Identification of two compound heterozygous mutations (R277X / IVS34-1G>C and R277X / R1511X) in the thyroglobulin gene in a brazilian family with congenital goiter and defective thyroglobulin synthesis.

MOYA M. CHRISTIAN; GUTNISKY J. VIVIANA; RIVOLTA M. CARINA; DOMENÉ SABINA; VARELA VIVIANA; VONO-TONIOLO J; MEDEIROS-NETO GERALDO; TARGOVNIK M. HECTOR

Villa Carlos Paz, Cordoba, Argentina

Congreso; XVI Sociedad Latinoamericana de Enfermedades Tiroideas; 2003

Sociedad Latinoamericana de Enfermedades Tiroideas

In this work we have extended our inicial molecular Studies of a noncosanguineous family with two siblings and one of their nephews ith congenital goiter, hypothyroidism, and marked impairment of thyroglobulin síntesis. Genomic DNA sequencing revealed that the index patient (affected nephew) was heterocygous for a single base change of a cytosine to a thymine at nucleotide 886 in exon 7 (886C>T, mother’s mutation) in one allele and for a novel guanine to cytosine transversion at position -1 of the splice acceptor site in intron 34 (IVS34-1G>C, father’s mutation) in the other allele. On the other hand, the two affected siblings inherited the 886C>T mutation from their mother and a previously reported cytosine to a thymine transition at nucleotide 4588 in exon 22 from their father (4588C>T). The 886C>T and 4588C>T substitutions resulted in premature stop codons at amino acids 277 (R227X) and 1511 (R1511X), respectively. Single Strand Conformation Polymorphism (SSCP) (exon 7 and 35) and TaqI rstriction análisis (exon 22) indicated that the two affected siblings, the nephew’s mother, the unaffected nephew and the affected nephew are all heterocygous for the R277X mutation. The two affected siblngs, their father, and three unaffected siblings, are all heterocygous for the R1511X mutation, while the affected nephew and his father are heterocygous for the IVS34-1G>C mutation. Interestingly, insertion/deletion (indel) polymorphism (intron 18), short tandem repeats (STR) (intron 29) and 7589G>A single nucleotide polymorphism (SNP) (exon 44) markers were highly informative. The 541 bp indel allele is associated with the R277X, the R1511X and the IVS34-1G>C mutations. The 29.3 STR allele is associated with the R277X and the R1511X mutations, and the 29.2 STR allele with the IVS34-1G>C. In conclusión, this family carries two compound heterocygous mutations of the Tg gene: R277X/IVS34-1G>C and R277X/R1511X. The Studies described here may help our understanding of the pathophysiology of congenital goiters with defective Tg synthesis.