Two novel missense mutations in the thyroid peroxidase gene, R665W and G771R, result in a localization defect and cause congenital hypothyroidism

Umeki, Kazumi; Kotani, Takuya; Kawano, Junichi; Suganuma, Tatsuo; Yamamoto, Ikuo; Aratake, Yatsuki; Furujo, Mahoko; Ichiba, Yasuyuki

doi:10.1530/eje.0.1460491

Cited by 44 publications

(55 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By immunofluorescence, we observed a defect in the transport of the mutant TPO 766 -775 to the plasma membrane (data not shown). A similar observation was described recently by Umeki et al (51), who showed that when the Gly 771 is replaced by Arg 771 in the TPO genes of patients, this results in a localization defect (accumulation of mutated TPO in the endoplasmic reticulum) and causes congenital hypothyroidism. To overcome this problem, we decided to extract all membrane proteins from wt and stably transfected CHO and to study them by Western blotting and ELISA.…”

Section: Fig 2 Analysis Of T13-specific Mimotopes By the Spot Technsupporting

confidence: 84%

Localization of the Discontinuous Immunodominant Region Recognized by Human Anti-thyroperoxidase Autoantibodies in Autoimmune Thyroid Diseases

Bresson¹,

Cérutti²,

Devauchelle³

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

The discontinuous immunodominant region (IDR) recognized by autoantibodies directed against the thyroperoxidase (TPO) molecule, a major autoantigen in autoimmune thyroid diseases, has not yet been completely localized. By using peptide phage-displayed technology, we identified three critical motifs, LXPEXD, QSYP, and EX(E/D)PPV, within selected mimotopes which interacted with the human recombinant anti-TPO autoantibody (aAb) T13, derived from an antibody phage-displayed library obtained from thyroid-infiltrating TPO-selected B cells of Graves' disease patients. Mimotope sequence alignment on the TPO molecule, together with the binding analysis of the T13 aAb on TPO mutants expressed by Chinese hamster ovary cells, demonstrated that regions 353-363, 377-386, and 713-720 from the myeloperoxidase-like domain and region 766 -775 from the complement control protein-like domain are a part of the IDR recognized by the recombinant aAb T13. Furthermore, we demonstrated that these regions were involved in the binding to TPO of sera containing TPO-specific autoantibodies from patients suffering from Hashimoto's and Graves' autoimmune diseases. Identification of the IDR could lead to improved diagnosis of thyroid autoimmune diseases by engineering "mini-TPO" as a target autoantigen or designing therapeutic peptides able to block undesired autoimmune responses.Human thyroid peroxidase (TPO), 1 described previously as the "thyroid microsomal antigen" (1), is a membrane-bound enzyme expressed at the apical pole of thyrocytes (2). TPO generates the functional form of thyroglobulin by iodination and coupling of tyrosine residues (3). During autoimmune thyroid diseases (AITD), TPO represents a major target for the immune system (4, 5), leading to high titer TPO-specific autoantibodies (aAbs) in the sera of patients suffering from Hashimoto's thyroiditis and Graves' disease. Besides their role as efficient and early diagnostic markers of AITD, TPO-specific aAbs also act as effector molecules either through modulating antigen presentation to T cells or by mediating thyroid destruction after complement activation or antibody-dependent cell cytotoxicity (6 -12). Alignment studies and structural homologies have shown that TPO is formed by three distinct domains: a myeloperoxidase (MPO)-like, a complement control protein (CCP)-like, and an EGF-like domain, from the N-to the Cterminal extremities (13). Although the structure of each domain has been elucidated in part by three-dimensional modeling (13-16), the full three-dimensional structure of TPO remains unknown, even though low resolution crystals have been obtained (17,18). The flexibility observed for the hinge regions probably make difficult the exact positioning of each domain in relation to the others (15).These observations denote a highly complex structure of TPO, thus explaining the reason why TPO aAbs from patients' sera preferentially recognize discontinuous epitopes on . Different approaches have been used to determine the epitopic regions recognized by anti-TPO aAbs from ...

show abstract

Section: Fig 2 Analysis Of T13-specific Mimotopes By the Spot Technsupporting

confidence: 84%

Localization of the Discontinuous Immunodominant Region Recognized by Human Anti-thyroperoxidase Autoantibodies in Autoimmune Thyroid Diseases

Bresson¹,

Cérutti²,

Devauchelle³

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The TPO gene spans over 150 kb on the short arm of chromosome 2, locus 2p25, and consists of 17 exons (9,10). Published molecular genetic studies suggest that TPO gene mutations are one of the most common causes of thyroid dyshormonogenesis, with several different inactivating mutations being identified in patients with total iodide organification defects (TIOD; (7,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)). The inheritance is autosomal recessive (16,29).…”

