New insights into thyroglobulin gene: Molecular analysis of seven novel mutations associated with goiter and hypothyroidism

Citterio, Cintia E.; Machiavelli, Gloria A.; Miras, Mirta; Gruñeiro‐Papendieck, Laura; Lachlan, Katherine; Sobrero, Gabriela; Chiesa, Ana; Walker, Judith S.; Muñoz, Liliana; Testa, Graciela; Belforte, Fiorella S.; González-Sarmiento, Rogelio; Rivolta, Carina M.; Targovnik, Héctor M.

doi:10.1016/j.mce.2012.11.002

Cited by 30 publications

(22 citation statements)

References 38 publications

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“…Two siblings (F5a, b) were compound heterozygous for a known nonsense mutation (p.R296*) and a rare, novel missense variant, (p.C160S) that affects a highly conserved cysteine residue in TG (Genomic Evolutionary Rate Profiling score 5.84). Cysteine residues within repetitive domains in the TG form intramolecular disulphide bonds needed for protein folding; thus, p.C160S may be deleterious to TG affecting the tertiary structure as predicted by PolyPhen (16–18). Two siblings (F7a, b) harbored the same homozygous TG splice region variant (c.638+5 G>A) inherited from heterozygous parents; although the pathogenicity of this cannot be ascertained in silico , it is unique to the affected siblings, and adjacent to a known pathogenic mutation (c.638+1G>A) (19), supporting causality, albeit in association with a mild CH phenotype.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, the location of novel variants in TPO (heme-binding region or substrate-binding region) and DUOX2 (R354W; peroxidase-like domain) mirrors that of previously described pathogenic mutations. Analysis of novel variants in TG is hindered by an incomplete knowledge of its functional domains or crystal structure, but those identified affect similar regions to previously documented mutations (N-terminal cysteine-rich repetitive elements, C-terminal ACHE-like domain) also supporting causality (8, 16, 18, 28). …”

Section: Discussionmentioning

confidence: 99%

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Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ

Nicholas

Serra

Cangül

et al. 2016

The Journal of Clinical Endocrinology & Metabolism

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Context:Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken.Objective:Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS.Patients, Design, and Setting:We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.Results:Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases.Conclusions:The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ

Nicholas

Serra

Cangül

et al. 2016

The Journal of Clinical Endocrinology & Metabolism

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“…Thyroid volume was calculated by multiplication of length, breadth and depth and a corrective factor of 0.52 for each lobe. Reference range for 6-11 years: 2.7 ± 0.8 ml (Citterio et al, 2013a). Scintigraphy showed a normally located thyroid gland and his potassium perchlorate discharge test was negative (4%).…”

Section: Patientmentioning

confidence: 99%

“…Several patients were identified with dyshormonogenesis caused by mutations in the TG gene (Abdul-Hassan et al, 2013;Agretti et al, 2013;Alzahrani et al, 2006;Cangul et al, 2014;Caputo et al, 2007aCaputo et al, , 2007bCaron et al, 2003;Citterio et al, 2011Citterio et al, , 2013aCitterio et al, , 2013bCorral et al, 1993;González-Sarmiento et al, 2001;Gutnisky et al, 2004;Hermanns et al, 2013;Hishinuma et al, 1999Hishinuma et al, , 2005Hishinuma et al, , 2006Ieiri et al, 1991;Kahara et al, 2012;Kanou et al, 2007;Kim et al, 2008;Kitanaka et al, 2006;Liu et al, 2012;Machiavelli et al, 2010;Moya et al, 2011;Narumi et al, 2011;Niu et al, 2009;Pardo et al, 2008Pardo et al, , 2009Pérez-Centeno et al, 1996;Peteiro-Gonzalez et al, 2010;Raef et al, 2010;Rivolta et al, 2005;Targovnik et al, 1993Targovnik et al, , 1995Targovnik et al, , 2001Targovnik et al, , 2010bTargovnik et al, , 2012van de Graaf et al, 1999). These defects are inherited in an autosomal recessive manner and affected individuals are either homozygous or compound heterozygous for the mutations.…”

Section: Introductionmentioning

confidence: 99%

Novel compound heterozygous Thyroglobulin mutations c.745+1G>A/c.7036+2T>A associated with congenital goiter and hypothyroidism in a Vietnamese family. Identification of a new cryptic 5′ splice site in the exon 6

Citterio

Morales

Bouhours‐Nouet

et al. 2015

Molecular and Cellular Endocrinology

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“…TPO is also responsible for the iodination of selected tyrosil residues of thyroglobulin (organification), forming monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues, and for the coupling of MIT and DIT resulting in the formation of T 3 and T 4 [18]. The matrix for the synthesis and storage of T 4 and T 3 is thyroglobulin (Tg), a large glycoprotein secreted by the thyroid follicular cells [19,20]. H 2 O 2 is generated by the dual oxidase 2 (DUOX2), a calcium dependent flavoprotein NADPH oxidase, which requires a maturation factor known as DUOXA2 [21].…”

Section: Introductionmentioning

confidence: 99%

Iodide transport: implications for health and disease

Pesce

Kopp

2014

Int J Pediatr Endocrinol

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Disorders of the thyroid gland are among the most common conditions diagnosed and managed by pediatric endocrinologists. Thyroid hormone synthesis depends on normal iodide transport and knowledge of its regulation is fundamental to understand the etiology and management of congenital and acquired thyroid conditions such as hypothyroidism and hyperthyroidism. The ability of the thyroid to concentrate iodine is also widely used as a tool for the diagnosis of thyroid diseases and in the management and follow up of the most common type of endocrine cancers: papillary and follicular thyroid cancer. More recently, the regulation of iodide transport has also been the center of attention to improve the management of poorly differentiated thyroid cancer. Iodine deficiency disorders (goiter, impaired mental development) due to insufficient nutritional intake remain a universal public health problem. Thyroid function can also be influenced by medications that contain iodide or interfere with iodide metabolism such as iodinated contrast agents, povidone, lithium and amiodarone. In addition, some environmental pollutants such as perchlorate, thiocyanate and nitrates may affect iodide transport. Furthermore, nuclear accidents increase the risk of developing thyroid cancer and the therapy used to prevent exposure to these isotopes relies on the ability of the thyroid to concentrate iodine. The array of disorders involving iodide transport affect individuals during the whole life span and, if undiagnosed or improperly managed, they can have a profound impact on growth, metabolism, cognitive development and quality of life.

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New insights into thyroglobulin gene: Molecular analysis of seven novel mutations associated with goiter and hypothyroidism

Cited by 30 publications

References 38 publications

Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ

Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ

Novel compound heterozygous Thyroglobulin mutations c.745+1G>A/c.7036+2T>A associated with congenital goiter and hypothyroidism in a Vietnamese family. Identification of a new cryptic 5′ splice site in the exon 6

Iodide transport: implications for health and disease

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