ICEECE2012 Oral Communications Thyroid Clinical I (6 abstracts)
Identification and functional analysis of DUOX2 variants: biallelic mutations are associated with permanent congenital hypothyroidism
M. Muzza 1 , I. Zamproni 2 , L. Persani 3 , F. Cortinovis 2 , M. Vigone 2 , S. Rabbiosi 2 , L. Beccaria 4 , T. Visser 5 , J. Moreno 6 , G. Weber 2 & L. Fugazzola 1
1University of Milan, Milan, Italy; 2San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; 3University of Milan and Istituto Auxologico Italiano, Milan, Italy; 4A Manzoni Hospital, Lecco, Italy; 5Erasmus Medical Center, Rotterdam, The Netherlands; 6INGEMM- Institute for Medical and Molecular Genetics, La Paz University Hospital, Madrid, Spain.
Since the first identification of DUOX2 as an actor in the pathogenesis of congenital hypothyroidism (CH), several mutations have been associated with transient or permanent CH, with a high intra- and interfamilial phenotypic variability. In the present study, we report clinical and molecular studies of 7 unrelated children and 2 couple of siblings affected with CH and partial iodide organification defect (PIOD).
We identified nine novel and five previously reported DUOX2 mutations (seven missense, six stop codon – three nonsense and three frameshift – and one splice site mutations) using specific PCR primers able to distinguish the two highly homologous DUOX1 and DUOX2 sequences. The missense mutations involve conserved residues located in critical regions for protein function. Functional analysis of these variants indicated a significant impairment of H2O2 generation. Moreover, the nonsense mutants are shown to totally abolish the DUOX2 activity by different mechanisms: nonsense-mediated RNA decay, exon skipping and protein truncation.
Six out of eight cases with compound heterozygous variations had permanent hypothyroidism, but without evident correlations between the type of mutation and the phenotype in terms of TSH levels and discharge rates. However, two siblings showed biallelic mutations and transient CH. On the other hand, among the three patients harboring monoallelic mutations, one had transient and two permanent CH.
In conclusion, in our cohort most biallelic pathogenic DUOX2 variants were associated with permanent CH. The existence of other H2O2 generating systems and differences in age, ethnicity and iodine intake may account for the discrepant biallelic transient cases while the monoallelic cases with permanent CH could be explained by cryptic DUOX2 variations or alterations involving other thyroid mechanisms.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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Endocrine Abstracts
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