Molecular Characterization of Iodotyrosine Dehalogenase Deficiency in Patients with Hypothyroidism (original) (raw)
Related papers
Molecular and Cellular Endocrinology, 2010
Iodotyrosine deiodinase is a thyroidal enzyme that deiodinates mono-and di-iodotyrosines (MIT, DIT) and recycles iodine, a scarce element in the environment, for the efficient synthesis of thyroid hormone. Failure of this enzyme leads to hypothyroidism, goiter and mental retardation, a clinical phenotype yet described in the 1950s, whose diagnostic hallmark is the elevation of iodotyrosines in serum and urine.
Iodotyrosine Deiodinase Defect Identified via Genome-Wide Approach
The Journal of Clinical Endocrinology & Metabolism, 2012
Context: Diagnosis of congenital hypothyroidism is hampered by the heterogeneity of inborn errors of thyroid metabolism and the possible delay in hypothyroidism development leading to missed cases by neonatal screen. Objective: In the current study, we used a whole-genome approach to identify the mutation responsible for severe hypothyroidism and a huge goiter in the eldest child born to healthy first cousins. Results: We identified a homozygous mutation of the iodotyrosine deiodinase gene (IYD). We delineated the phenotype of this defect in detail, including urinary monoiodotyrosine (MIT) and diiodotyrosine (DIT) excretion. Moreover, a 4.5-yr-old sister was found homozygous for the mutation. Her clinical and biological data were normal, except for elevated MIT and DIT excretion. The urinary loss of MIT and DIT iodine observed in most affected individuals was quite limited compared to the total iodine loss, except for the hypothyroid homozygote. Hypothyroidism could therefore be partially induced by a relative iodine deficiency caused by urinary iodine loss through MIT and DIT excretion, even in cases of normal iodine intake. The wide inter-and intrafamilial variability of the disease severity remains unclear. Conclusions: Besides refining the phenotype of the IYD defect, our observation shows that a global, genome-wide approach to the heterogeneous inborn thyroid defects was efficient in rapidly identifying the mutation in the proband and the disease recurrence in the still euthyroid sister. Although facilitated by consanguinity in this family, novel sequencing techniques will soon make whole-genome approaches readily amenable to more common cases. (J Clin Endocrinol Metab 97: E1276-E1283, 2012) C ongenital hypothyroidism (CH) is a frequent congenital disorder affecting 1 in 3500 newborns. About 85% of cases are due to thyroid dysgenesis (absent, hypoplasic, or ectopic thyroid gland) and 15% to inborn thyroid dyshormonogenesis (1-5). Deficits in thyroid hormone synthesis are transmitted as autosomal recessive traits and include defects in iodide transmembrane transport [sodium-iodide symporter (NIS), pendrin], iodide organification [thyroid peroxidase (TPO), dual oxidase 2 (DUOX2), dual oxidase 2 maturation factor (DUOXA2)], thyroglobulin (TG), and iodide recycling (iodotyrosine deiodinase) (6-12). The latter group of disorders causes CH with goiter. The TSH receptor defect and other abnormalities in the hypothalamo-pituitary axis are other rare monogenic causes of CH without goiter that may mimic as thyroid dysgenesis (13-15).
Advanced biomedical research, 2016
Congenital hypothyroidism (CH) due to the thyroid dyshormonogenesis is more prevalent in Iran in comparison to other countries. Sodium iodide symporter (NIS) is one of the plasma membrane glycoproteins that is located on the basolateral side of thyroid follicular cells and mediates active I(-) trapping into these cells. Playing a prominent role in thyroid hormone synthesis, NIS gene mutations can be a cause of permanent CH with the etiology of dyshormonogenesis. The aim of this study was to investigate the occurrence of T354P mutation of the NIS gene, in a group of children affected with permanent CH in Isfahan. Thirty-five patients with the etiology of dyshormonogenesis, and 35 healthy children, collected between 2002 and 2011 in Isfahan Endocrine and Metabolism Research Center, were examined for T354P mutation of the NIS gene by direct polymerase chain reaction-sequencing method. No T354P mutation was detected in any of the studied children. More subjects with confirmed iodide tra...
Revista Romana de Medicina de Laborator, 2019
The aim of this study was to evaluate the prevalence of the Iodothyronine Deiodinase 2 gene Thr92Ala polymorphism in children from West of Romania with congenital hypothyroidism (CH) and association with TSH levels in response to levothyroxine monotherapy. Genotyping in 50 children with CH and 52 healthy controls was done using real time PCR. The results showed that there was no statistical difference between the frequencies of genotypes in patients vs. controls. Patients were treated with L-thyroxine and most had normal values for fT3 and fT4. However, high TSH values were found in 21 patients (42%) after treatment. Among patients with high TSH values, AA genotypes were significantly more prevalent (p = 0.044) than TT and AT genotypes. Our results suggest that for the D2 gene Ala92Thr polymorphism, the AA genotype may be detrimental for achieving euthyroidism in patients with CH and levothyroxine monotherapy, therefore polytherapy could be considered as a better approach in these p...
