Isolation of a complementary DNA clone for thyroid microsomal antigen. Homology with the gene for thyroid peroxidase.

Seto, Pui; Hirayu, Hideshi; Magnusson, Ronald P.; Gestautas, Jane; Portmann, Luc; DeGroot, Leslie J.; Rapoport, Basil

doi:10.1172/jci113181

Cited by 77 publications

(20 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2 A). In addition, two point mutations were found by comparison with published sequences ( 10,11,14,19) (Fig. 2 A; coordinates as in reference 19).…”

Section: Resultsmentioning

confidence: 99%

“…D.M., a 4-mo-old adopted male, was referred to the endocrine service (Centro de Investigationes Endocrinologicas, CONICET, Hospital de niftos "Ricardo Gutierrez," Buenos Aires, Argentina), where a diagnosis of hypothyroidism was made. The serum thyroxine (14) level was 0.1 tg/dl (normal, [5][6][7][8][9][10][11][12][13] Ag/dl) and the patient was immediately given thyroid hormone therapy. At the age of 5 yr the physical examination showed moderate to severe mental retardation with speech difficulties and stunted growth.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter.

Abramowicz¹,

Targovnik²,

Varela³

et al. 1992

J. Clin. Invest.

171

104

View full text Add to dashboard Cite

Thyroid peroxidase (TPO) is the key enzyme in the synthesis ofthyroid hormones, and the TPO defects are believed to be the most prevalent causes of the inborn errors of thyroid metabolism. We investigated an adopted boy with iodide organification defect, who presented with florid hypothyroidism at the age of4 mo, poorly complied with thyroxine treatment, and developed a compressive goiter necessitating partial resection at the age of 12 yr.Biochemical studies revealed the absence ofTPO activity in the resected tissue. Genomic DNA studies identified a 4 basepair insertion in the eighth exon of the TPO gene, and showed that the patient was homozygous for this frameshift mutation. The direct genetic diagnosis of this mutation can be made by digestion of polymerase chain reaction products with NaeI restriction enzyme. This will help assessing its prevalence among the heterogenous genetic group of TPO defects. (J. Clin. Invest. 1992. 90:1200-1204.) Key words: alternative splicing.

show abstract

“…2 A). In addition, two point mutations were found by comparison with published sequences ( 10,11,14,19) (Fig. 2 A; coordinates as in reference 19).…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter.

Abramowicz¹,

Targovnik²,

Varela³

et al. 1992

J. Clin. Invest.

171

104

View full text Add to dashboard Cite

show abstract

“…For example, a reported fusion protein originally described as reactive with 19 of 20 Hashimoto's sera (reference 18, clone C2) has, upon immunopurification with anti-,B-galactosidase MAbs, been found to react with fewer Hashimoto's sera in an ELISA assay (39). In the present study, using eukaryotic recombinant TPO, we show that all 36 Hashimoto's sera, selected to represent a range of anti-MSA levels seen in this disease, were reactive.…”

Section: Resultsmentioning

confidence: 99%

“…This conclusion was based on immunologic evidence (12)(13)(14)(15) and subsequently confirmed by the molecular cloning of the cDNA for these proteins (16)(17)(18)(19) and the discovery that their derived amino acid sequences are the same (18,20).…”

Section: Introductionmentioning

confidence: 91%

Generation of recombinant, enzymatically active human thyroid peroxidase and its recognition by antibodies in the sera of patients with Hashimoto's thyroiditis.

Kaufman¹,

Rapoport²,

Seto³

et al. 1989

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thyroid peroxidase (TPO), 1 a heme-containing glycoprotein on the thyrocyte apical membrane that plays a key role in thyroid hormone biosynthesis, is also the dominant autoantigen in human autoimmune thyroiditis (1)(2)(3). A remarkable feature of polyclonal TPO autoantibodies in the sera of all patients is that their epitopes are largely directed to a restricted area on the native antigen, termed the immunodominant region (IDR)(reviewed in Ref.…”

mentioning

confidence: 99%

Localization of the Thyroid Peroxidase Autoantibody Immunodominant Region to a Junctional Region Containing Portions of the Domains Homologous to Complement Control Protein and Myeloperoxidase

Guo

McLachlan

Rapoport

2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Thyroid peroxidase (TPO) autoantibody epitopes are largely restricted to an immunodominant region (IDR) on the extracellular region of the native molecule. Localization of the IDR has been a longstanding and difficult goal. The TPO extracellular region comprises a large myeloperoxidase-like domain, linked to the plasma membrane by two smaller domains with homology to complement control protein (CCP) and epidermal growth factor (EGF), respectively. Recent studies have focused on the CCP-and EGF-like domains as the putative location of the TPO autoantibody IDR. To address this issue, we attempted to express on the surface of transfected cells native TPO in which the CCP-and EGF-like domains were deleted, either together or individually. We used a quartet of human monoclonal autoantibodies that define the TPO IDR, as well as polyclonal TPO autoantibodies in patients' sera, to detect these mutated TPO molecules by flow cytometry. The combined CCP/EGF-like domain deletion did not produce a signal with TPO autoantibodies but did not traffic to the cell surface. In contrast, both monoclonal and polyclonal autoantibodies recognized TPO with the juxtamembrane EGF-like domain deleted equally as well as the wild-type TPO on the cell surface. TPO with the CCP-like domain deleted expressed normally on the cell surface, as determined using the polyclonal mouse antiserum. Nevertheless, this modified TPO molecule was recognized very poorly by both the human monoclonal autoantibodies and the polyclonal autoantibodies in patients' sera. In conclusion, we have clearly excluded the juxtamembrane EGF-like domain as being part of the IDR. In contrast, a component of the CCP-like domain does contribute to the IDR. These data, together with findings from other studies, localize the TPO autoantibody IDR to the junction of the CCP-like domain and the much larger myeloperoxidase-like domain on TPO.Thyroid peroxidase (TPO), 1 a heme-containing glycoprotein on the thyrocyte apical membrane that plays a key role in thyroid hormone biosynthesis, is also the dominant autoantigen in human autoimmune thyroiditis (1-3). A remarkable feature of polyclonal TPO autoantibodies in the sera of all patients is that their epitopes are largely directed to a restricted area on the native antigen, termed the immunodominant region (IDR)(reviewed in Ref. 4). This epitopic profile contrasts with antibodies generated in mice by immunization with purified TPO together with adjuvant, which have a wide range of epitopes on both native and denatured TPO (5). Even within the IDR, TPO autoantibodies in an individual patient maintain the same epitopic fingerprint over many years (lack of epitope spreading) (6), a phenomenon that appears to have a genetic basis (7).The role of TPO autoantibodies in the pathogenesis of disease is debated. Some evidence supports their involvement in thyrocyte damage by antibody-mediated cellular cytotoxicity (8, 9). Perhaps more important is the influence of antibodies complexed to antigen in modulating antigen processing with enhancemen...

show abstract

Isolation of a complementary DNA clone for thyroid microsomal antigen. Homology with the gene for thyroid peroxidase.

Cited by 77 publications

References 15 publications

Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter.

Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter.

Generation of recombinant, enzymatically active human thyroid peroxidase and its recognition by antibodies in the sera of patients with Hashimoto's thyroiditis.

Localization of the Thyroid Peroxidase Autoantibody Immunodominant Region to a Junctional Region Containing Portions of the Domains Homologous to Complement Control Protein and Myeloperoxidase

Contact Info

Product

Resources

About