The rs1991517 polymorphism is a genetic risk factor for congenital hypothyroidism

Kollati, Yedukondalu; Akella, Radha Rama Devi; Naushad, Shaik Mohammad; Thalla, Maunika; Reddy, G. Bhanuprakash; Dirisala, Vijaya R.

doi:10.1007/s13205-020-02273-7

Cited by 9 publications

(4 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our previous studies, we established the reference intervals for thyroid-stimulating hormone (TSH) through NBS data, and the specific genotype-phenotype correlations were exhibited in confirmed CH cases with TSHR, TPO, and TG gene variants [12]. Previously, we published an in silico analysis on p.D727E in the TSHR gene, which might control the signal transduction (cAMP-mediated) pathway, consequently contributing to the pathophysiology of CH [26]. In this study, we specifically focused on an in silico analysis of three variants: p.S398T in TPO, and p.G653D and p.R1999W in TG.…”

Section: Resultsmentioning

confidence: 99%

Molecular insights into the role of genetic determinants of congenital hypothyroidism

Kollati

Akella

Naushad³

et al. 2021

Genomics Inform

Self Cite

View full text Add to dashboard Cite

In our previous studies, we have demonstrated the association of certain variants of the thyroid-stimulating hormone receptor (TSHR), thyroid peroxidase (TPO), and thyroglobulin (TG) genes with congenital hypothyroidism. Herein, we explored the mechanistic basis for this association using different in silico tools. The mRNA 3'-untranslated region (3'-UTR) plays key roles in gene expression at the post-transcriptional level. In TSHR variants (rs2268477, rs7144481, and rs17630128), the binding affinity of microRNAs (miRs) (hsa-miR-154-5p, hsa-miR-376a-2-5p, hsa-miR-3935, hsa-miR-4280, and hsa-miR-6858-3p) to the 3'-UTR is disrupted, affecting post-transcriptional gene regulation. TPO and TG are the two key proteins necessary for the biosynthesis of thyroid hormones in the presence of iodide and H2O2. Reduced stability of these proteins leads to aberrant biosynthesis of thyroid hormones. Compared to the wild-type TPO protein, the p.S398T variant was found to exhibit less stability and significant rearrangements of intra-atomic bonds affecting the stoichiometry and substrate binding (binding energies, ΔG of wild-type vs. mutant: ‒15 vs. ‒13.8 kcal/mol; and dissociation constant, Kd of wild-type vs. mutant: 7.2E-12 vs. 7.0E-11 M). The missense mutations p.G653D and p.R1999W on the TG protein showed altered ΔG (0.24 kcal/mol and 0.79 kcal/mol, respectively). In conclusion, an in silico analysis of TSHR genetic variants in the 3'-UTR showed that they alter the binding affinities of different miRs. The TPO protein structure and mutant protein complex (p.S398T) are less stable, with potentially deleterious effects. A structural and energy analysis showed that TG mutations (p.G653D and p.R1999W) reduce the stability of the TG protein and affect its structure-functional relationship.

show abstract

Section: Resultsmentioning

confidence: 99%

Molecular insights into the role of genetic determinants of congenital hypothyroidism

Kollati

Akella

Naushad³

et al. 2021

Genomics Inform

Self Cite

View full text Add to dashboard Cite

show abstract

“…Newborn screening (NBS) programs have successfully improved the diagnosis and treatment of CH and resulted in better neurodevelopmental outcomes. 1,4,5 It is estimated that one-third of the hormone thyroxine (T4) from the mother will pass to the fetus during pregnancy. The maternal hormone T4, which has a half-life of six days, is metabolized and excreted by three or four weeks of age.…”

Section: Abstrakmentioning

confidence: 99%

Screening T4 and TSH in Early Detection of Congenital Hypothyroidism in Newborns: What’s the Dilemma?