Endocrine Research, 2014
Purpose: Mutations in the TPO gene have been reported to cause congenital hypothyroidism (CH), and our aim in this study was to determine the genetic basis of congenital hypothyroidism in two affected children coming from a consanguineous family. Methods: Since CH is usually inherited in autosomal recessive manner in consanguineous/multi case-families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the candidate genes. First we investigated the potential genetic linkage of the family to any known CH locus using microsatellite markers and then screened for mutations in linked-gene by Sanger sequencing. Results: The family showed potential linkage to the TPO gene and we detected a non-sense mutation (Y55X) in both cases that had total iodode organification defect (TIOD). The mutation segregated with disease status in the family. Y55X is the only truncating mutation in the exon 2 of the TPO gene reported in the literature and results in the earliest stop codon known in the gene to date. Conclusions: This study confirms the pathogenicity of Y55X mutation and demonstrates that a nonsense mutation in the aminoterminal coding region of the TPO gene could totally abolish the function of the TPO enzyme leading to TIOD. Thus it helps to establish a strong genotype/phenotype correlation associated with this mutation. It also highlights the importance of molecular genetic studies in the definitive diagnosis and accurate classification of CH.
Postgraduate Medical Journal, 1986
We studied two sisters who developed large non-toxic goitres in adolescence. Deiodinase deficiency was diagnosed by a rapid thyroid uptake ofradioactive iodine (RAI) at 2 hours associated with a marked fail in thyroidal 131I by 24 hours. Serial RAI scans in the second patient documented evolution of the iodine-deficient state. Conservation of intra-thyroidal iodine stores was maintained by avid iodine uptake and failure to release organified 1311. With progressive loss of inorganic iodine, hypothyroidism developed, associated with a rise in serum TSH which further exacerbated the loss of iodine. Treatment with L-thyroxine resulted in an improvement ofthyroid function, but normalization was achieved only after small doses of Lugol's iodine were administered. These studies illustrate the variable nature and late onset of an inborn error of thyroid metabolism. This family supports an autosomal recessive mode of inheritance for deiodinase deficiency. We have documented progression from a euthyroid to hypothyroid state resulting from decompensation of iodine conservation mechanisms. Case reports Case I This 23 year old woman was born in Jerusalem to nonconsanguineous Tunisian Jewish parents. Except
International journal of preventive medicine, 2013
Considering the high prevalence of congenital hypothyroidism (CH) in Isfahan and its different etiologies in comparison with other countries, the high rate of parental consanguinity, and the role of NIS gene in permanent CH due to dyshormonogenesis, the aim of this study was to investigate the G395R mutation of the NIS gene in patients with permanent CH due to dyshormonogenesis In this case-control study, patients diagnosed with permanent CH due to dyshormonogenesis during CH screening program were selected. Venous blood sample was obtained to determine the G395R mutations of NIS gene using polymerase chain reaction (PCR) sequencing method. In this study, 35 CH patients with permanent CH due to dyshormonogenesis and 35 neonates with normal screening results as a control group were studied. We did not find any changes of the mentioned mutation of NIS gene in the patients' group. Considering the findings of the current study, it seems that further studies with larger sample size a...
2008
Objective: To extend the molecular analysis of the IVS30+1G>T intronic thyroglobulin (TG) mutation, and to report the eleven year follow-up of the affected patients. Methods: Two siblings with severe congenital hypothyroidism with fetal and neonatal goiter, harboring the IVS30+1G>T mutation were included. Nodular and non-nodular thyroid tissue specimens were collected. Specifi c thyroid genes expression was evaluated by real-timePCR and by immunohistochemistry. Results: In non-nodular tissue specifi c thyroid genes mRNA were reduced when compared to normal thyroid sample. In the nodule, TPO and NIS expression was very low. Microscopic examinations showed very large follicular-lumina and swollen vesicles of endoplasmatic-reticulum. Strong cytoplasmatic and low follicular-lumen TG immunostaining were detected. Intracellular NIS, membrane TPO and TSHR immunostaining had higher positivity in nonnodular sample. Both patients had a long-term adequate developmental outcome, besides one patient have been lately-treated. Conclusions: IVS30+1G>T mutation not only lead to very enlarge endoplasmatic-reticulum, but also to alterations of specifi c thyroid genes expression. The clinical evolution of patients harboring these mutations strengthen the concept of the infl uence of environment, like iodine nutrition, to determine the fi nal phenotypic appearance.
Genetic disorders of thyroid development, hormone biosynthesis and signalling
Clinical Endocrinology
Development and differentiation of the thyroid gland is directed by expression of specific transcription factors in the thyroid follicular cell which mediates hormone biosynthesis. Membrane transporters are rate-limiting for cellular entry of thyroid hormones (TH) (T4 and T3) into some tissues, with selenocysteine-containing, deiodinase enzymes (DIO1 and DIO2) converting T4 to the biologically active hormone T3. TH regulate expression of target genes via hormone-inducible nuclear receptors (TRα and TRβ) to exert their physiological effects. Primary congenital hypothyroidism (CH) due to thyroid dysgenesis may be mediated by defects in thyroid transcription factors or impaired thyroid stimulating hormone receptor function. Dyshormonogenic CH is usually due to mutations in genes mediating thyroidal iodide transport, organification or iodotyrosine synthesis and recycling. Disorders of TH signalling encompass conditions due to defects in membrane TH transporters, impaired hormone metabolism due to deficiency of deiodinases and syndromes of Resistance to thyroid hormone due to pathogenic variants in either TRα or TRβ. Here, we review the genetic basis, pathogenesis and clinical features of congenital, dysgenetic or dyshormonogenic hypothyroidism and disorders of TH transport, metabolism and action.