A frame shift mutation in a hot spot region of the nuclear autoantigen La (SS-B)

A hot spot region was identified in the exon 7 of the nuclear autoantigen La (SS-B). Two La cDNAs were identified which contained a frame shift mutation in the hot spot region. One La cDNA was isolated from a cDNA library made from peripheral blood lymphocytes of an autoimmune patient with primary Sjögren's Syndrome, the other La cDNA was isolated from a human liver cDNA library. The patient's La cDNA had a deletion and the liver La cDNA had an insert of an (A)-residue at the same position. Inserts of 4, 16 and 24 more or less homogeneous (A)-residues were found at the same site in the three La retropseudogenes. The hot spot region located in one of the major autoepitope regions of the La antigen. Both frame shift mutations resulted in premature stop codons. In case of the human liver La cDNA, the premature stop codon located a single amino acid downstream of the frame shift mutation, while it located eleven amino acids downstream of the frame shift mutation in the patient's La cDNA. In consequence, only the sequence of the La peptide encoded by the patient's La cDNA markedly differed from the corresponding La peptide sequence. Translation of the patient's mutant La mRNA in transfected mouse cells resulted in a C-terminally truncated La peptide. Due to the lack of the nuclear location signal it remained in the cytoplasm. The modified La peptide shared homology with (i) La protein itself and (ii) a series of DNA binding proteins including other autoantigens and viral proteins such as topoisomerase I, RNA dependent RNA polymerase of influenza virus and reverse transcriptase. The self-homology region includes the amino acids which the La protein shares with B1 Laminin. It represents a putative neo-epitope that could be involved in triggering of the autoimmune response.