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

2002 ◽  
pp. 491-498 ◽  
Author(s):  
K Umeki ◽  
T Kotani ◽  
J Kawano ◽  
T Suganuma ◽  
I Yamamoto ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Congenital Hypothyroidism ◽  
Cellular Localization ◽  
Thyroid Peroxidase ◽  
Missense Mutations ◽  
Thyroid Hormone Biosynthesis ◽  
Thyroid Dyshormonogenesis ◽  
Hormone Biosynthesis ◽  
Iodide Organification Defect ◽  
Organification Defect

OBJECTIVE: Thyroid peroxidase (TPO) deficiency is one of the causes of thyroid dyshormonogenesis, because TPO plays a key role in thyroid hormone biosynthesis. To determine the frequency and pattern of TPO abnormalities, we have been screening TPO genes of patients with congenital goitrous hypothyroidism. SUBJECTS AND METHODS: TPO genes of a patient with congenital goitrous hypothyroidism and her parents were directly sequenced, and two novel missense mutations (R665W and G771R) were found. The former was derived from her father and the latter from her mother. R665 and G771 were well conserved in the peroxidase superfamily. When mRNAs containing each of the mutations were transfected into CHO-K1 cells, each cell showed faint TPO enzyme activity. However, immunofluorescence and immunoelectron microscopic analyses revealed that neither of the mutated TPOs reached the plasma membrane. CONCLUSIONS: Two novel missense mutations in the TPO gene were found. TPO proteins encoded by these mutated alleles showed abnormal cellular localization; namely, localization on the plasma membrane was disturbed. The loss of plasma membrane localization in mutated TPOs brought about the iodide organification defect, which was diagnosed as congenital hypothyroidism.

scholarly journals Mutation screening of the thyroid peroxidase gene in a cohort of 55 Portuguese patients with congenital hypothyroidism

2005 ◽  
Vol 152 (2) ◽  
pp. 193-198 ◽  
Author(s):  
Carina Rodrigues ◽  
Paula Jorge ◽  
José Pires Soares ◽  
Isaura Santos ◽  
Regina Salomão ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Mutation Screening ◽  
Gene Mutations ◽  
Human Thyroid ◽  
Thyroid Peroxidase ◽  
Molecular Testing ◽  
Missense Mutations ◽  
Human Thyroid Peroxidase ◽  
Iodide Organification Defect ◽  
Organification Defect

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.

scholarly journals Two Different Mutations in the Thyroid Peroxidase Gene of a Large Inbred Amish Kindred: Power and Limits of Homozygosity Mapping1

1999 ◽  
Vol 84 (3) ◽  
pp. 1061-1071
Author(s):  
Silvana Pannain ◽  
Roy E. Weiss ◽  
Charles E. Jackson ◽  
Donald Dian ◽  
John C. Beck ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Family Members ◽  
Thyroid Peroxidase ◽  
Missense Mutations ◽  
Polymorphic Markers ◽  
Dna Pooling ◽  
Nuclear Families ◽  
A Genome ◽  
Iodide Organification Defect ◽  
Organification Defect

Approximately 10% of newborns with congenital hypothyroidism are unable to convert iodide into organic iodine. This iodide organification defect has a prevalence of 1 in 40,000 newborns and may be caused by defects in the thyroid peroxidase enzyme (TPO), the hydrogen peroxide-generating system, the TPO substrate thyroglobulin, or inhibitors of TPO. We identified a high incidence of severe hypothyroidism due to a complete iodide organification defect in the youngest generation of five nuclear families belonging to an inbred Amish kindred. Genealogical records permitted us to trace their origin to an ancestral couple 7–8 generations back and to identify an autosomal recessive pattern of inheritance. Initial studies of homozygosity by descent using two polymorphic markers within the TPO gene showed no linkage to the phenotype. In fact, 4 of 15 affected siblings from 2 of the nuclear families were heterozygous, resulting in homozygosity values of 73% and 53% in affected and unaffected family members, respectively. A genome-wide homozygosity screen using DNA pools from affected and unaffected family members localized the defect to a locus close to the TPO gene. Linkage analysis using 4 additional polymorphic markers within the TPO gene reduced the number of homozygous unaffected siblings to zero without altering the percent homozygosity initially found in the affected. Sequencing of the TPO gene revealed 2 missense mutations, E799K and R648Q. TPO 779K was found in both alleles of the 11 affected homozygotes, both mutations were present in each of the 3 affected compound heterozygotes, and there were no TPO mutations in 1 subject with hypothyroidism of different etiology. These results demonstrate the power of the DNA pooling strategy in the localization of a defective gene and the pitfalls of linkage analysis when 2 relatively rare mutations coexist in an inbred population.

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

2003 ◽  
Vol 22 (3) ◽  
pp. 259-259 ◽  
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

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

2006 ◽  
Vol 91 (7) ◽  
pp. 2678-2681 ◽  
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.

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

2003 ◽  
Vol 59 (2) ◽  
pp. 198-206 ◽  
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

Congenital Hypothyroidism

2017 ◽  
Author(s):  
Mary Lee Gregory
Keyword(s):  
Thyroid Hormone ◽  
Congenital Hypothyroidism ◽  
Hormone Treatment ◽  
Thyroid Stimulating Hormone ◽  
Congenital Defects ◽  
Central Hypothyroidism ◽  
Severe Intellectual Disability ◽  
Iodine Supplementation ◽  
Thyroid Hormone Biosynthesis ◽  
Hormone Biosynthesis

Congenital hypothyroidism (CH) results from the effects of insufficient thyroid hormone on the developing fetus and infant, and is characterized by severe intellectual disability and growth inhibition. CH can result from maternal iodine deficiency, which can be abolished by appropriate dietary iodine supplementation. Alternately, CH may be caused by congenital defects of the thyroid gland and thyroid hormone biosynthesis abnormalities (primary congenital hypothyroidism), or by “central hypothyroidism,” in which the brain produces insufficient thyroid stimulating hormone. Treatment of these latter etiologies requires administration of thyroid hormone.

scholarly journals Thyroid Peroxidase Revisited – Whatʼs New?

2019 ◽  
Vol 51 (12) ◽  
pp. 765-769 ◽  
Author(s):  
Marlena Godlewska ◽  
Damian Gawel ◽  
Ashley M. Buckle ◽  
J. Paul Banga
Keyword(s):  
Thyroid Hormone ◽  
Environmental Factors ◽  
Recent Progress ◽  
Thyroid Peroxidase ◽  
Autoimmune Thyroid Diseases ◽  
Autoimmune Thyroid ◽  
Thyroid Hormone Biosynthesis ◽  
Hormone Biosynthesis ◽  
Genetic And Environmental Factors ◽  
Thyroid Dysfunctions

AbstractThyroid peroxidase (TPO) is an enzyme that participates in thyroid hormone biosynthesis. TPO is also a major autoantigen in autoimmune thyroid diseases (AITD). In this review, we summarize the latest developments in the field of TPO research. We present the current understanding of immunodominant serologic determinants, frequency of TPO-specific autoantibodies in the population, as well as genetic and environmental factors contributing to their development. Moreover, we report recent progress in the clinical utilities of TPO autoantibody testing, including thyroid dysfunctions and extra-thyroidal disorders.

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