monoiodotyrosine and Congenital-Hypothyroidism

Thyroid peroxidase (TPO) is a membrane-bound glycoprotein located at the apical side of the thyroid follicular cells that catalyzes both iodination and coupling of iodotyrosine residues within the thyroglobulin molecule, leading to the synthesis of thyroid hormone. Variants in TPO cause congenital hypothyroidism (CH) by iodide organification defect and are commonly inherited in an autosomal recessive fashion. In the present work, we report a detailed population analysis and bioinformatic prediction of the TPO variants indexed in the Genome Aggregation Database (gnomAD) v2.1.1. The proportion of missense cysteine variants and nonsense, frameshift, and splice acceptor/donor variants were analyzed in each ethnic group (European (Non-Finnish), European (Finnish), African/African Americans, Latino/Admixed American, East Asian, South Asian, Ashkenazi Jewish, Other). The results showed a clear predominance of frameshift variants in the East Asian (82%) and European (Finnish) (75%) population, whereas the splice site variants predominate in African/African Americans (99.46%), Other (96%), Latino/Admixed American (94%), South Asian (86%), European (Non-Finnish) (56%) and Ashkenazi Jewish (56%) populations. The analysis of the distribution of the variants indexed in gnomAD v2.1.1 database revealed that most missense variants identified in the An peroxidase domain map in exon 8, followed by exons 11, 7 and 9, and finally in descending order by exons 10, 6, 12 and 5. In total, 183 novel TPO variants were described (13 missense cysteine's variants, 158 missense variants involving the An peroxidase domain and 12 splicing acceptor or donor sites variants) which were not reported in the literature and that would have deleterious effects on prediction programs. In the gnomAD v2.1.1 population, the estimated prevalence of heterozygous carriers of the potentially damaging variants was 1:77. In conclusion, we provide an updated and curated reference source of new TPO variants for application in clinical diagnosis and genetic counseling. Also, this work contributes to elucidating the molecular basis of CH associated with TPO defects.

Topics: Algorithms; Computational Biology; Congenital Hypothyroidism; Cysteine; Humans; Iodide Peroxidase; Iodides; Monoiodotyrosine; Mutation; Peroxidases; Thyroglobulin; Thyroid Hormones

DEHAL1 (also named IYD) is the thyroidal enzyme that deiodinates mono- and diiodotyrosines (MIT, DIT) and recycles iodine, a scarce element in the environment, for the efficient synthesis of thyroid hormone. Failure of this enzyme leads to the iodotyrosine deiodinase deficiency (ITDD), characterized by hypothyroidism, compressive goiter and variable mental retardation, whose diagnostic hallmark is the elevation of iodotyrosines in serum and urine. However, the specific diagnosis of this type of hypothyroidism is not routinely performed, due to technical and practical difficulties in iodotyrosine determinations. A handful of mutations in the DEHAL1 gene have been identified as the molecular basis for the ITDD. Patients harboring DEHAL1 defects so far described all belong to consanguineous families, and psychomotor deficits were present in some affected individuals. This is probably due to the lack of biochemical expression of the disease at the beginning of life, which causes ITDD being undetected in screening programs for congenital hypothyroidism, as currently performed. This worrying feature calls for efforts to improve pre-clinical detection of iodotyrosine deiodinase deficiency during the neonatal time. Such a challenge poses questions of patho-physiological (natural history of the disease, environmental factors influencing its expression) epidemiological (prevalence of ITDD) and technical nature (development of optimal methodology for safe detection of pre-clinical ITDD), which will be addressed in this review.

Topics: Biomarkers; Congenital Hypothyroidism; Diiodotyrosine; Genotype; Humans; Hydrolases; Hypothyroidism; Infant, Newborn; Iodide Peroxidase; Iodides; Membrane Proteins; Monoiodotyrosine; Neonatal Screening; Phenotype; Prevalence

Topics: Biopsy; Chemical Phenomena; Chemistry; Chromosomes; Congenital Hypothyroidism; Culture Techniques; Decarboxylation; Female; Genes, Dominant; Genes, Recessive; Goiter; Humans; Hypothyroidism; Iodine; Iodine Isotopes; Male; Metabolism, Inborn Errors; Monoiodotyrosine; Oxidoreductases; Thyroid Gland; Thyroxine; Triiodothyronine

Topics: Congenital Hypothyroidism; Diiodotyrosine; Humans; Iodide Peroxidase; Monoiodotyrosine; Mutation

The recent cloning of the human iodotyrosine deiodinase (IYD) gene enables the investigation of iodotyrosine dehalogenase deficiency, a form a primary hypothyroidism resulting from iodine wasting, at the molecular level.. In the current study, we identify the genetic basis of dehalogenase deficiency in a consanguineous family.. Using HPLC tandem mass spectrometry, we developed a rapid, selective, and sensitive assay to detect 3-monoiodo-l-tyrosine and 3,5-diodo-l-tyrosine in urine and cell culture medium. Two subjects from a presumed dehalogenase-deficient family showed elevated urinary 3-monoiodo-l-tyrosine and 3,5-diodo-l-tyrosine levels compared with 57 normal subjects without thyroid disease. Subsequent analysis of IYD revealed a homozygous missense mutation in exon 4 (c.658G>A p.Ala220Thr) that co-segregates with the clinical phenotype in the family. Functional characterization of the mutant iodotyrosine dehalogenase protein showed that the mutation completely abolishes dehalogenase enzymatic activity. One of the heterozygous carriers for the inactivating mutation recently presented with overt hypothyroidism indicating dominant inheritance with incomplete penetration. Screening of 100 control alleles identified one allele positive for this mutation, suggesting that the c.658G>A nucleotide substitution might be a functional single nucleotide polymorphism.. This study describes a functional mutation within IYD, demonstrating the molecular basis of the iodine wasting form of congenital hypothyroidism. This familial genetic defect shows a dominant pattern of inheritance with incomplete penetration.

