Mutations of the thyroid peroxidase gene in patients with total iodide organification defect.

GRUNEIRO-PAPENDIECK LAURA; CHIESA ANA; RIVOLTA M. CARINA; SEBASTIAN A. ESPERANTE; MOYA M. CHRISTIAN; DOMENÉ SABINA; VARELA VIVIANA; HEINRICH J J; TARGOVNIK M. HECTOR

Cancun, Mexico

Congreso; Sociedad Latinoamericana de Endocrinologia Pediatrica (SLEP); Sociedad Mexicana de Endocrinologia Pediatrica (SMEP); 2003

Sociedad Latinoamericana de Endocrinologia Pediatrica (SLEP); Sociedad Mexicana de Endocrinologia Pediatrica (SMEP)

Introduction Congenital hypothyroidism (CH) is a prevalent disease affecting approximately 1:3000 newborn. Thryroid disgenesis is responsible for the 80-85% of this disorder while an eutopic gland is present in the other 10-15%. In these patients, thyroid insufficiency may be caused by defects in various genes: the symporter Na+/I-, thyroglobulin, pendrine, thyroid peroxidase (TPO) and thyroid oxidase 1 (THOX 1) or 2 (THOX 2). Mutations in the last three genes cause organification defects.Objective To identify the TPO gene mutations in patients with congenital goiter and CH, clinical and biochemically selected.Patients and Methods We studied 14 unrelated patients with congenital goiter detected most of them by newborn CH screening. All selected patients showed at diagnosis or evaluation at age three high TSH levels, low T4, elevated thyroglobulin values and perchlorate discharge test> 50%. Genomic DNA was studied by single strand conformation polymorphism (SSCP) and all 17 exons of the TPO gene were amplified by PCR. The resulting  amplified products were electrophoresed on poliacrilamide gels and those which presented an aberrant migration pattern were sequenced.Results 5 different mutations (4 new (NM) and 1 previously described) were detected in exons 5, 8, 9 and 14: 1) NM a frameshift mutation a C deletion nt 477 in exn 5 2) NM a missense mutation in exon 8 nt1010 A>C 3) NM missense mutation in exon 9 nt1586 C>T 4) NM missense mutation in exon 14 nt2512 T>C 5) frameshift mutation in exon 8 GGCC duplication nt1276-1277. All these mutations were found always in heterocygosis in 6 patients that coincidentally were those who had the highest levels of thyroglobulin (range 314-4012 ng/ml) and perchlorate discharge (70-99%). Six polymorphisms not previously described were found in exons 9 and 10 and introns 4, 8, 16. In those cases in which new mutations were identified 100 chromosomes from the general population were analyzed with SSCP.Conclusions Our findings confirm the genetic heterogeneity of TPO defects. As our patients were all heterocygous for different mutations (4 of them newly described), screening for another mutation on the second allele of the TPO gene as well as identification of THOX 1 and 2 defects should be carried out in further studies.