Variable Clinical Phenotypes in a Family with Homozygous c.1159G&gt;A Mutation in the Thyroid Peroxidase&lt;b&gt; &lt;/b&gt;Gene

Lee, Ching Chin; Harun, Fatimah; Jalaludin, Muhammad Yazid; Heh, Choon Han; Othman, Rozana; Kang, In Nee; Junit, Sarni Mat

doi:10.1159/000359922

Cited by 7 publications

(4 citation statements)

References 16 publications

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“…The third child had no symptoms, but received ultrasonography at age 8 months due to the family history, and goiter was shown. Lee et al described three siblings with a homozygous TPO mutation (p.Gly387Arg) [11]. The p.Arg341Gln mutation was analyzed as a representative of nonfunctional mutations.…”

Section: Discussionmentioning

confidence: 99%

“…In a series of expression experiments, we assessed a previously reported TPO mutants (p.Arg341Gln [10]) as a representative of nonfunctional mutation. We also analyzed the p.Gly387Arg mutation that was observed in patients showing the mild TPO deficiency phenotype [11]. Stable HEK293 cell lines expressing each TPO protein (WT, p.Asp224del, p.Trp527Cys, p.Gly387Arg and p.Arg341Gln) were established using the piggyback system according to the manufacturer's protocol.…”

Section: Patientsmentioning

confidence: 99%

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Mild thyroid peroxidase deficiency caused by <i>TPO</i> mutations with residual activity: Correlation between clinical phenotypes and enzymatic activity

et al. 2017

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Thyroid peroxidase (TPO) deficiency, caused by biallelic TPO mutations, is a well-established genetic form of congenital hypothyroidism (CH). More than 100 patients have been published, and the patients have been diagnosed mostly in the frame of newborn screening (NBS) programs. Correlation between clinical phenotypes and TPO activity remains unclear. Here, we report clinical and molecular findings of two unrelated TPO mutation-carrying mildly hypothyroid patients. The two patients were born at term after an uneventful pregnancy and delivery, and were NBS negative. They sought medical attention due to goiter at age 8 years. Evaluation of the thyroid showed mild elevation of serum TSH levels, normal or slightly low serum T levels, high serum T to T molar ratio, high serum thyroglobulin levels, and high thyroidal I uptake. We performed next-generation sequencing-based genetic screening, and found that one patient was compound heterozygous for two novel TPO mutations (p.Asp224del; c.820-2A>G), and the other was homozygous for a previously known mutation (p.Trp527Cys). In vitro functional analyses using HEK293 cells showed that the two amino acid-altering mutations (p.Asp224del and p.Trp527Cys) caused partial loss of the enzymatic activity. In conclusion, we report that TPO mutations with residual activity are associated with mild TPO deficiency, which is clinically characterized by marked goiter, mild TSH elevation, high serum T to T molar ratio, and high serum thyroglobulin levels. Our findings illuminate the hitherto under-recognized correlation between clinical phenotypes and residual enzymatic activity among patients with TPO deficiency.

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Section: Discussionmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

Mild thyroid peroxidase deficiency caused by <i>TPO</i> mutations with residual activity: Correlation between clinical phenotypes and enzymatic activity

et al. 2017

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“…The synthesis of thyroid hormones (T 4 and T 3 ) is affected in 20% of all cases involving inborn genetic errors in the enzymatic cascade, which is defined as thyroid dyshormonogenesis [1]. Most often, these defects appear to be transmitted in an autosomal recessive manner [6], but autosomal dominant inheritance has also been reported [7].…”

Section: Introductionmentioning

confidence: 99%

Molecular insights into the role of genetic determinants of congenital hypothyroidism

Kollati

Akella

Naushad³

et al. 2021

Genomics Inform

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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.

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“…Defects in the TPO gene are the cause of the majority of cases of thyroid dyshormonogenesis with permanent congenital hypothyroidism (2,3). Although TPO mutations have been characterized in subjects of various populations in Asia (4,5,6,7,8,9,10,11) including Japanese, Chinese, Malaysian, and Indian, none have been reported in the Thai population to date. Herein, we report on a novel compound heterozygous TPO mutation in a German-Thai patient with permanent congenital hypothyroidism who presented with a huge multinodular goiter necessitating surgical removal.…”

Section: Introductionmentioning

confidence: 99%

A Novel Mutation in Thyroid Peroxidase Gene Causing Congenital Goitrous Hypothyroidism in a German-Thai Patient

Sriphrapradang¹,

Thewjitcharoen²,

Chanprasertyothin³

et al. 2016

Jcrpe

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Thyroid dyshormonogenesis is responsible for 10-15% of all cases of congenital hypothyroidism and is usually inherited. We report a 26-year-old German-Thai male with congenital hypothyroidism caused by a compound heterozygous mutation in the thyroid peroxidase (TPO) gene. He was diagnosed with congenital goitrous hypothyroidism at 4 months of age and had been treated with levothyroxine replacement therapy. His goiter size had increased due to poor compliance to treatment. Ultrasonography of the thyroid gland showed a pattern suspicious for malignancy. The patient later underwent near-total thyroidectomy. Pathologic examination results were consistent with a multinodular goiter and no malignancy. Genetic analyses by direct sequencing of the entire exons and flanking regions of the TPO gene were performed in the index case and family members. The analyses revealed a compound heterozygote of novel TPO mutation of c.1727C>T in exon 10 resulting in amino acid substitution (p.Ala576Val) and c.2268_2269insT in exon 13 causing a frameshift mutation which introduced a stop codon after the insertion site. The latter has been reported in Chinese subjects. However, there is no previous report of c.1727C>T mutation in the literature. We found the allele contained a novel exon 10 mutation inherited from the patient’s German mother and an exon 13 mutation from his Thai father. Analysis using two bioinformatic software programs indicated that this variant was likely to cause damage in the resulting protein molecule. The present report emphasizes the importance of regular follow-up and patient compliance to levothyroxine replacement in patients with goitrous congenital hypothyroidism to avoid prolonged stimulation of thyroid tissue by thyroid-stimulating hormone.

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Variable Clinical Phenotypes in a Family with Homozygous c.1159G>A Mutation in the Thyroid Peroxidase<b> </b>Gene

Cited by 7 publications

References 16 publications

Mild thyroid peroxidase deficiency caused by <i>TPO</i> mutations with residual activity: Correlation between clinical phenotypes and enzymatic activity

Mild thyroid peroxidase deficiency caused by <i>TPO</i> mutations with residual activity: Correlation between clinical phenotypes and enzymatic activity

Molecular insights into the role of genetic determinants of congenital hypothyroidism

A Novel Mutation in Thyroid Peroxidase Gene Causing Congenital Goitrous Hypothyroidism in a German-Thai Patient

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