TARGOVNIK Hector Manuel
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IODIDE ORGANIFICATION DEFECT IN PATIENTS WITH CONGENITAL HYPOTHYROIDISM (CH): MUTATIONS OF THE THYROPEROXIDASE (TPO) AND DUAL OXIDASE2 (DUOX2) GENES
GRUÑEIRO-PAPENDIECK, LAURA; CHIESA, ANA; VARELA, VIVIANA; RIVOLTA, CARINA; TARGOVNIK, HECTOR
Congreso; ESPE/LWPES 7th Joint Meeting Paediatric Endocrinology; 2005
Thyroid insufficiency in congenital hypothyroid patients with eutopic gland may be caused by altered iodine organification due to defects of the thyroid peroxidase (TPO) and less frequently in dual oxidase 1 and 2. To identify TPO and DUOX2 gene mutations we studied 15 of 50 patients with CH and goitre, detected most of them by newborn sreening, selected if they had had at diagnosis or revaluation high TSH levels and thyroglobulin values, low T4 and perchlorate discharge test ³ 45 %. All 17 exons of TPO gene and DNA coding sequences and the flanking regions of th N-terminal and central regions of DUOX 2 gene were studied by SSCP and DNA sequencing of fragments with abnormal migration. 5 different mutations for the TPO gene were found in heterocygosis in 6 patients in exons 5, 8, 9 and 14; a frameshift mutation a C deletion nt 477 in exon 5, a missense mutation in exon 8 nt 1010 A>C, a missense mutation in exon 9 nt l586 C>T ,a missense mutation in exon l4 nt 2512 T>C and a frameshift mulation in exon 8 GGCC duplication nt 1276-1277. Only 1 patient was doble heterozygote. Mutations of the DUOX2 gene were found in two families; in the first 2 affected siblings, the father and two healthy brothers were heterozygous for a single base change of a adenine to cytosine transversion at position "C2 of the splice acceptor site in the intron 19 (2652 (-2) A>C). A second heterozygous mutation in exon 11 was identified in the mother and the 2 affected children. A del GTTC at position 2895 in exon 21 (mutation already described) and a new missense mutation in exon 2 was found in the proband of the second family. Our findings confirm the prevalence and genetic heterogeneity of TPO and DUOX 2 defects in patients with CH and severe organification disorders.