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ANALYSIS OF THREE NOVEL MUTATIONS INTO THYROGLOBULIN GENE ASSOCIATED WITH GOITER AND HYPOTHYROIDISM
SIFFO, SOFIA; CITTERIO, CINTIA E.; ADROVER E
Mar del Plata
Congreso; LXI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA; 2016
Thyroid dyshormonogenesis due to thyroglobulin (TG) gene mutations have an estimated incidence of approximately 1 in 100,000 newborns. The clinical spectrum ranges from euthyroid to mild or severe hypothyroidism. The majority of patients have congenital goiter or goiter appearing shortly after birth. Human TG gene is a single copy gene, 270 kb long which maps on chromosome 8q24 and contains an 8.5-kb coding sequence divided into 48 exons. Up to now, 62 inactivating mutations in the TG gene have been identified in patients with congenital goiter. The 180 bp of the promoter region and all 48 exons of the TG gene, including splicing signals and the flanking intronic regions were amplified using the primers and PCR conditions reported elsewhere. TG PCR fragments were sequenced using sense and antisense specific primers or M13 universal primers.The purpose of the present study was to identify and characterize new mutations in the TG gene. We report 7 patients from 6 unrelated families with goiter, hypothyroidism and low levels of serum TG. All patients underwent clinical, biochemical and imaging evaluation. Molecular analyses revealed three novel inactivating TG mutations: c.5560G>T [p.E1835X, exon 30], c.7084G>C [p.A2343P,exon 41] and c. 7093T>C [p.W2346R, exon 41], and four previously reported mutations: c.378C>A [p.Y107X] c.886C>T [p.R277X], c.1351C>T [p.R432X] and c.7006C>T [p.R2317X]. One patient was homozygous for p.W2346R mutation, four were compound heterozygous mutations and the remaining two siblings from another family with typical phenotype had a single p.E1835X mutated allele. p.E1835X includes regions I, II and only a part of region III of TG. Lacks all the carboxyl-terminal hormonogenic sites.In conclusion, our results confirm the genetic heterogeneity of TG defects and the pathophysiological importance of altered TG folding as a consequency of truncated TG proteins and missense mutations located in ACHE-like domain.