Differentiation of two abnormalities in thyroid peroxidase causing organification defect and goitrous hypothyroidism

Objective: Defects in the human thyroid peroxidase (TPO) gene are reported to be one of the causes of congenital hypothyroidism (CH) due to a total iodide organification defect. The aim of the present study was to determine the nature and frequency of TPO gene mutations in patients with CH, characterised by elevated TSH levels and orthotopic thyroid gland, identified in the Portuguese National Neonatal Screening Programme. Subjects and methods: The sample comprised 55 patients, from 53 unrelated families, with follow-up in the endocrinology clinics of the treatment centres of Porto and Lisbon. Mutation screening in the TPO gene (exons 1–17) was performed by single-strand conformational analysis followed by sequencing of fragments with abnormal migration patterns. Results: Eight different mutations were detected in 13 patients (seven homozygotes and six compound heterozygotes). Novel mutations included three missense mutations, namely 391T > C (S131P), 1274A > G (N425S) and 2512T > A (C838S), as well as the predictable splice mutation 2748G > A (Q916Q/spl?). The undocumented polymorphism 180-47A > C was also detected. Conclusion: The results are in accordance with previous observations confirming the genetic heterogeneity of TPO defects. The proportion of patients in which the aetiology was determined justifies the implementation of this molecular testing in our CH patients with dyshormonogenesis.

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Five novel inactivating mutations in the thyroid peroxidase gene responsible for congenital goiter and iodide organification defect

Human Mutation ◽

10.1002/humu.9175 ◽

2003 ◽

Vol 22 (3) ◽

pp. 259-259 ◽

Cited By ~ 23

Author(s):

Carina M. Rivolta ◽

Sebastián A. Esperante ◽

Laura Gruñeiro-Papendieck ◽

Ana Chiesa ◽

Christian M. Moya ◽

...

Keyword(s):

Thyroid Peroxidase ◽

Peroxidase Gene ◽

Congenital Goiter ◽

Iodide Organification Defect ◽

Organification Defect ◽

Inactivating Mutations

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Goitrous Congenital Hypothyroidism and Hearing Impairment Associated with Mutations in the TPO and SLC26A4/PDS Genes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-0142 ◽

2006 ◽

Vol 91 (7) ◽

pp. 2678-2681 ◽

Cited By ~ 22

Author(s):

Nicole Pfarr ◽

Guntram Borck ◽

Andrew Turk ◽

Ulrike Napiontek ◽

Annerose Keilmann ◽

...

Keyword(s):

Missense Mutation ◽

Hearing Impairment ◽

Congenital Hypothyroidism ◽

Sensorineural Deafness ◽

Primary Hypothyroidism ◽

Thyroid Peroxidase ◽

Compound Heterozygous ◽

Sequence Variant ◽

Organification Defect

Abstract Context: Pendred syndrome (PS) and thyroid peroxidase (TPO) deficiency are autosomal-recessive disorders that result in thyroid dyshormonogenesis. They share congenital hypothyroidism, goiter, and an iodide organification defect as common features. Whereas the hallmark of PS is sensorineural deafness, other forms of congenital hypothyroidism may also lead to hearing impairment. Therefore, a definite diagnosis may be difficult and require molecular genetic analyses. Case Report: The propositus presented at birth with primary hypothyroidism and goiter. He also had congenital bilateral moderate hearing loss, and PS was suspected. Methods: We sequenced the SLC26A4/PDS and TPO genes in the propositus and tested familial segregation of mutations in all available family members who were phenotypically normal. The functional consequences of the identified pendrin mutation (p.R776C) were studied in vitro. Results: Sequencing of the SLC26A4/PDS gene revealed a single monoallelic missense mutation in the propositus (p.R776C). This mutation, which was inherited from his unaffected mother, has previously been identified in an individual with deafness and an enlarged vestibular aqueduct. Sequencing of the TPO gene revealed compound heterozygosity for a novel nonsense mutation (p.Q235X) and a known missense mutation (p.Y453D). The mutant pendrin (p.R776C) retained its ability to transport iodide in vitro. Conclusions: These results show that the propositus carries three sequence variants in two genes: a monoallelic SLC26A4/PDS sequence variant and compound heterozygous TPO mutations. Our study illustrates that if only a single heterozygous SLC26A4/PDS mutation is found in a patient with goiter and deafness, other genetic explanations should be considered.

