EVIDENCE FOR THE SEGREGATION OF 3 DIFFERENT MUTATED ALLELES OF THE THYROGLOBULIN GENE IN A BRAZILIAN FAMILY WITH CONGENITAL GOITER AND HYPOTHYROIDISM

We have previously reported a Brazilian family with congenital goiter, hypothyroidism, and marked impairment of thyroglobulin (Tg) synthesis . Analysis of the Tg mRNA in the goiter of one of the siblings reveale d a cytosine to thymine transition creating a stop codon at position 1 510. This point mutation is removed from the majority of Tg mRNA trans cripts by the preferential generation in the goiter of a 171 nt delete d Tg mRNA by alternative splicing. The nonsense mutation destroys a Ta qI site at this position in the mutant Tg gene. Using polymerase chain reaction (PCR) amplification and TaqI digestion we found that two sib lings affected with goiter and hypothyroidism, as well as the father a nd three siblings with normal thyroid function, are all heterozygous f or the nonsense mutation. This implies that an additional mutation mus t be present in the affected individuals, generating a compound hetero zygote genotype. A new polymorphism within the thyroglobulin gene repr esented by three alleles has been detected. This was documented by the TaqI restriction enzyme and phTgM3 probe hybridization that showed a three allelic polymorphism with fragment sizes of 16.5 kb (allele A), 14.5 kb (allele B) and 11.0 kb (allele C). Segregation analysis of the se alleles in the family indicated that the two affected siblings were homozygous for the allele C. In contrast the unaffected father and th ree other siblings, who carried the nonsense mutation, were heterozygo us for alleles B and C. Analysis of the Tg genotypes implies that two additional mutations of the Tg gene must segregate in this family to a ccount for the observed phenotypes.