Mashabi

2024

J Biomedika dan Kesehat

View full text Add to dashboard Cite

Untreated congenital hypothyroidism (CH) leads to intellectual disability. Newborn screening (NBS) for CH should be done on all infants. Prompt diagnosis by NBS leads to early and adequate treatment outcomes in very normal neurocognitive outcomes in adulthood. Newborn screening (NBS) for congenital hypothyroidism (CH) is one of the major achievements in preventive medicine. Most neonates born with CH have a normal appearance and no detectable physical signs. Blood spot thyroid stimulating hormone (TSH), thyroxine (T4), or both can be used for CH screening. The latter is more sensitive but not cost-effective, so screening by TSH or T4 is used in various programs worldwide. TSH screening is more specific in the diagnosis of CH. T4 screening is more sensitive in detecting newborns with rare hypothalamic-pituitary-hypothyroidism, but it’s less specific with a high frequency of false positives especially in low birth weight and premature infants. NBS alone is not sufficient to prevent adverse outcomes from CH in a pediatric population. In addition to NBS, the management of CH requires timely confirmation of the diagnosis and accurate interpretation of thyroid function testing, effective treatment, and consistent follow-up. Doctors need to consider hypothyroidism in the face of clinical symptoms, even if NBS thyroid test results are normal. When clinical symptoms and signs of hypothyroidism appear (such as large posterior fontanelles, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum thyroid hormone and free thyroxine is indicated, regardless of NBS results. So all these babies should be treated as having CH during the first 3 years of life, taking into account the risk of mental retardation. Re-evaluation after 3 years is required in such patients.

show abstract

“…One of the most frequent endocrine illnesses among children is congenital hypothyroidism (CH) [6] and [7]. The majority of cases of CH are caused by thyroid dysgenesis or, less frequently, dyshormonogenesis; hence, newborns with these underlying causes require lifelong hormone replacement [8] and [16]. Some of those identified with CH during the neonatal period, however, have a temporary thyroid malfunction and can thus quit taking medication following a 3-year trial off-therapy.…”

Section: Thyroidmentioning

confidence: 99%

Screening for Thyroid Dysfunction among Preterm Infants at Manfalout General Hospital, Assiut, Egypt

Mohamed

El-Masry

Hassan

et al. 2021

Annals of Neonatology Journal

View full text Add to dashboard Cite

Background: Neonatal hypothyroidism is a serious endocrinal disorder that must be diagnosed promptly to avoid irreversible neurological deficits. Aim of work: screening of all preterm infants for thyroid dysfunction. Patients and methods: All preterm infants enrolled to this study were subjected to thorough history taking and complete physical examinations. Investigations: initially screening for hypothyroidism was done according to Egyptian screening program and serum TSH, T4, and free T4 were done within the 1st week of life and repeated at the end of 2nd and 4th week of life for those with abnormal results only. Results: Abnormal thyroid function was detected in 178 (50%) preterm infants.Twenty-two infants were excluded from the study. Mean serum levels of TSH, T4 and free T4 were higher among group II infants (more mature) than 1st group (less mature). The mean levels of T4 and free T4 were higher at the end of 4th week of life than their levels during the 1st week of life. Transient hypothyroxinemia was more frequent thyroid dysfunction disorders among both groups (52.5 % and 38 % for 1st and 2nd groups respectively). Neonatal hypothyroidism, transient primary neonatal hypothyroidism, and transient hyperthyrotropinemia were detected in 9 (11.25%), 18 (22.5%), and 11 neonates (13.75%), respectively for the 1st group and observed in 7 (9.2%), 14 (18.4%), and 9 neonates (11.8%), respectively for the second group Conclusions: Thyroid dysfunction was moderately common among preterm neonates. Protocol for thyroid function tests among preterm infants is essential.

show abstract

The rs1991517 polymorphism is a genetic risk factor for congenital hypothyroidism

Cited by 9 publications

References 38 publications

Molecular insights into the role of genetic determinants of congenital hypothyroidism

Molecular insights into the role of genetic determinants of congenital hypothyroidism

Screening T4 and TSH in Early Detection of Congenital Hypothyroidism in Newborns: What’s the Dilemma?

Screening for Thyroid Dysfunction among Preterm Infants at Manfalout General Hospital, Assiut, Egypt

Contact Info

Product

Resources

About