A 138-NUCLEOTIDE DELETION IN THE THYROGLOBULIN RIBONUCLEIC-ACID MESSENGER IN A CONGENITAL GOITER WITH DEFECTIVE THYROGLOBULIN SYNTHESIS

Two siblings (HSN and AcSN) with congenital goitrous hypothyroidism we re investigated in terms of clinical, biochemical, and molecular biolo gy. Diagnosis of defective thyroglobulin (Tg) was based on findings of low serum T-4, low normal or normal serum T-3, a negative perchlorate discharge test, and the virtual absence of the serum Tg response to c hallenge by bovine TSH. Only minute amounts of Tg-related antigens wer e detected by RIA in the goitrous tissue (HSN, 0.82 mg/g, compared to 70-90 mg/g in normal thyroid tissue), as confirmed by sodium dodecyl s ulfate-agarose gel electrophoresis that indicated the virtual absence of Tg. The Tg messenger ribonucleic acids (mRNAs) from controls and HS N thyroid tissue were first reverse transcribed and then divided into several portions from positions 57-8448; the resulting complementary D NAs were, in turn, amplified by reverse polymerase chain reaction. The amplification of nucleotides 5165-6048 from control thyroid tissue Tg mRNA showed a fragment of 884 base pairs (bp). In contrast, the fragm ent present in the HSN was +/- 750 bp and lacked the normal fragment. The sequencing of the smaller fragment revealed that 138 bp were missi ng between positions 5590-5727 of the HSN Tg mRNA. This deletion does not affect the reading frame of the resulting mRNA and is potentially fully translatable into a Tg polypeptide chain that is shorter by 46 r esidues. A cysteine residue is maintained by the junction between the proximal T from leucine 1831 and the distal GT from cysteine 1877. DNA genomic polymerase chain reaction amplification excludes a deletion i n the Tg gene and indicates that the deleted 138-nucleotide sequences lie in the same exon. The functional consequences of the deletion are not entirely clear, but it is conceivable that the excision of this se gment of the Tg molecule could affect the protein structure, resulting in its premature degradation, very low colloid storage, and diminishe d thyroid hormone production rate.