TWO COMPOUND HETEROZYGOUS MUTATIONS (p.Q72fsX86/p.C808R; p.N129fsX208/ p.G387R) IN THE THYROID PEROXIDASE GENE RESPONSIBLE FOR CONGENITAL GOITER AND IODIDE ORGANIFICATION DEFECT.

RIVOLTA, CARINA MARCELA; VARELA, VIVIANA; GRUÑEIRO-PAPENDIECK, LAURA; CHIESA, ANA; GONZÁLEZ-SARMIENTO, ROGELIO; TARGOVNIK, HÉCTOR MANUEL

Santiago, Chile

Congreso; XII Congress of Latin American Thyroid Society (SLAT); 2007

Sociedad Latino Americana de Tiroides (SLAT)

Iodide organification defects are associated with  mutations in the thyroid peroxidase (TPO) gene  and characterized by a positive perchlorate discharge test. These mutations originate a congenital goitrous hypothyroidism, transmitted in an autosomal recessive mode. Objetive: In the present study, we extended our initial molecular studies in the six patients heterozygous for the TPO mutations (AE, p.N307T; CR, p.P499L; TM, p.C808R; PD, p.R396fsX472; SF, p.N307T; GA, p.N129fsX208)in order to identify the second mutation in this autosomal recessive disease. Methods: The promoter and the complete coding regions of the human TPO and DUOXA2 genes, along with the flankings intronic regions of each intron were analized by direct DNA sequencing. Results: Four different inactivating TPO mutations were identified in the patients GA and TM, two previously identified (c.387delC, p.N129fsX208; c.2422T>C, p.C808R) and two novel mutations (c.1159G>A, p.G387R; c.215delA, p.Q72fsX86). This implies the inheritance of two different compound heterozygous mutations, p.N129fsX208/p.G387R in patient GA and p.Q72fsX86/p.C808R in patient TM. The wild-type cysteine 808 is strictely conservated in all TPO species. The remaining 4 unrelated patient (AE, CR, PD and SF) did not show additional inactivating mutations in TPO gene and all have only the wild-type sequencing in the recently identified DUOXA2 gene. Conclusions: We have reported two unrelated patients with iodide organification defect caused by two compound heterozygous mutations, p.Q72fsX86/p.C808R and p.N129fsX208/ p.G387R, in the TPO gene and four unrelated patient with monoallelic TPO defect. Identification of the molecular basis of this disorder might be helpful for understanding the pathophysiology of this congenital hypothyroidism.