The clinical and molecular characterization of patients with dyshormonogenic congenital hypothyroidism reveals specific diagnostic clues for DUOX2 defects

M. Muzza, S. Rabbiosi, M. C. Vigone, I. Zamproni, V. Cirello, M. A. Maffini, K. Maruca, N. Schoenmakers, L. Beccaria, F. Gallo, S. M. Park, P. Beck-Peccoz, L. Persani, G. Weber, L. Fugazzola

Research output: Contribution to journalArticle

Abstract

Context: Mutations in the DUOX2 gene have been associated with transient or permanent congenital hypothyroidism due to a dyshormonogenic defect. Objective: This study aimed to verify the prevalence of DUOX2 mutationsandthe associated clinical features in children selected by criteria supporting a partial iodide organification defect (PIOD). Patients and Methods: Thirty children with PIOD-like criteria were enrolled and genotyped. A detailed clinical characterization was undertaken together with the functional analysis of the DUOX2 variations and the revision of the clinical and molecular data of the literature. Results: In this large selected series, the prevalence of the DUOX2 mutations was high (37%). We identified 12 missense variants, one splice site, and three frameshift DUOX2 mutations. Functional analyses showed significant impairment of H2O2 generation with five missense variants. Stopcodon mutants were shown to totally abolish DUOX2 activity by nonsense-mediated RNA decay, exon skipping, or protein truncation. DUOX2 mutations, either mono- or biallelic, were most frequently associated with permanent congenital hypothyroidism. Moreover, the present data suggested that, together with goiter and PIOD, the most significant features to select patients for the DUOX2 analysis are the low free T4 and the high TSH concentrations at the first postnatal serum sampling, despite borderline blood spot TSH. Interestingly, the analysis of previously described DUOX2 mutated cases confirmed the validity of these findings. Conclusions: The defects in the peroxide generation system are common among congenital hypothyroidism patients with PIOD. The most robust clinical parameters for selecting patients for DUOX2 analysis have been identified, and several DUOX2 variants have been functionally characterized.

Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number3
DOIs
Publication statusPublished - 2014

Fingerprint

Congenital Hypothyroidism
Iodides
Defects
Mutation
Frameshift Mutation
Peroxides
RNA Stability
Goiter
Exons
Functional analysis
Blood
Genes
Serum
RNA
Sampling
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

The clinical and molecular characterization of patients with dyshormonogenic congenital hypothyroidism reveals specific diagnostic clues for DUOX2 defects. / Muzza, M.; Rabbiosi, S.; Vigone, M. C.; Zamproni, I.; Cirello, V.; Maffini, M. A.; Maruca, K.; Schoenmakers, N.; Beccaria, L.; Gallo, F.; Park, S. M.; Beck-Peccoz, P.; Persani, L.; Weber, G.; Fugazzola, L.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 99, No. 3, 2014.

Research output: Contribution to journalArticle

Muzza, M. ; Rabbiosi, S. ; Vigone, M. C. ; Zamproni, I. ; Cirello, V. ; Maffini, M. A. ; Maruca, K. ; Schoenmakers, N. ; Beccaria, L. ; Gallo, F. ; Park, S. M. ; Beck-Peccoz, P. ; Persani, L. ; Weber, G. ; Fugazzola, L. / The clinical and molecular characterization of patients with dyshormonogenic congenital hypothyroidism reveals specific diagnostic clues for DUOX2 defects. In: Journal of Clinical Endocrinology and Metabolism. 2014 ; Vol. 99, No. 3.
@article{e374f796b35d4f0a8873646e4f153e7b,
title = "The clinical and molecular characterization of patients with dyshormonogenic congenital hypothyroidism reveals specific diagnostic clues for DUOX2 defects",
abstract = "Context: Mutations in the DUOX2 gene have been associated with transient or permanent congenital hypothyroidism due to a dyshormonogenic defect. Objective: This study aimed to verify the prevalence of DUOX2 mutationsandthe associated clinical features in children selected by criteria supporting a partial iodide organification defect (PIOD). Patients and Methods: Thirty children with PIOD-like criteria were enrolled and genotyped. A detailed clinical characterization was undertaken together with the functional analysis of the DUOX2 variations and the revision of the clinical and molecular data of the literature. Results: In this large selected series, the prevalence of the DUOX2 mutations was high (37{\%}). We identified 12 missense variants, one splice site, and three frameshift DUOX2 mutations. Functional analyses showed significant impairment of H2O2 generation with five missense variants. Stopcodon mutants were shown to totally abolish DUOX2 activity by nonsense-mediated RNA decay, exon skipping, or protein truncation. DUOX2 mutations, either mono- or biallelic, were most frequently associated with permanent congenital hypothyroidism. Moreover, the present data suggested that, together with goiter and PIOD, the most significant features to select patients for the DUOX2 analysis are the low free T4 and the high TSH concentrations at the first postnatal serum sampling, despite borderline blood spot TSH. Interestingly, the analysis of previously described DUOX2 mutated cases confirmed the validity of these findings. Conclusions: The defects in the peroxide generation system are common among congenital hypothyroidism patients with PIOD. The most robust clinical parameters for selecting patients for DUOX2 analysis have been identified, and several DUOX2 variants have been functionally characterized.",
author = "M. Muzza and S. Rabbiosi and Vigone, {M. C.} and I. Zamproni and V. Cirello and Maffini, {M. A.} and K. Maruca and N. Schoenmakers and L. Beccaria and F. Gallo and Park, {S. M.} and P. Beck-Peccoz and L. Persani and G. Weber and L. Fugazzola",
year = "2014",
doi = "10.1210/jc.2013-3618",
language = "English",
volume = "99",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "The Endocrine Society",
number = "3",

