THYROIDS FROM SIBLINGS WITH PENDREDS-SYNDROME CONTAIN THYROGLOBULIN MESSENGER-RIBONUCLEIC-ACID VARIANTS

We studied thyroid tissue from two siblings with Pendred's syndrome (f amilial goiter and congenital deafness), both with the Mondini-type in ner ear malformation, goiter, and hypothyroidism. Iodine trapping and peroxidase levels were grossly normal. Thyroglobulin (Tg), the only io doprotein found, had a normal monomer size (330 kilodaltons), but low content of hormone and iodine. Tg's expected N-terminal peptides of 26 and 18 kilodaltons, usually formed in association with iodination and thyroid hormone synthesis, were absent, but appeared after iodination in vitro. Reverse transcription of ribonucleic acid from Pendred thyr oid tissue and amplification by polymerase chain reaction of specific regions encoding the most important hormonogenic sites of Tg revealed a normal complementary DNA sequence corresponding to the first 100 ami no acid residues in Tg's N-terminus. However, 3 of 35 clones of the S' -region corresponding to the Tg C-terminus exhibited a deletion of nuc leotides 7860-7994; this deletion was not present in any of the 150 cl ones from 7 other thyroids we examined. Four Pendred clones had a 2-nu cleotide deletion at positions 7870-7871, a change that would result i n a premature stop codon and was found in thyroids from several other subjects as well. We conclude that the messenger ribonucleic acid enco ding the 3'-region of Tg can be abnormal in Pendred's syndrome. Some, but not all, of these changes also occur in other human thyroids. Furt her work is necessary to show if and how these alterations relate to d efective hormone synthesis and goiter.