BASES GENETICAS Y MOLECULARES DE LAS ENFERMEDADES HEREDITARIAS

RIVOLTA, CARINA M.; TARGOVNIK, HECTOR M.

Buenos Aires, Argentina

Simposio; Genética Humana; 2005

Instituto de Investigación y Desarrollo, Academia Nacional de Ciencias de Buenos Aires

The structural organization gene and the molecular basis of these alterations have been known by means of molecular genetics. The development of new molecular diagnostic tools let us to detect  carriers of mutations in the specific genes, who are clinically and biochemically asymptomatic, in order to establish preventive measures which can reduce the development of the disease or its expansion. Thyroid diseases constitute a heterogeneous collection of abnormalities associated with mutations in genes responsible for the development of thyroid, TTF-1 (thyroid transcription factors-1, also known as TITF1, NKX2-1 or T/EBP), TTF-2 (thyroid transcriptions factors-2, also known as  TITF2, FOXE1 or FKHL15) and  PAX8, or in one of the genes coding for the proteins responsible for thyroid hormone synthesis such as thyroglobulin, thyroperoxidase, sodium/iodide symporter, hydrogen peroxide-generanting system (Duox2) or pendrin genes. Seven mutations in the thyroglobulin gene have been described by our laboratory: g.IVS3-3C>G, p.R277X, p.362fsX382, p.R1511X, g.IVS30+1G>T, g.IVS34-1G>C, p.R2223H.  Our recent results revealed five novel inactivating thyroperoxidase mutations associated with congenital goiter and iodide organification defects : one frameshift mutation (p.N129fsX208) and four missense mutations ( p.N307T, p.V433M, p.P499L, p.C808R). The congenital hypothyroidism with dyshormonogenesis is transmitted as an autosomal recessive trait, whereas the dysembryogenesis, the resistance to thyroid hormone and toxic thyroid hyperplasia show an autosomal dominant transmission.  Somatic mutations of the TSH receptor have been found in hyperfunctioning thyroid adenomas. The resistance to thyroid hormone is an syndrome of reduced tissue responsiveness to hormonal action caused by mutations located in the   thyroid hormone receptor b (TRb) gene. In one such patient, we have identified 1297-1304delGCCTGCCA mutation in exon 10 of the TRb gene. In conclusion, genetic tools are used today to improve carrier detection, prenatal and presyntomatic diagnosis for different diseases. So, predisponent factors can be determinated in complex illness like diabetes and hypertension.