Thorpe, Karen Louise; (1999) Gene structure phylogeny and mutation analysis of RING3 - A novel MHC-encoded gene. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The human major histocompatibility complex (MHC), on the short arm of chromosome 6, contains a cluster of genes which show diverse immune functions, like the recognition of foreign antigen and the generation of an inflammatory response. However, the RINGS gene shows no obvious immune function despite its location in the centre of the MHC. RING3 was found to span 12 kb and contains 13 exons, with two alternative start codons. The RINGS gene was also isolated in the mouse and mapped to a syntenic position in the murine MHC. Comparison of the RINGS gene structure in human, mouse and chicken revealed a perfect conservation in the intron/exon boundaries of the coding exons and high conservation at the amino acid level. The ORFX gene, a human homologue of RING3, was isolated and mapped to 9q34. This gene shows a highly conserved gene structure but is almost three times larger than RING3, mainly due to the presence of repeat elements. Evolutionary analysis indicates that RING3 may be over 1 billion years old with homologues isolated in yeast, worm, fly, fish, chicken, mouse and human. The gene structure has been conserved for at least 350 million years and linkage to the MHC has been established in five vertebrate species. Evidence also suggests that ORFX and RING3 arose by an ancient duplication 350-400 million years ago. Both RING3 and ORFX are ubiquitously expressed in human adult and foetal tissues, with a highly abundant expression in the testis. Human and mouse have three variant RING3 transcripts, one of which is purely testis-specific. Growing evidence suggests that RING3 may be a nuclear kinase with a raised activity in certain types of leukaemia. Mutation analysis of the RING3 coding regions in ALL, CML and normal individuals, revealed a low level of polymorphism across the gene. However, for one deletion mutation, a significant deviation from Hardy-Weinberg proportions was observed in the leukaemic samples.

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