Haplotype Analysis Reveals Founder Effects of Thyroglobulin Gene Mutations C1058R and C1977S in Japan

Hishinuma, Akira; Fukata, Shuji; Nishiyama, Soroku; Nishi, Yoshikazu; Ohishi, Masamichi; Murata, Yoshiharu; Ohyama, Yukako; Matsuura, Nobuo; Kasai, Kikuo; Harada, Shohei; Kitanaka, Susumu; Takamatsu, Junta; Kiwaki, Kohji; Ohye, Hidemi; Uruno, Takashi; Tomoda, Chisato; Tajima, Toshihiro; Kuma, Kanji; Miyauchi, Akira; Ieiri, Tamio

doi:10.1210/jc.2005-2702

Cited by 71 publications

(73 citation statements)

References 18 publications

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“…This observation is true in the absence of the ensuing hinge sequence (mouse Tg-E1192X) or in its presence (mouse Tg-A1435X), and it is also true for Tg bearing a partial hinge sequence (mouse Tg-L1363X). Indeed, we have learned of a homozygous hypothyroid patient bearing the equivalent human Tg-L1364X mutation, 4 and these findings are also consistent with Tg-W1418X as a mutation-linked to human hypothyroidism (22). From our studies, it appears that virtually all of the association of I-II-III with molecular chaperones BiP and GRP94 (a feature linked to Tg retention within the ER) can be attributed to region I alone (Fig.…”

Section: Discussionsupporting

confidence: 78%

“…4). There is reason to think that the latter construct might not be secretion-competent because it is so similar to the human Tg-W1418X mutation that has been reported as a heterozygous allele in human hypothyroidism (22). In fact, with or without the ϳ245-residue hinge, region I alone was incompetent for secretion (Fig.…”

Section: Figure 1 Secretory Chel Rescue Of I-ii-iii Requires a Fullymentioning

confidence: 88%

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Repeat Motif-containing Regions within Thyroglobulin

Lee

Arvan

2011

Journal of Biological Chemistry

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Thyroglobulin (precursor for thyroid hormone synthesis) is a large secreted glycoprotein comprising contiguous region I (multiple type-1 repeating units engaging the first ϳ1,191 residues, followed by a ϳ245-residue hinge region), regions II-III (multiple type-2 and 3 repeating units, comprising ϳ720 residues), and the C-terminal cholinesterase-like (ChEL) domain (ϳ570 residues). A signal peptide attached to ChEL makes an independent secretory protein that binds to I-II-III, stabilizing it and rescuing the secretion of I-II-III that would otherwise be trapped in the endoplasmic reticulum (ER). In this study, we found that a signal peptide attached to regions II-III also makes for an efficient secretory protein that neither demonstrably interacts nor has its secretion enhanced by the presence of secretory ChEL. By contrast, region I, either with or without the hinge region, cannot be secreted on its own and remains in the ER where it is bound to ER chaperones BiP and GRP94. Whereas ChEL can rescue secretion of I-II-III, it can rescue I-II only very weakly, and region I not at all. Yet, ChEL begins to rescue region I in cells that also co-express secretory II-III. The data suggest that conformational maturation of region I is a limiting step in the thyroglobulin maturation process, and this step is facilitated by the presence of both regions II-III and ChEL. Mutations causing hypothyroidism might induce solely local/regional misfolding or may interfere more globally by impeding interactions between regions that are required for thyroglobulin secretion.In vertebrates, thyroid hormones are first created in the apical luminal cavity of follicles of the thyroid gland, upon iodination of the thyroglobulin (Tg) 3 protein (1, 2). It is the structure of Tg (3, 4) rather than the specificity of the peroxidase (5) that is thought to catalyze the coupling of di-iodotyrosyl residues 5 and 130 at the N terminus of Tg (6, 7), forming thyroxine within the Tg molecule. Even in the endostyle of protochordates (the earliest species in which thyroid hormone synthesis is known to occur), a Tg-like protein has been reported (8), whereas no other thyroidal proteins have yet been discovered to substitute effectively for Tg in this role.The primary sequence of Tg (ϳ2,746 residues in mouse Tg after signal peptide cleavage) comprises disulfide-rich contiguous regions: region I (multiple type-1 repeating units engaging the first ϳ1,191 residues followed by a ϳ245-residue hinge region); II-III (multiple type-2 and type-3 repeating units, spanning ϳ720 residues); and the C-terminal cholinesterase-like (ChEL) domain (ϳ570 residues). The genetic origins of these units are still being discovered, but the type-1 repeat is a structural motif that is appears in evolution as a protease inhibitor (9); the type-2 and type-3 repeats have limited homology to other proteins; whereas ChEL exhibits homology to acetylcholinesterase (10 -12). Because no crystallographic data are yet available, the precise physical relationships between the Tg regions remain ...

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Section: Discussionsupporting

confidence: 78%

Section: Figure 1 Secretory Chel Rescue Of I-ii-iii Requires a Fullymentioning

confidence: 88%

Repeat Motif-containing Regions within Thyroglobulin

Lee

Arvan

2011

Journal of Biological Chemistry

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“…Together, the data in Fig. 4, A and B, suggest that C1245R in the hinge segment is impaired in a late stage of Tg oxidation that is linked to neonatal hypothyroidism (32,33).…”

Section: I-ii-iii Oxidative Folding-earlymentioning

confidence: 61%

“…Most interesting from these studies is that the Tg-C1245R point mutation in the hinge segment, responsible for human congenital hypothyroid goiter (32,33), directly impairs efficient D-to-E maturation (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

“…Hishinuma et al (32,33) described two missense mutations in the hinge segment in which cysteine substitution is linked to thyroid pathology: a mild defect associated with adenomatous goiter in patients expressing Tg-C1977S and more severe congenital hypothyroid goiter caused by Tg-C1245R. Upon neonatal screening, both cause elevation of serum thyroid-stimulating hormone, and based upon analysis of goiter tissue, both activate the thyroidal ER stress response, with the Tg-C1245R mutant inducing more ER molecular chaperones than Tg-C1977S (34).…”

Section: I-ii-iii Oxidative Folding-earlymentioning

confidence: 99%

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Maturation of Thyroglobulin Protein Region I

Lee

Jeso

Arvan

2011

Journal of Biological Chemistry

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Background:We have investigated which portion of thyroglobulin is engaged in its final oxidative maturation. Results: We demonstrate that terminal oxidation of thyroglobulin is linked to region I of the protein. Conclusion:Final acquisition of secretory competence includes conformational maturation in the interval between linker and hinge segments of region I. Significance: The results can explain human goitrous hypothyroidism, especially that caused by Tg-C1245R.

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