Sequence Analysis of Thyroid Transcription Factor-1 Gene Reveals Absence of Mutations in Patients with Thyroid Dysgenesis but Presence of Polymorphisms in the 5' Flanking Region and Intron.

Abstract

Abstract. Congenital hypothyroidism is caused by several mechanisms.The most common cause worldwide is iodine deficiency, but in iodine-sufficient regions thyroid dysgenesis is the most common cause of congenital hypothyroidism.In the present study we analyzed the thyroid transcription factor-1 (TTF-1) gene in patients with congenital hypothyroidism due to thyroid dysgenesis: three patients with athyrosis, five with ectopy, and one with hypoplasia.Genomic DNA was isolated from peripheral leukocytes, and the TTF-1 gene, including a 5' flanking region, two exons and one intron was amplified by polymerase chain reaction (PCR) with 4 pairs of primers. The PCR products were directly sequenced by the Dye Terminator Cycle Sequencing method. We could not find any mutations specific for the thyroid dysgenesis in the 5' flanking region, two exons and one intron in the TTF-1 gene, but two heterozygous nucleotide substitutions were detected in the intron: a G to A transition at nucleotide 469 (G469A) and a C to A transversion at nucleotide 866 (C866A). The same nucleotide changes were detected in some normal subjects. Allelic frequencies of the polymorphisms G469A and C866A were 23% and 10%, respectively.Another normal polymorphism in the 5' flanking region was a G to T transversion at nucleotide -845 from the transcription start site (G-845T). The allelic frequency of the polymorphism G-845T was 28%. We also found 12 polymorphisms in the 5' flanking region, two in the intron and one in the 3' untranslated region. These polymorphisms were detected in 100% chromosomes. These results suggest that congenital hypothyroidism associated with thyroid dysgenesis is unlikely to be caused by mutations in the TTF-1 gene in which, however, were detected normal polymorphisms in the 5' flanking region, intron and 3' untranslated region.

Thyrotropin Receptor and Thyroid Transcription Factor-1 Genes Variant in Chinese Children with Congenital Hypothyroidism

“…In this case, we analyzed the TTF-1 gene. Consistent with the early studies [29,37,38], no mutation or polymorphism in the coding region of TTF-1 was found. It confirmed that mutations in TTF-1 coding region were likely to be an rare event and were not significant in the pathogenesis of thyroid dysgenesis.…”

“…Up to now, most molecular genetic researches on CH have been done in western countries, some have been carried out in Japanese population [6,28,29]. However,TSHR and TTF-1 genes mutations/variants have not been reported in Chinese population.…”

Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency

“…failed to show NKX2-1 mutations in patients with various types of thyroid dysgenesis (7)(8)(9). In contrast, two patients with a large chromosomal deletion spanning the NKX2-1 gene were found to be affected by a variety of symptoms in the CNS, thyroid, and lung (10,11).…”

Brain–lung–thyroid Syndrome

“…Авторы пришли к выводу, что NKX2-1-мутации не являются частой причиной врожден-ного гипотиреоза. Тем не менее частота NKX2-1-мутаций может быть выше у пациентов с врожденным гипотире-озом, ассоциированным с неврологической патологией и заболеваниями дыхательных путей [16][17][18][19]. В недавнем европейском исследовании у 2 из 150 детей с врожденным гипотиреозом были обнаружены мутации гена NKX2-1.…”