of the hundreds of human thyroglobulin genetic variants, most exhibit increased susceptibility to misfolding with defective export from the endoplasmic reticulum, triggering hypothyroidism as well as thyroidal endoplasmic reticulum stress. The human disease of hypothyroidism with defective thyroglobulin (either homozygous, or compound heterozygous) can be experimentally modeled in thyrocyte cell culture, or in whole animals, such as mice that are readily amenable to genetic manipulation. From a combination of approaches, it can be demonstrated that in the setting of thyroglobulin misfolding, thyrocytes under chronic continuous ER stress exhibit increased susceptibility to cell death, with interesting cell biological and pathophysiological consequences.

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“…The iodination of proteins contained within the follicle lumen ( 4 ) includes tyrosyl residues on secreted Tg ( 5 ), triggering a coupling reaction that promotes formation of T 4 within Tg ( 6 , 7 , 8 ). Hundreds of different TG gene mutations altering the primary structure of the Tg protein have been linked to defective thyroid hormone biosynthesis ( 9 ). Tg is synthesized within the endoplasmic reticulum (ER); most if not all mutant Tg is thought to misfold and become entrapped within the ER ( 3 ).…”

mentioning

confidence: 99%

Maintaining the thyroid gland in mutant thyroglobulin–induced hypothyroidism requires thyroid cell proliferation that must continue in adulthood

Zhang

Malik

Young

et al. 2022

Journal of Biological Chemistry

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Curating the gnomAD database: Report of novel variants in the thyrogobulin gene using in silico bioinformatics algorithms

Cited by 9 publications

References 127 publications

The p.Pro2232Leu variant in the ChEL domain of thyroglobulin gene causes intracellular transport disorder and congenital hypothyroidism

The p.Pro2232Leu variant in the ChEL domain of thyroglobulin gene causes intracellular transport disorder and congenital hypothyroidism

Defective Thyroglobulin: Cell Biology of Disease

Maintaining the thyroid gland in mutant thyroglobulin–induced hypothyroidism requires thyroid cell proliferation that must continue in adulthood

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