One Base Deletion (c.2422delT) in the TPO Gene Causes Severe Congenital Hypothyroidism

Cangül, Hakan; Doğan, Murat; Saglam, Yaman; Kendall, Michaela; Boelaert, Kristien; Barrett, Timothy

doi:10.4274/jcrpe.1404

Cited by 13 publications

(8 citation statements)

References 30 publications

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“…In the largest series of patients with TPO gene mutations (17), a study conducted in Israel, no significant correlation was observed between the specific type of mutation and the severity of clinical presentation. Further case reports for specific mutations should be accumulated in order to gain more detailed insights into the broad phenotypic variations in this entity (21,22). …”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…The first reported mutation in TPO gene was a homozygous GGCC insertion-duplication at position c.1186 in the exon 8 [54]. A homozygous TPO deletion (c.2422delT), associated with total iodine organification defect and abolition of TPO enzyme function [55], was detected in CH affected siblings from a consanguineous family [56]. A c.2268dup nonsense mutation in the exon 13 of the TPO gene had been reported to be common amongst dyshormonogenetic congenital hypothyroidism patients from Taiwan [57,58].…”

Section: Discussionmentioning

confidence: 99%

Explorative Investigation on Thyroid Peroxidase and Sodium Iodide Symporter Gene Variants in Down Syndrome

Dey¹,

Maiti²,

Sinha³

et al. 2016

J Down Syndr Chr Abnorm

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Objective: Down syndrome (DS), the most common cause of intellectual disability, is frequently associated with thyroid malfunction. Normal thyroid function is essential for growth, neuronal development as well as cognition. Sodium iodide symporter (NIS) and thyroid peroxidase (TPO) are important enzymes for thyroid and to understand their role in DS, we investigated variants in these two genes in families with DS probands (N=183) and controls (N=222). Methods: Genomic DNA isolated from peripheral blood was analyzed by sequencing for genotyping of target sites. Data obtained was analyzed by population-and family-based statistical methods. SNP-SNP interactions were analyzed by Multifactor dimensionality reduction (MDR) test. Results: Out of twelve, only two (rs4808708 and rs4808709) functional SNPs in NIS and among eleven only one SNP, rs1126799 in TPO were polymorphic. Case-control analysis failed to show any statistically significant difference. Family-based analysis revealed significant over transmission of rs1126799 'C' allele to probands. MDR analysis showed synergistic effect of rs1126799 with both rs4808708 and rs4808709. rs4808708 and rs4808709 showed redundancy amongst themselves. Conclusion: This pioneering association study on TPO and NIS gene variants in DS subjects showed synergistic interaction between the SNPs, in absence of any independent contribution, and together may regulate thyroid hormone metabolism.

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“…Three cases born to a consanguineous Turkish family were ascertained through our studies on the genetics of CH. [16][17][18][19][20][21][22][23][24][25][26] The older sister was first diagnosed at the age of 8 months with hormone values of thyroid-stimulating hormone (TSH) 132 mIU/L (normal 0.35-5.5), free thyroxine (fT 4 ) 0.3 ng/dL (normal 0.8-2.0), and T 3 20 ng/dL (normal 80-120). Thyroid ultrasonography showed a thyroid gland of normal size and location.…”

Section: Subjectsmentioning

confidence: 99%

“…To investigate genetic background of CH, we developed a two-tier strategy combining genetic linkage studies and full sequencing of candidate genes in familial cases and identified several mutations to date in different CH genes. [16][17][18][19][20][21][22][23][24][25][26] In the current study we aimed to determine genetic cause of CH in a consanguineous family with three affected siblings. Here we report a homozygous duplication (c.1184_1187dup4) in the TPO gene detected in all cases and associated clinical phenotypes.…”

Section: Introductionmentioning

confidence: 99%

A Homozygous TPO Gene Duplication (c.1184_1187dup4) Causes Congenital Hypothyroidism in Three Siblings Born to a Consanguineous Family

2015

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Congenital hypothyroidism (CH) is the most common neonatal endocrine disease, and germ-line mutations in the TPO gene cause the inherited form of the disease. Our aim in this study was to determine the genetic basis of congenital hypothyroidism in three affected children coming from a consanguineous Turkish family. Because CH is usually inherited in autosomal recessive manner in consanguineous/multicase 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 conventional sequencing. The family showed potential linkage to the TPO gene and we detected a homozygous duplication (c.1184_1187dup4) in all cases. The mutation segregated with disease status in the family. This study confirms the pathogenicity of the c.1184_1187dup4 mutation in the TPO gene and helps establish a 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.

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One Base Deletion (c.2422delT) in the TPO Gene Causes Severe Congenital Hypothyroidism

Cited by 13 publications

References 30 publications

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

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

Explorative Investigation on Thyroid Peroxidase and Sodium Iodide Symporter Gene Variants in Down Syndrome

A Homozygous TPO Gene Duplication (c.1184_1187dup4) Causes Congenital Hypothyroidism in Three Siblings Born to a Consanguineous Family

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