Recurrence of the p.R277X/p.R1511X compound heterozygous mutation in the thyroglobulin gene in unrelated families with congenital goiter and hypothyroidism: haplotype analysis using intragenic thyroglobulin polymorphisms

CAPUTO, MARIELA; RIVOLTA, CARINA MARCELA; GUTNISKY, VIVIANA JUDITH; GRUÑEIRO-PAPENDIECK, LAURA; CHIESA, ANA; MEDEIROS-NETO, GERALDO; GONZÁLEZ-SARMIENTO, ROGELIO; TARGOVNIK, HÉCTOR MANUEL

JOURNAL OF ENDOCRINOLOGY

Society for Endocrinology

Lugar: Londres, UK; Año: 2007 vol. 195 p. 167 - 177

0022-0795

Thyroglobulin (TG) functions as thematrix for thyroid hormone synthesis. Thirty-five different loss-of-function mutations in the TG gene have been reported. Thesemutations are transmitted in an autosomal recessive mode. The objective of this study is to analyze the recurrence of the p.R277X/p.R1511X compound heterozygous mutation in the TG gene in two unrelated families (one Argentinian and another Brazilian) with congenital hypothyroidism, goiter and impairment of TG synthesis. The first and last exon of the TG gene, the exons where previously mutations and single nucleotide polymorphisms (SNPs) were detected, aswell as theTGpromoter,were analyzed by automatic sequencing in one affected member of the each family. Four microsatellite markers localized in introns 10, 27, 29 and 30 of the TG gene, one insertion/deletion intragenic polymorphism and 15 exonic SNPs were used for haplotype analysis. A p.R277X/p.R1511 compound heterozygous mutation in the TG gene was found in two members of an Argentinian family. The same mutations had been also reported previously in two members of a Brazilian family. We constructed mutationassociated haplotypes by genotypingmembers of the two families. Our results suggest that the cosegregating haplotype is different in each one of these families. Different haplotypes segregated with the p.R277X and p.R1511mutations demonstrating the absence of a founder effect for these mutations between Argentinian and Brazilian populations. However, haplotyping of Argentinian patients showed the possibility that the p.R277X alleles might be derived from a common ancestral chromosome.