Topics: Adolescent; Adult; Amino Acid Sequence; Calibration; Cell Line; Chromatography, High Pressure Liquid; Congenital Hypothyroidism; Diiodotyrosine; DNA Mutational Analysis; Female; Goiter; Humans; Hydrolases; Male; Membrane Proteins; Molecular Sequence Data; Monoiodotyrosine; Mutation, Missense; Phenotype; Plasmids; Reference Standards; Reproducibility of Results; Thyroglobulin; Thyroid Hormones; Transfection; Young Adult

A 16-year-old male cretin with congenital goitrous hypothyroidism and 95% discharge in the perchlorate test underwent thyroidectomy. Thyroid studies disclosed negligible peroxidase (TPO) activity in the tyrosine iodinase assay, 6 nmoles I- inc./g (normals: 220-410). Using the same particulate preparations, a high activity was obtained in the guaiacol assay, 485 U/mg vs. 176 U/mg of a control gland. Goitre TPO was solubilized by treating the thyroid pellets with deoxycholate, trypsin and acetone. Soluble goitre TPO was further purified on Sephadex G-200. By this procedure we obtained a single peak of enzyme activity for oxidizing guaiacol, although no activity was found for iodinating tyrosine. I2 formation, as measured by the triiodide assay, was only 28% of that expected for normal TPO when compared for guaiacol oxidation. It is concluded that this abnormal TPO was the cause of the congenital hypothyroidism of the patient. We suggest the term "thyroid peroxidase-iodinase defect" for defining this newly found inborn error.

Topics: Adolescent; Amino Acid Metabolism, Inborn Errors; Chromatography, Gel; Congenital Hypothyroidism; Goiter; Humans; Iodide Peroxidase; Male; Monoiodotyrosine; NADH Dehydrogenase; Peroxidases; Thyroglobulin; Thyroid Function Tests; Thyroid Gland

Topics: Congenital Hypothyroidism; Diiodotyrosine; Female; Goiter; Humans; Hypothyroidism; Infant; Infant, Newborn; Iodine Radioisotopes; Iodoproteins; Male; Metabolic Clearance Rate; Monoiodotyrosine; Radioimmunoassay; Thyroglobulin; Thyroid Function Tests; Thyrotropin; Triiodothyronine

Topics: Adult; Centrifugation, Density Gradient; Chromatography, DEAE-Cellulose; Congenital Hypothyroidism; Diiodotyrosine; Female; Goiter; Humans; Immunoelectrophoresis; Iodoproteins; Ketoglutaric Acids; Male; Middle Aged; Mitochondria; Monoiodotyrosine; Peptide Hydrolases; Peroxidases; Thyroglobulin; Thyroid Function Tests; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Transaminases; Tyrosine Transaminase

Topics: Age Determination by Skeleton; Child; Congenital Hypothyroidism; Diiodotyrosine; Goiter; Humans; Iodides; Iodine Radioisotopes; Male; Metabolism, Inborn Errors; Microscopy, Electron; Monoiodotyrosine; Thyroglobulin; Thyroid Gland; Thyroxine

Topics: Child; Child, Preschool; Congenital Hypothyroidism; Humans; Hypothyroidism; Infant; Iodine; Male; Monoiodotyrosine; Thyroid Hormones; Time Factors; Tyrosine

Topics: Adolescent; Congenital Hypothyroidism; Enzymes; Fluids and Secretions; Genetics, Medical; Goiter; Humans; Iodine Isotopes; Metabolism, Inborn Errors; Monoiodotyrosine; Thyroid Hormones; Thyroxine; Urine

Topics: Congenital Hypothyroidism; Humans; Hypothyroidism; Monoiodotyrosine; Syndrome; Tyrosine

Five to 10 per cent of cretinism in the United States is due to some congenital enzymatic defect in thyroid hormone synthesis. The clinical signs of hypothyroidism appear in early infancy. Differentiation from athyreotic cretinism is important because the metabolic defect tends to be familial and its presence in the patient's infant relatives should be diagnosed as early as possible. The differentiation is easily made if a goiter is discernible, but if it is not, radioiodine uptake should be measured, for in this condition the uptake is normal or greater. Thyroid replacement is the treatment in either the athyreotic state or the metabolic deficiency. The three known defects in thyroid hormone synthesis are (1) failure to oxidize iodine to elemental iodine resulting in failure of all subsequent processes; (2) failure to deiodinate free iodotyrosine, and (3) failure to form iodothyronine although the previous steps are accomplished.

Topics: Congenital Hypothyroidism; Goiter; Humans; Hypothyroidism; Infant; Iodides; Iodine; Iodine Radioisotopes; Monoiodotyrosine; Syndrome; Thyroid Hormones

Topics: Congenital Hypothyroidism; Goiter; Humans; Monoiodotyrosine; Peptides

Topics: Biochemical Phenomena; Congenital Hypothyroidism; Humans; Incidence; Monoiodotyrosine; Tyrosine

Topics: Blood; Child; Congenital Hypothyroidism; Goiter; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Monoiodotyrosine; Thyroxine; Tyrosine