Compound heterozygosity for a novel hemizygous missense mutation and a partial deletion affecting the catalytic core of the H2O2-generating enzyme DUOX2 associated with transient congenital hypothyroidism.
Hum Mutat
; 31(4): E1304-19, 2010 Apr.
Article
em En
| MEDLINE
| ID: mdl-20187165
ABSTRACT
Dual oxidases (DUOX) 1 and 2 are components of the thyroid H(2)O(2)-generating system. H(2)O(2) is used by thyroperoxidase to oxidize iodide for thyroid hormonogenesis. Mutations in the DUOX2 gene have been described in transient and permanent congenital thyroid dyshormonogenesis. We report here a novel genetic defect causing congenital hypothyroidism in a French-Canadian patient. At neonatal screening, the patient had high TSH and low total T(4) levels. (99m)Tc scan showed a normally shaped orthotopic but mildly enlarged thyroid gland, suggesting dyshormonogenesis. Thyroxine treatment was given from 1 month to 17 years, after which it was stopped for re-evaluation and the patient remained euthyroid. The transient congenital hypothyroidism phenotype prompted us to screen for mutations in DUOX2 and DUOXA2 genes using the PCR-amplified direct sequencing method. We found complete inactivation of DUOX2 caused by a partial genomic deletion of one allele inherited from the mother associated with a paternally inherited missense mutation (c.4552G>A, p.Gly1518Ser). The deleted fragment encompasses the entire COOH-terminal end which is responsible for the NADPH-oxidase activity. The Gly1518Ser DUOX2 protein is expressed at the cell surface of transfected cells albeit at low level, but it is non-functional. This study provides further evidence that the permanent or transient nature of congenital hypothyroidism is not directly related to the number of inactivated DUOX2 alleles, suggesting the existence of other pathophysiological factors.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Deleção de Sequência
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NADPH Oxidases
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Domínio Catalítico
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Mutação de Sentido Incorreto
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Hipotireoidismo Congênito
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Heterozigoto
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Peróxido de Hidrogênio
Tipo de estudo:
Risk_factors_studies
Limite:
Adolescent
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Adult
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Female
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Humans
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Infant
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Male
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Middle aged
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Newborn
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Pregnancy
Idioma:
En
Revista:
Hum Mutat
Ano de publicação:
2010
Tipo de documento:
Article