Molecular Analysis of Thyroglobulin Mutations Found in Patients with Goiter and Hypothyroidism.

SOFÍA SIFFO; EZEQUIELA ADROVER; CINTIA E. CITTERIO; MIRTA B. MIRAS; VIVIANA A. BALBI; ANA CHIESA; JACQUES WEILL; GABRIELA SOBRERO; VER
ONICA G. GONZÁLEZ; PATRICIA PAPENDIECK; ELENA BUENO MARTINEZ; ROGELIO GONZÁLEZ-SARMIENTO; CARINA M. RIVOLTA; HÉCTOR M. TARGOVNIK

MOLECULAR AND CELLULAR ENDOCRINOLOGY.

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2017

0303-7207

Thyroid dyshormonogenesis due to thyroglobulin (TG) gene mutations have an estimated incidence ofapproximately 1 in 100,000 newborns. The clinical spectrum ranges from euthyroid to mild or severehypothyroidism. Up to now, one hundred seventeen deleterious mutations in the TG gene have beenidentified and characterized.The purpose of the present study was to identify and characterize new mutations in the TG gene. Wereport eight patients from seven unrelated families with goiter, hypothyroidism and low levels of serumTG. All patients underwent clinical, biochemical and image evaluation. Sequencing of DNA, genotyping,as well as bioinformatics analysis were performed.Molecular analyses revealed three novel inactivating TG mutations: c.5560G>T [p.E1835*], c.7084G>C[p.A2343P] and c.7093T>C [p.W2346R], and four previously reported mutations: c.378C>A [p.Y107*],c.886C>T [p.R277*], c.1351C>T [p.R432*] and c.7007G>A [p.R2317Q]. Two patients carried homozygousmutations (p.R277*/p.R277*, p.W2346R/p.W2346R), four were compound heterozygous mutations(p.Y107*/p.R277* (two unrelated patients), p.R432*/p.A2343P, p.Y107*/p.R2317Q) and two siblings fromanother family had a single p.E1835* mutated allele. Additionally, we include the analysis of 48 patientsfrom 31 unrelated families with TG mutations identified in our present and previous studies. Ourobservation shows that mutations in both TG alleles were found in 27 families (9 as homozygote and 18as heterozygote compound), whereas in the remaining four families only one mutated allele wasdetected. The majority of the detected mutations occur in exons 4, 7, 38 and 40. 28 different mutationswere identified, 33 of the 96 TG alleles encoded the change p.R277*.In conclusion, our results confirm the genetic heterogeneity of TG defects and the pathophysiologicalimportance of the predicted TG misfolding and therefore thyroid hormone formation as a consequence oftruncated TG proteins and/or missense mutations located within its ACHE-like domain.