The p.A2215D Thyroglobulin Gene Mutation Leads to Deficient Synthesis and Secretion of the Mutated Protein and Congenital Hypothyroidism with Wide Phenotype Variation

Pardo, Viviane; Vono-Toniolo, Jussara; Rubio, Ileana G.S.; Knobel, Meyer; Possato, R.; Targovnik, Héctor M.; Kopp, Peter; Medeiros‐Neto, Geraldo

doi:10.1210/jc.2009-0150

Cited by 43 publications

(42 citation statements)

References 32 publications

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“…Fifty-two mutations have been identified and characterized in the human TG: 11 splice site mutations, 11 nonsense mutations, 23 missense mutations, 6 deletions (5 single and 1 involving a large number of nucleotides) and 1 single nucleotide insertion [10,11,12,13,14,15,17,30,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58] (table 1; fig. 2, 3).…”

Section: Tg Mutations and Congenital Hypothyroidismmentioning

confidence: 99%

“…The p.C1058R and p.C1977S mutations are the most frequently identified TG mutations in Japanese population [30], whereas the frequent mutations p.R277X [41,44,45,48,49,53,55,57,58], p.R1511X [38,44,46,49,56], p.A2215D [48,52,53,55] and p.R2223H [15,43,55] were found in Caucasian population (table 1). …”

Section: Tg Mutations and Congenital Hypothyroidismmentioning

confidence: 99%

“…Exon skipping in the TG gene can be caused by single nucleotide substitutions in donor or acceptor splice sites involving the +1/+2 (g.IVS3+2T>G [54], g.IVS5+1G>A [14], g.IVS24+1G>C [30], g.IVS30+1G>A [30], g.IVS30 +1G>T [39,42,52,53], g.IVS35+1delG [57], g.IVS45 +2T>A [30]) or –1/–3 position, (g.IVS3–3C>G [17], g.IVS10–1G>A [30], g.IVS34–1G>C [44], g.IVS46–1G>A [53]), respectively (fig. 2; table 1).…”

Section: Tg Mutations and Congenital Hypothyroidismmentioning

confidence: 99%

“…The 11 inactivating mutations that generate a truncated protein have been localized in exons 7 (p.R277X) [41,44,45,48,49,53,55,57,58], 9 (p.R432X, p.Q692X) [30], 10 (p.Q717) [58], 20 (p.W1418X) [30], 22 (p.R1511X) [38,44,46,49,56], 27 (p.Q1765X, p.Q1777X) [54,56], 37 (p.Q2142X) [53], 40 (p.R2317X) [55] and 46 (p.Q2638X) [30] of the TG gene (fig. 3; table 1).…”

Section: Tg Mutations and Congenital Hypothyroidismmentioning

confidence: 99%

“…The p.R277X mutation is the most frequently reported mutation in the TG gene and affected individuals are either homozygous or compound heterozygous mutations [41,44,45,48,49,53,55,57,58]. This mutation has been found in families from Brazil, Argentina, Galicia and France [41,44,45,48,49,53,55,57,58].…”

Section: Tg Mutations and Congenital Hypothyroidismmentioning

confidence: 99%

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Thyroglobulin Gene Mutations in Congenital Hypothyroidism

Targovnik

Citterio

Rivolta³

2011

Horm Res Paediatr

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Human thyroglobulin (TG) gene is a single copy gene, 270 kb long, that maps on chromosome 8q24.2–8q24.3 and contains an 8.5-kb coding sequence divided into 48 exons. TG is exclusively synthesized in the thyroid gland and represents a highly specialized homodimeric glycoprotein for thyroid hormone biosynthesis. Mutations in the TG gene lead to permanent congenital hypothyroidism. The presence of low TG level and also normal perchlorate discharge test in a goitrous individual suggest a TG gene defect. Until now, 52 mutations have been identified and characterized in the human TG gene with functional impact such as structural changes in the protein that alter the normal protein folding, assembly and biosynthesis of thyroid hormones. 11 of the mutations affect splicing sites, 11 produce premature stop codons, 23 lead to amino acid changes, 6 deletions (5 single and 1 involving a large number of nucleotides) and 1 single nucleotide insertion. TG mutations are inherited in an autosomal recessive manner and affected individuals are either homozygous or compound heterozygous. The p.R277X, p.C1058R, p.C1977S, p.R1511X, p.A2215D and p.R2223H mutations are the most frequently identified TG mutations. This mini-review focuses on genetic and clinical aspects of TG gene defects.