Section: Introductionmentioning

confidence: 99%

High prevalence of thyroid peroxidase gene mutations in patients with thyroid dyshormonogenesis

Avbelj

Tahirović²,

Debeljak³

et al. 2007

eur j endocrinol

View full text Add to dashboard Cite

Objective: Thyroid dyshormonogenesis is a genetically heterogeneous group of inherited disorders in the enzymatic cascade of thyroid hormone synthesis that result in congenital hypothyroidism (CH). Thyroid peroxidase gene (TPO) mutations are one of the most common causes of thyroid dyshormonogenesis. The aim of this study was to identify TPO gene defects in a cohort of patients with thyroid dyshormonogenesis from Slovenia, Bosnia, and Slovakia. Design and methods: Forty-three patients with permanent CH and orthoptic thyroid glands from 39 unrelated families participated in the study. Mutational analysis of the TPO gene and part of its promoter consisted of single-stranded conformation polymorphism analysis, sequencing, and restriction fragment length polymorphism (RFLP) analysis. Results: TPO gene mutations were identified in 46% of participants. Seven different mutations were identified, four mutations of these being novel, namely 613COT (R175X), 1519_1539del (A477_N483del), 2089GOA (G667S), and 2669GOA (G860R). Only a single allele mutation was identified in 65% of the TPO mutation carriers. Conclusions:The results showed a higher prevalence of TPO gene mutations in thyroid dyshormonogenesis when compared with published studies. The high percentage of single allele mutations implied possible intronic or regulatory TPO gene mutations or monoallelic expression.

show abstract

“…This amino acid substitution was not identified in 50 healthy controls. Two known different heterozygous polymorphisms were also found:1207 G®T and 1283 C®G in exon 8 [7,8]. The other was a heterozygous 10 base deletion of intron 15-exon 16 boundary (Fig.…”

Section: Resultsmentioning

confidence: 89%

“…Approval of the Hokkaido University School of Medicine ethics committee was also received. Genomic DNA was extracted and each exon of the TPO gene was amplified by polymerase-chain-reaction (PCR) using primers according to previous studies in a Perkin-Elmer Gene Amp PCR System 2400 thermal cycler (PE Applied Biosystems, Foster City, CA) [4,7]. After amplification, the purified PCR products were sequenced directly with an ABI PRISM Dye Terminator Cycle Sequencing Kit and an ABI 373A automated fluorescent sequencer (PE Applied Biosystems, Foster City, CA) from both strands.…”

Section: Case Reportmentioning

confidence: 99%

“…The genetic impairment of the TPO gene is the cause of thyroid dyshormonogenesis among congenital hypothyroidism, characterized by iodide organification defects [1,2]. So far frameshift mutations, missense mutations, splicing mutations, nonsense mutations and gene deletion of the TPO gene have been reported in congenital hypothyroidism [1][2][3][4][5][6][7][8][9][10]. Furthermore, it is of note that mutations of the TPO gene have been identified in follicular thyroid carcinoma and adenoma [4,11,12].…”

mentioning

confidence: 99%

See 1 more Smart Citation

Two Novel Mutations in the Thyroid Peroxidase Gene with Goitrous Hypothyroidism

2005

View full text Add to dashboard Cite

Abstract. We encountered a Japanese patient with goitrous hypothyroidism due to iodide organification defect in the thyroid gland. Sequence analysis identified two novel mutations (E378K in exon 8 and a heterozygous 10 base deletion of the intron 15-exon 16 boundary) in the thyroid peroxidase (TPO) gene. As individuals with goitrous hypothyroidism caused by TPO gene mutation develop thyroid cancer, regular and careful follow-up for such patients must be done.

show abstract

Two novel missense mutations in the thyroid peroxidase gene, R665W and G771R, result in a localization defect and cause congenital hypothyroidism

Cited by 44 publications

References 31 publications

Localization of the Discontinuous Immunodominant Region Recognized by Human Anti-thyroperoxidase Autoantibodies in Autoimmune Thyroid Diseases

Localization of the Discontinuous Immunodominant Region Recognized by Human Anti-thyroperoxidase Autoantibodies in Autoimmune Thyroid Diseases

High prevalence of thyroid peroxidase gene mutations in patients with thyroid dyshormonogenesis

Two Novel Mutations in the Thyroid Peroxidase Gene with Goitrous Hypothyroidism

Contact Info

Product

Resources

About