Structural organization and chromosomal localization of the human type II deiodinase gene

Fs, Celi; Canettieri, Gianluca; Mentuccia, D.; Proietti-Pannunzi, Laura; Fumarola, Angela; Sibilla, R; Predazzi, V; Ferraro, Maria; Andreoli, M; Centanni, Marco

doi:10.1530/eje.0.1430267

Cited by 20 publications

(12 citation statements)

References 20 publications

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“…The genomic organization of rtD2 gene is identical to that of the human D2 gene (Celi et al, 2000) indicating that D2 gene structure has been conserved during evolution from lower vertebrate to human. The rtD2 mRNA contains six 5 0 -AUUUA-3 0 motifs, one in the 5 0 UTR and ®ve in the 3 0 UTR (Fig.…”

Section: D2 Amino Acids Sequence and Gene Structure Are Evolutionarilymentioning

confidence: 91%

Type II iodothyronine deiodinase is preferentially expressed in rainbow trout (oncorhynchus mykiss) liver and gonads*

Sambroni

Gutieres

Cauty

et al. 2001

Molecular Reproduction Devel

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It is well admitted that thyroid hormones (TH) play a role in the development of vertebrates. The major secretory product of the thyroid is a pro-hormone, T(4), which is activated in peripheral tissues by outer ring deiodination to T(3). We have isolated from rainbow trout testis, a full length cDNA encoding type II iodothyronine deiodinase (rtD2). The cDNA was 2410 nucleotides long and coded for a polypeptide of 264 amino acids including a selenocysteine residue. The predicted molecular weight of rtD2 was 29.3 kDa and the isoelectric point 8.71. The deduced amino acids sequence showed 80% identity with Fundulus heteroclitus D2 (fhD2) but only 68-69% identity with rat, mouse, and human D2. The 3' UTR contained a putative selenocysteine insertion sequence (SECIS) similar to that described in human cDNA. The rtD2 gene was isolated and the gene structure was similar to that described in human with two exons separated by a large intron. We studied rtD2 gene expression by Northern blot analysis using total RNA extracted from testis, ovary, and other tissues. We found a high expression of a 3 kb transcript in liver and in gonads. A lower expression was also detected in posterior kidney. In testis, rtD2 mRNA expression was dependent on spermatogenic stages: it increased at the onset of spermatogenesis. Our results show that the structural characteristics of the D2 protein and gene have been highly conserved during evolution. The rtD2 mRNA expression in the gonads suggests that rtD2 may be a key factor regulating local supply of active T(3) during rainbow trout gametogenesis.

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Section: D2 Amino Acids Sequence and Gene Structure Are Evolutionarilymentioning

confidence: 91%

Type II iodothyronine deiodinase is preferentially expressed in rainbow trout (oncorhynchus mykiss) liver and gonads*

Sambroni

Gutieres

Cauty

et al. 2001

Molecular Reproduction Devel

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“…D2 polymorphisms " The human D2 gene (15 kb) maps to chromosome 14q24.2-q24.3 and consists of three exons (13). The D2-rs12885300 (D2-ORF a -Glu3Asp) and D2-rs225014 (D2-Thr92Ala) polymorphisms in exons 1 and 2, respectively, have been frequently evaluated in clinical research.…”

Section: Effect Of Deiodinase Polymorphisms On Mrna and Protein Synthmentioning

confidence: 99%

GENETICS IN ENDOCRINOLOGY: Genetic variation in deiodinases: a systematic review of potential clinical effects in humans

Verloop

Dekkers

Peeters

et al. 2014

European Journal of Endocrinology

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Iodothyronine deiodinases represent a family of selenoproteins involved in peripheral and local homeostasis of thyroid hormone action. Deiodinases are expressed in multiple organs and thyroid hormone affects numerous biological systems, thus genetic variation in deiodinases may affect multiple clinical endpoints. Interest in clinical effects of genetic variation in deiodinases has clearly increased. We aimed to provide an overview for the role of deiodinase polymorphisms in human physiology and morbidity. In this systematic review, studies evaluating the relationship between deiodinase polymorphisms and clinical parameters in humans were eligible. No restrictions on publication date were imposed. The following databases were searched up to August 2013: Pubmed, EMBASE (OVID-version), Web of Science, COCHRANE Library, CINAHL (EbscoHOST-version), Academic Search Premier (EbscoHOST-version), and ScienceDirect. Deiodinase physiology at molecular and tissue level is described, and finally the role of these polymorphisms in pathophysiological conditions is reviewed. Deiodinase type 1 (D1) polymorphisms particularly show moderate-to-strong relationships with thyroid hormone parameters, IGF1 production, and risk for depression. D2 variants correlate with thyroid hormone levels, insulin resistance, bipolar mood disorder, psychological well-being, mental retardation, hypertension, and risk for osteoarthritis. D3 polymorphisms showed no relationship with inter-individual variation in serum thyroid hormone parameters. One D3 polymorphism was associated with risk for osteoarthritis. Genetic deiodinase profiles only explain a small proportion of inter-individual variations in serum thyroid hormone levels. Evidence suggests a role of genetic deiodinase variants in certain pathophysiological conditions. The value for determination of deiodinase polymorphism in clinical practice needs further investigation.

