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Screening for mutations in transcription factors in a Czech cohort of 170 patients with congenital and early-onset hypothyroidism: identification of a novel PAX8 mutation in dominantly inherited early-onset non-autoimmune hypothyroidism

Eva Al Taji, Heike Biebermann¹, Zdeka Límanová², Olga Hníková, Jaroslav Zikmund, Christof Dame³, Annette Grüters¹, Jan Lebl⁴ and Heiko Krude¹

Department of Paediatrics, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic, ¹ Institute of Experimental Paediatric Endocrinology, University Children’s Hospital Charité, Berlin, Germany, ² 3rd Medical Clinic, 1st Faculty of Medicine, Charles University, Prague, Czech Republic, ³ Department of Neonatology, Campus Virchow-Klinikum, University Children’s Hospital Charité, Berlin, Germany and ⁴ Department of Paediatrics, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic

(Correspondence should be addressed to E Al Taji; Email: evataji{at}seznam.cz)

Objective: Mutations in NKX2.1, NKX2.5, FOXE1 and PAX8 genes, encoding for transcription factors involved in the development of the thyroid gland, have been identified in a minority of patients with syndromic and non-syndromic congenital hypothyroidism (CH).

Design: In a phenotype-selected cohort of 170 Czech paediatric and adolescent patients with non-goitre CH, including thyroid dysgenesis, or non-goitre early-onset hypothyroidism, PAX8, NKX2.1, NKX2.5, FOXE1 and HHEX genes were analysed for mutations.

Methods: NKX2.1, NKX2.5, FOXE1 and HHEX genes were directly sequenced in patients with syndromic CH. PAX8 mutational screening was performed in all 170 patients by single-stranded conformation polymorphism, followed by direct sequencing of samples with abnormal findings. The R52P PAX8 mutation was functionally characterized by DNA binding studies.

Results: We identified a novel PAX8 mutation R52P, dominantly inherited in a three-generation pedigree and leading to non-congenital, early-onset, non-goitre, non-autoimmune hypothyroidism with gradual postnatal regression of the thyroid size and function. The R52P PAX8 mutation results in the substitution of a highly conserved residue of the DNA-binding domain with a loss-of-function effect. Conclusions: The very low frequency of genetic defects in a population-based cohort of children affected by non-goitre congenital and early-onset hypothyroidism, even in a phenotype-focussed screening study, suggests the pathogenetic role of either non-classic genetic mechanisms or the involvement of genes unknown so far. Identification of a novel PAX8 mutation in a particular variant of non-congenital early-onset hypothyroidism indicates a key function of PAX8 in the postnatal growth and functional maintenance of the thyroid gland.