}

TY - JOUR

T1 - The clinical and molecular characterization of patients with dyshormonogenic congenital hypothyroidism reveals specific diagnostic clues for DUOX2 defects

AU - Muzza, M.

AU - Rabbiosi, S.

AU - Vigone, M. C.

AU - Zamproni, I.

AU - Cirello, V.

AU - Maffini, M. A.

AU - Maruca, K.

AU - Schoenmakers, N.

AU - Beccaria, L.

AU - Gallo, F.

AU - Park, S. M.

AU - Beck-Peccoz, P.

AU - Persani, L.

AU - Weber, G.

AU - Fugazzola, L.

PY - 2014

Y1 - 2014

N2 - Context: Mutations in the DUOX2 gene have been associated with transient or permanent congenital hypothyroidism due to a dyshormonogenic defect. Objective: This study aimed to verify the prevalence of DUOX2 mutationsandthe associated clinical features in children selected by criteria supporting a partial iodide organification defect (PIOD). Patients and Methods: Thirty children with PIOD-like criteria were enrolled and genotyped. A detailed clinical characterization was undertaken together with the functional analysis of the DUOX2 variations and the revision of the clinical and molecular data of the literature. Results: In this large selected series, the prevalence of the DUOX2 mutations was high (37%). We identified 12 missense variants, one splice site, and three frameshift DUOX2 mutations. Functional analyses showed significant impairment of H2O2 generation with five missense variants. Stopcodon mutants were shown to totally abolish DUOX2 activity by nonsense-mediated RNA decay, exon skipping, or protein truncation. DUOX2 mutations, either mono- or biallelic, were most frequently associated with permanent congenital hypothyroidism. Moreover, the present data suggested that, together with goiter and PIOD, the most significant features to select patients for the DUOX2 analysis are the low free T4 and the high TSH concentrations at the first postnatal serum sampling, despite borderline blood spot TSH. Interestingly, the analysis of previously described DUOX2 mutated cases confirmed the validity of these findings. Conclusions: The defects in the peroxide generation system are common among congenital hypothyroidism patients with PIOD. The most robust clinical parameters for selecting patients for DUOX2 analysis have been identified, and several DUOX2 variants have been functionally characterized.

AB - Context: Mutations in the DUOX2 gene have been associated with transient or permanent congenital hypothyroidism due to a dyshormonogenic defect. Objective: This study aimed to verify the prevalence of DUOX2 mutationsandthe associated clinical features in children selected by criteria supporting a partial iodide organification defect (PIOD). Patients and Methods: Thirty children with PIOD-like criteria were enrolled and genotyped. A detailed clinical characterization was undertaken together with the functional analysis of the DUOX2 variations and the revision of the clinical and molecular data of the literature. Results: In this large selected series, the prevalence of the DUOX2 mutations was high (37%). We identified 12 missense variants, one splice site, and three frameshift DUOX2 mutations. Functional analyses showed significant impairment of H2O2 generation with five missense variants. Stopcodon mutants were shown to totally abolish DUOX2 activity by nonsense-mediated RNA decay, exon skipping, or protein truncation. DUOX2 mutations, either mono- or biallelic, were most frequently associated with permanent congenital hypothyroidism. Moreover, the present data suggested that, together with goiter and PIOD, the most significant features to select patients for the DUOX2 analysis are the low free T4 and the high TSH concentrations at the first postnatal serum sampling, despite borderline blood spot TSH. Interestingly, the analysis of previously described DUOX2 mutated cases confirmed the validity of these findings. Conclusions: The defects in the peroxide generation system are common among congenital hypothyroidism patients with PIOD. The most robust clinical parameters for selecting patients for DUOX2 analysis have been identified, and several DUOX2 variants have been functionally characterized.

UR - http://www.scopus.com/inward/record.url?scp=84895793589&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84895793589&partnerID=8YFLogxK

U2 - 10.1210/jc.2013-3618

DO - 10.1210/jc.2013-3618

M3 - Article

C2 - 24423310

AN - SCOPUS:84895793589

VL - 99

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 3

ER -