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“…The mRNA of the D2 gene is unusually long (6 -7 kb) compared with the other two selenodeiodinases, containing long 5Ј-and 3Ј-untranslated regions (UTRs) (1,(3)(4)(5). The 5Ј-UTR of the D2 mRNA is ϳ700 nt long and has an inhibitory effect on D2 translation.…”

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confidence: 99%

“…It causes a fivefold reduction in D2 activity in HEK-293 cells (9). This 5Ј-UTR contains three short open reading frames [sORFs (1,4,5); Fig. 1].…”

mentioning

confidence: 99%

A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters

Peeters

Beld

Attalki

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

101

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Type II deiodinase (D2) is important in the regulation of local thyroid hormone bioactivity in certain tissues. D2 in skeletal muscle may also play a role in serum triiodothyronine (T 3) production. In this study, we identified a polymorphism in the 5Ј-UTR of the D2 gene (D2-ORFa-Gly3Asp). We investigated the association of D2-ORFa-Gly3Asp, and of the previously identified D2-Thr92Ala polymorphism, with serum iodothyronine levels. D2-ORFa-Gly3Asp was identified by sequencing the 5Ј-UTR of 15 randomly selected individuals. Genotypes for D2-ORFa-Gly3Asp were determined in 156 healthy blood donors (age 46.3 Ϯ 12.2 yr) and 349 ambulant elderly men (age 77.7 Ϯ 3.5 yr) and related to serum iodothyronine and TSH levels. D2-ORFa-Asp 3 had an allele frequency of 33.9% in blood bank donors and was associated with serum thyroxine (T 4; Gly/Gly vs. Gly/Asp vs. Asp/Asp ϭ 7.06 Ϯ 0.14 vs. 6.74 Ϯ 0.15 vs. 6.29 Ϯ 0.27 g/dl, P ϭ 0.01), free T 4 (1.22 Ϯ 0.02 vs. 1.16 Ϯ 0.02 vs. 1.06 Ϯ 0.04 ng/dl, P ϭ 0.001), reverse T 3 (P ϭ 0.01), and T3/T4 ratio (P ϭ 0.002) in a dose-dependent manner, but not with serum T 3 (P ϭ 0.59). In elderly men, D2-ORFa-Asp 3 had a similar frequency but was not associated with serum iodothyronine levels. This new polymorphism in the 5Ј-UTR of D2 is associated with iodothyronine levels in blood donors but not in elderly men. We hypothesize that this might be explained by the decline in skeletal muscle size during aging, resulting in a relative decrease in the contribution of D2 to serum T 3 production.iodothyronines; open reading frame; population; association THYROID HORMONE IS ESSENTIAL for growth, development, and regulation of energy metabolism (14). It stimulates metabolic rate by increasing ATP turnover and by regulating the expression of uncoupling proteins in the mitochondria of fat and skeletal muscle (26,33). Production of thyroid hormone is regulated by the classic hypothalamus-pituitary-thyroid axis, whereas the biological activity of thyroid hormone, i.e., the availability of triiodothyronine (T 3 ), is mainly regulated by the three different selenodeiodinases (D1-D3) (2, 15). Tissue distribution and enzymatic activity of the three deiodinases are highly specific, and they all play a different physiological role. D2 is present in brain, pituitary, thyroid, brown adipose tissue, skeletal muscle, and aortic smooth muscle cells in humans (2,6,15,17,20,30,31). It converts thyroxine (T 4 ) to T 3 by outer-ring deiodination, and it is important in the regulation of local thyroid hormone bioactivity in D2-expressing tissues. D2 in skeletal muscle may also contribute to serum T 3 production (2, 30).The mRNA of the D2 gene is unusually long (6 -7 kb) compared with the other two selenodeiodinases, containing long 5Ј-and 3Ј-untranslated regions (UTRs) (1, 3-5). The 5Ј-UTR of the D2 mRNA is ϳ700 nt long and has an inhibitory effect on D2 translation. It causes a fivefold reduction in D2 activity in HEK-293 cells (9). This 5Ј-UTR contains three short open reading frames [sORFs (1, 4, 5); Fig. 1]. The most ...

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Structural organization and chromosomal localization of the human type II deiodinase gene

Cited by 20 publications

References 20 publications

Type II iodothyronine deiodinase is preferentially expressed in rainbow trout (oncorhynchus mykiss) liver and gonads*

Type II iodothyronine deiodinase is preferentially expressed in rainbow trout (oncorhynchus mykiss) liver and gonads*

GENETICS IN ENDOCRINOLOGY: Genetic variation in deiodinases: a systematic review of potential clinical effects in humans

A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters

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