A nonsense mutation causes hereditary goitre in the Afrikander cattle and unmasks alternative splicing of thyroglobulin transcripts.

The hereditary goitre of Afrikander cattle is an autosomal recessive disease characterized in homozygotes by the production of abnormal thyroglobulin (Tg) and the coexistence in the thyroid of normal-sized 8.4-kilobase (kb) Tg mRNA with a misspliced 7.3-kb message having lost exon 9. We have cloned and sequenced the cDNA segment corresponding to the abnormal exon 8-exon 10 junction and the relevant genomic DNA region. The mutation responsible for the disease is a cytosine to thymine transition creating a stop codon at position 697 in exon 9. The original reading frame is maintained in the 7.3-kb mRNA, which, as it lacks the mutated exon, is translatable into a potentially functional protein. This puzzling phenotype in which a mutated exon is apparently removed selectively from transcripts by alternative splicing leads us to suggest that the 7.3-kb transcript could be present in normal animals. Using a sensitive oligonucleotide hybridization assay, we have demonstrated that a 7.3-kb mRNA lacking exon 9 does exist in normal thyroids as a minor mRNA species. As it is fully translatable, the 7.3-kb mRNA is expected to be more stable than the normal-sized 8.4-kb message. This probably accounts for the higher proportion of 7.3-kb transcript found in the goitre.