Large fetal goiter in a patient with congenital hypothyroidism is associated with intron

PARDO, VIVIANE; RUBIO, LLEANA G. S.; KNOBEL, MEYER; OLIVEIRA, M. H.; MOURA, M.; RIVOLTA, CARINA MARCELA; TARGOVNIK, HÉCTOR MANUEL; MEDEIROS-NETO, GERALDO

Phoenix, Arizona

Congreso; 77th Annual Meeting of the American Thyroid Association (ATA); 2006

Ameican Thyroid Association

Thyroglobulin (TG) is a large glycoprotein that functions as the matrix for thyroid hormone synthesis. At least, twelve altemative splice products have been identified in wild type TG mRNA. Several mutations in TG gene have been associated with congenital hypothyroidism (CH). Some of these mutations promote aberrant altemative splicing and consequently modify the mature transcript and the structure of the TG protein. The aim of this study was to identify TG gene mutations associated with CH in a patient with large fetal goiter detected during the third trimester of gestation. This patient is from the Northeast region of Brazil, and her brother had also a confirmed diagnosis of CH. The parents are consanguineous. 1 all patients the deficiency of TG synthesis was confinned by the absence of serum TG elevation after 24 and 48 hs of the stimulation with recombinant human TSH (0.45mg). DNA samples were obtained from peripheral blood leukocytes, and TG exons and exons/introns borders were amplified by PCR and sequenced. We were able to identify the previously described homozygous mutation g.IVS30+1G>T (in donor splice site) in the index patient and her brother. Their parents and maternal uncle the mutation was in heterozygous condition. In previous studies of other Brazilian family we demonstrated that this mutation causes an aberrant alternative splicing in pre-mRNA, promoting the loss of the entire exon 30. The loss of 138pb (46 aminoacids) can modify the tertiary/quaternary structure ofprotein, and may be retained inside R.E.R, preventing the honnone synthesis. In conclusion, this mutation promotes important impaired TG synthesis, affecting the gland development in intrauterine life, causing a large fetal goiter. This study shows the importance of molecular diagnoses of congenital hypothyroidism to allow an early treatment, avoiding damages in neuropsicomotor development.