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Section: Tg Mutations and Congenital Hypothyroidismmentioning

confidence: 99%

Section: Tg Mutations and Congenital Hypothyroidismmentioning

confidence: 99%

Section: Tg Mutations and Congenital Hypothyroidismmentioning

confidence: 99%

Section: Tg Mutations and Congenital Hypothyroidismmentioning

confidence: 99%

Section: Tg Mutations and Congenital Hypothyroidismmentioning

confidence: 99%

See 3 more Smart Citations

Thyroglobulin Gene Mutations in Congenital Hypothyroidism

Targovnik

Citterio

Rivolta³

2011

Horm Res Paediatr

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Dyshormonogenetic goiter‐like changes in a child with congenital hypothyroidism and a euthyroid adult

Perry

Hope

Yang

2012

Diagnostic Cytopathology

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Dyshormonogenetic goiter is a rare entity that presents in patients who typically have a history of congenital hypothyroidism, and generally arises from a genetic mutation compromising the production of functional thyroxine or thyroglobulin. Clinically, physical manifestations of goiter can result if left untreated. Histologically, the thyroid lesions usually show prominent bridging fibrosis, multiple thyroid nodules with different architectures, microfollicular arrangement, scant colloid, and enlarged vesicular or hyperchromatic nuclei. Cytologically, the features of the lesion are not distinguishable from follicular lesion and follicular neoplasm. We describe two patients exhibiting similar histological and cytological features resembling dyshormonogenetic goiter with cytologic misinterpretation as follicular neoplasm. One was a child with an established history of congenital hypothyroidism. The other was an adult euthyroid patient who presented with an associated parathyroid adenoma. These findings further affirm that cytologically and histologically, morphologic features associated with dyshormonogenetic goiter can also be found in patients without a history of congenital hypothyroidism.

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Clinical, biochemical, and molecular findings in Argentinean patients with goitrous congenital hypothyroidism

Chiesa

Rivolta

Targovnik

et al. 2010

Endocr

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We describe the clinical, biochemical, and molecular findings of a cohort of Argentinean patients with congenital hypothyroidism (CH) and goiter studied to characterize iodide organification and thyroglobulin (TG) defects. 20 CH patients (16 unrelated) were grouped according to serum TG levels and a perchlorate discharge test (PDT) in: group 1 (G1): nine patients with high TG and PDT > 10% who were studied for tiroperoxidase (TPO), dual oxidase 2 (DUOX2), and dual oxidase A2 (DUOXA2) defects and group 2 (G2): 11 patients with low TG and PDT < 10% studied for TG defects. Goiter characteristics, outcome, and TT₄ and TT₃ levels without treatment were compared between groups. 6/9 G1 patients harbored mutations in TPO gene and 3/9 in DUOX2 gene. In G2, mutations of TG gene were found in 3/11 homozygous, 5/11 compound heterozygous, and 3/11 heterozygous patients. Goiter was only evidenced by thyroid scan in the neonatal period in both groups; was moderately enlarged in patients diagnosed during infancy. In the late detected patients, goiter was big and nodular in G1 while diffuse and moderate in G2. Early detected patients grew and developed normally while those diagnosed late were severely mentally retarded in G1 and only mildly retarded in G2. Thyroid hormone levels of G1 were significantly lower than those of G2 P < 0.01. Molecular approach to characterize defects in organification and TG defects was optimized by TG measurements and PDT. Clinical and biochemical differences based on molecular findings will allow further investigations on genotype-phenotype relationships.

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The p.A2215D Thyroglobulin Gene Mutation Leads to Deficient Synthesis and Secretion of the Mutated Protein and Congenital Hypothyroidism with Wide Phenotype Variation

Cited by 43 publications

References 32 publications

Thyroglobulin Gene Mutations in Congenital Hypothyroidism

Thyroglobulin Gene Mutations in Congenital Hypothyroidism

Dyshormonogenetic goiter‐like changes in a child with congenital hypothyroidism and a euthyroid adult

Clinical, biochemical, and molecular findings in Argentinean patients with goitrous congenital hypothyroidism

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