Molecular analysis of congenital goitres with hypothyroidism caused by defective thyroglobulin synthesis. Identification of a novel c.7006C&gt;T [p.R2317X] mutation and expression of minigenes containing nonsense mutations in exon 7

Machiavelli, Gloria A.; Caputo, Mariela; Rivolta, Carina M.; Olcese, María C.; Gruñeiro‐Papendieck, Laura; Chiesa, Ana; González‐Sarmiento, Rogelio; Targovnik, Héctor M.

doi:10.1111/j.1365-2265.2009.03621.x

Cited by 22 publications

(36 citation statements)

References 46 publications

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“…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%

“…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%

“…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%

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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%

See 2 more Smart Citations

Thyroglobulin Gene Mutations in Congenital Hypothyroidism

Targovnik

Citterio

Rivolta³

2011

Horm Res Paediatr

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“…Since the first description of TG gene mutations in patients with congenital goiter and hypothyroidism (Ieiri et al, 1991), at least 50 different mutations have been found scattered in most of the coding exons of the human TG gene: including 23 missense mutations,10 nonsense mutations, five single and one large nucleotide deletions, one single nucleotide insertion, and 10 splice site mutations (Machiavelli et al, 2010;Targovnik et al, 2010). These findings suggest that the recessive form of this disease results, to different degrees, from loss of function of normal protein.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Genetic Analysis of a Compound Heterozygous Mutation in the Thyroglobulin Gene in a Chinese Twin Family With Congenital Goiter and Hypothyroidism

Liu

Zhang

et al. 2012

Twin Res Hum Genet

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Mutations in the thyroglobulin (TG) gene, which has an estimated incidence of approximately 1 in 100,000 new-borns, cause autosomal recessive congenital hypothyroidism. The mutational spectrum of the TG gene and the phenotype–genotype correlations have not yet fully been established. We report a compound heterozygous mutation in the TG gene in a Chinese twin family with congenital goiter and hypothyroidism. We also describe the gene mutation associated with the genotype–phenotype of these children with congenital goiter and hypothyroidism. The whole coding sequence of the TG gene was analyzed by direct sequence, and the identified changes in the sequence were tested for benign polymorphism by denaturing high-performance liquid chromatography screening of the mutation and sequencing 200 chromosomes from normal controls. Analysis of the TG gene of the affected twin revealed a compound heterozygous mutation, including a novel missense mutation G2687A, which is predicted to result in a glutamine to arginine substitution at codon 877, and a known nonsense mutation C7006T, predicted to result in an arginine to stop codon at codon 2317. Analysis of 200 normal chromosomes did not identify the same change in healthy subjects. This is the first report of a TG gene mutation in the Chinese Han population. Our study provides further evidence that mutations in the TG gene cause congenital goiter and hypothyroidism, demonstrates genetic heterogeneity of the mutation, and increases our understanding of phenotype–genotype correlations in 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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Molecular analysis of congenital goitres with hypothyroidism caused by defective thyroglobulin synthesis. Identification of a novel c.7006C>T [p.R2317X] mutation and expression of minigenes containing nonsense mutations in exon 7

Cited by 22 publications

References 46 publications

Thyroglobulin Gene Mutations in Congenital Hypothyroidism

Thyroglobulin Gene Mutations in Congenital Hypothyroidism

Clinical and Genetic Analysis of a Compound Heterozygous Mutation in the Thyroglobulin Gene in a Chinese Twin Family With Congenital Goiter and Hypothyroidism

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

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