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Partial iodide organification defect caused by a novel mutation of the thyroid peroxidase gene in three siblings

Clinical Endocrinology ◽

10.1046/j.1365-2265.2003.01823.x ◽

2003 ◽

Vol 59 (2) ◽

pp. 198-206 ◽

Cited By ~ 31

Author(s):

Tomio Kotani ◽

Kazumi Umeki ◽

Jun-ichi Kawano ◽

Tatsuo Suganuma ◽

Akira Hishinuma ◽

...

Keyword(s):

Novel Mutation ◽

Thyroid Peroxidase ◽

Peroxidase Gene ◽

Iodide Organification Defect ◽

Organification Defect

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Thyroid Peroxidase Deficiency and Total Iodide Organification Defect

Comprehensive Handbook of Iodine ◽

10.1016/b978-0-12-374135-6.00056-x ◽

2009 ◽

pp. 539-547

Author(s):

Laura Fugazzola

Keyword(s):

Thyroid Peroxidase ◽

Iodide Organification Defect ◽

Organification Defect ◽

Peroxidase Deficiency

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BIOCHEMICAL STUDIES ON THE IODINE ORGANIFICATION DEFECT OF PENDRED'S SYNDROME

Acta Endocrinologica ◽

10.1530/acta.0.0890070 ◽

1978 ◽

Vol 89 (1) ◽

pp. 70-79 ◽

Cited By ~ 6

Author(s):

Hugo Niepomniszcze ◽

Aldo H. Coleoni ◽

Osvaldo J. Degrossi ◽

Luis M. Scavini ◽

H. Pablo Curutchet

Keyword(s):

Kinetic Studies ◽

Iodine Content ◽

Thyroid Peroxidase ◽

Enzyme Preparations ◽

Biochemical Studies ◽

Order Of Magnitude ◽

Km Value ◽

Pendred’S Syndrome ◽

To Come ◽

Organification Defect

ABSTRACT Biochemical studies were performed on the thyroid of a typical case of Pendred's syndrome who underwent total thyroidectomy. The patient, a euthyroid 14 year old female, presented congenital nerve deafness, goitre and impairment of thyroidal iodine organification. Thyroid peroxidase (TPO) activity was quantitatively normal. Using crude preparations, enzyme activity ranged from 176–366 nmoles of I−-incorporated (inc.) to tyrosine/g of tissue. Normal values are 220–410 nmoles I− inc./g. Digitonin pseudosolubilized TPO, assayed by the tyrosine-iodinase method, showed 44.9 nmoles I− inc./mg of protein for the Pendred's tissue, and 44.5 nmoles I− inc./mg for the control glands. Soluble TPO was utilized for enzyme-kinetic studies. The Km for H2O2, obtained in the triiodide assay with iodide as hydrogen donor, was in the same order of magnitude for both Pendred's and control thyroids, being 3 × 10−4 m and 3.5 × 10−4 m, respectively. In the guaiacol assay, the Pendred's Km value of 4 × 10−4 m was also normal for H2O2. Pre-incubation of enzyme preparations with 5 × 10−5 m haematin did not stimulate TPO activity. Thyroidal NADPH-cytochrome c reductase and monoamine oxidase activities were normal. A low concentration, 37 mg/g, of a qualitatively normal thyroglobulin was found in Pendred's goitre. The iodine content of thyroglobulin was 0.19 %. It is concluded that the four major components of the iodination process: 1) thyroid peroxidase, 2) iodide, 3) thyroglobulin and 4) H2O2 would be normally present in Pendred's glands. It is postulated that a failure of these major components to come together at the iodination site might be the explanation of the organification defect of Pendred's syndrome.

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