title: 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.
abstract: Thyroglobulin (TG) functions as the matrix for thyroid hormone synthesis. Thirty-five different loss-of-function mutations in the TG gene have been reported. These mutations 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, as well as the TG promoter, 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 mutation-associated haplotypes by genotyping members 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.R1511 mutations 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.
authors.affiliation: Laboratorio de Biología Molecular, Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, 1113 Buenos Aires, Argentina.
authors.forename: Mariela
authors.initials: M
authors.lastname: Caputo
authors.forename: Carina M
authors.initials: CM
authors.lastname: Rivolta
authors.forename: Viviana J
authors.initials: VJ
authors.lastname: Gutnisky
authors.forename: Laura
authors.initials: L
authors.lastname: Gruñeiro-Papendieck
authors.forename: Ana
authors.initials: A
authors.lastname: Chiesa
authors.forename: Geraldo
authors.initials: G
authors.lastname: Medeiros-Neto
authors.forename: Rogelio
authors.initials: R
authors.lastname: González-Sarmiento
authors.forename: Héctor M
authors.initials: HM
authors.lastname: Targovnik
mesh_terms: D001118:Argentina; D001345:Autoradiography; D001938:Brazil; D002648:Child; D003409:Congenital Hypothyroidism / Q000235:genetics* / Q000503:physiopathology; D005787:Gene Frequency; D005838:Genotype; D006042:Goiter / Q000235:genetics*; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D013954:Thyroglobulin / Q000235:genetics*; D013960:Thyroid Function Tests; D013961:Thyroid Gland / Q000503:physiopathology
chemical_list: D013954:Thyroglobulin