title: A nonsense mutation causes hereditary goitre in the Afrikander cattle and unmasks alternative splicing of thyroglobulin transcripts.
abstract: 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.
authors.forename: M H
authors.initials: MH
authors.lastname: Ricketts
authors.forename: M J
authors.initials: MJ
authors.lastname: Simons
authors.forename: J
authors.initials: J
authors.lastname: Parma
authors.forename: L
authors.initials: L
authors.lastname: Mercken
authors.forename: Q
authors.initials: Q
authors.lastname: Dong
authors.forename: G
authors.initials: G
authors.lastname: Vassart
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002418:Cattle Diseases / Q000235:genetics*; D003001:Cloning, Molecular; D005796:Genes; D006042:Goiter / Q000235:genetics / Q000662:veterinary*; D009154:Mutation; D009693:Nucleic Acid Hybridization; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics*; D013954:Thyroglobulin / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D013954:Thyroglobulin