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

New insights into thyroglobulin gene: molecular analysis of seven novel mutations associated with goiter and hypothyroidism
New insights into thyroglobulin gene: molecular analysis of seven novel mutations associated with goiter and hypothyroidism
The thyroglobulin (TG) gene is organized in 48 exons, spanning over 270 kb on human chromosome 8q24. Up to now, 62 inactivating mutations in the TG gene have been identified in patients with congenital goiter and endemic or non-endemic simple goiter.

The purpose of the present study was to identify and characterize newmutations in the TG gene. We report 13 patients from 7 unrelated families with goiter, hypothyroidism and low levels of serum TG. All patients underwent clinical, biochemical and imaging evaluation. Single-strand conformation polymorphism (SSCP) analysis, endonuclease restriction analysis, sequencing of DNA, genotyping, population screening, and bioinformatics studies were performed.

Molecularanalyses revealed sevennovel inactivating TG mutations: c.378C>A [p.Y107X], c.2359C>T [p.R768X], c.2736delG [p.R893fsX946], c.3842G>A [p.C1262Y], c.5466delA [p.K1803fsX1833], c.6000C>G [p.C1981W] and c.6605C>G [p.P2183R] and three previously reported mutations: c.886C>T [p.R277X], c.6701C>A [p.A2215D] and c.7006C>T [p.R2317X]. Six patients from two families were homozygous for p.R277X mutation, four were compound heterozygous mutations (p.Y107X/p.C1262Y, p.R893fsX946/p.A2215D, p.K1803fsX1832/p.R2317X), one carried three identified mutations (p.R277X/p.C1981W-p.P2183R) together with a hypothetical micro deletion and the remaining two siblings from another family with typical phenotype had a single p.R768X mutated allele.

In conclusion, our results confirm the genetic heterogeneity of TG defects and the pathophysiological importance of altered TG folding as a consequency of truncated TG proteins and missense mutations located in ACHE-like domain or that replace cysteine.
277-291
Citterio, Cintia E.
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Machiavelli, Gloria A.
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Miras, Mirta B.
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Gruñeiro-Papendieck, Laura
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Lachlan, Katherine
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Sobrero, Gabriela
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Chiesa, Ana
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Walker, Joanna
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Muñoz, Liliana
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Testa, Graciela
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Belforte, Fiorella S.
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Gonzalez-Sarmiento, Rogelio
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Rivolta, Carina M.
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Targovnik, Héctor M.
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Citterio, Cintia E.
d902b048-7023-4c20-acbe-9f931d2f9a84
Machiavelli, Gloria A.
f5690448-0552-42d8-9c6e-48911c729dc8
Miras, Mirta B.
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Gruñeiro-Papendieck, Laura
c89dbdca-a391-42a6-b14c-71301fa554f6
Lachlan, Katherine
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Sobrero, Gabriela
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Chiesa, Ana
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Walker, Joanna
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Muñoz, Liliana
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Testa, Graciela
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Belforte, Fiorella S.
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Gonzalez-Sarmiento, Rogelio
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Rivolta, Carina M.
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Targovnik, Héctor M.
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Citterio, Cintia E., Machiavelli, Gloria A., Miras, Mirta B., Gruñeiro-Papendieck, Laura, Lachlan, Katherine, Sobrero, Gabriela, Chiesa, Ana, Walker, Joanna, Muñoz, Liliana, Testa, Graciela, Belforte, Fiorella S., Gonzalez-Sarmiento, Rogelio, Rivolta, Carina M. and Targovnik, Héctor M. (2013) New insights into thyroglobulin gene: molecular analysis of seven novel mutations associated with goiter and hypothyroidism. Molecular and Cellular Endocrinology, 365 (2), 277-291. (doi:10.1016/j.mce.2012.11.002). (PMID:23164529)

Record type: Article

Abstract

The thyroglobulin (TG) gene is organized in 48 exons, spanning over 270 kb on human chromosome 8q24. Up to now, 62 inactivating mutations in the TG gene have been identified in patients with congenital goiter and endemic or non-endemic simple goiter.

The purpose of the present study was to identify and characterize newmutations in the TG gene. We report 13 patients from 7 unrelated families with goiter, hypothyroidism and low levels of serum TG. All patients underwent clinical, biochemical and imaging evaluation. Single-strand conformation polymorphism (SSCP) analysis, endonuclease restriction analysis, sequencing of DNA, genotyping, population screening, and bioinformatics studies were performed.

Molecularanalyses revealed sevennovel inactivating TG mutations: c.378C>A [p.Y107X], c.2359C>T [p.R768X], c.2736delG [p.R893fsX946], c.3842G>A [p.C1262Y], c.5466delA [p.K1803fsX1833], c.6000C>G [p.C1981W] and c.6605C>G [p.P2183R] and three previously reported mutations: c.886C>T [p.R277X], c.6701C>A [p.A2215D] and c.7006C>T [p.R2317X]. Six patients from two families were homozygous for p.R277X mutation, four were compound heterozygous mutations (p.Y107X/p.C1262Y, p.R893fsX946/p.A2215D, p.K1803fsX1832/p.R2317X), one carried three identified mutations (p.R277X/p.C1981W-p.P2183R) together with a hypothetical micro deletion and the remaining two siblings from another family with typical phenotype had a single p.R768X mutated allele.

In conclusion, our results confirm the genetic heterogeneity of TG defects and the pathophysiological importance of altered TG folding as a consequency of truncated TG proteins and missense mutations located in ACHE-like domain or that replace cysteine.

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More information

Accepted/In Press date: 16 November 2012
Published date: 30 January 2013
Organisations: Human Development & Health

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Local EPrints ID: 345483
URI: http://eprints.soton.ac.uk/id/eprint/345483
PURE UUID: 24b8ac1f-1bf3-42d3-8dba-e654b4910ac6

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Date deposited: 22 Nov 2012 10:15
Last modified: 09 Jan 2022 07:10

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Contributors

Author: Cintia E. Citterio
Author: Gloria A. Machiavelli
Author: Mirta B. Miras
Author: Laura Gruñeiro-Papendieck
Author: Katherine Lachlan
Author: Gabriela Sobrero
Author: Ana Chiesa
Author: Joanna Walker
Author: Liliana Muñoz
Author: Graciela Testa
Author: Fiorella S. Belforte
Author: Rogelio Gonzalez-Sarmiento
Author: Carina M. Rivolta
Author: Héctor M. Targovnik

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