Base substitution at different alternative splice donor sites of the tyrosinase gene in murine albinism.

The c2j albino mutation at the mouse tyrosinase locus arose spontaneously in the C57BL/6 inbred strain and causes complete absence of melanin synthesis, as does the "classical" c mutation of long-established albino inbred strains. Sequence analysis of c2j cDNA reveals a G-->T point mutation at nt 291, causing an arginine-->leucine substitution in codon 77, where the arginine position has been conserved in vertebrate tyrosinases and tyrosinase-related proteins. While c2j differs from c, in which there is a G-->C mutation at nt 369 causing a cysteine-->serine substitution, both mutations change the G1 position of alternative 5' splice donor sites in exon 1. Both c2j and c abolish the usage of the respective sites for alternative splicing of the tyrosinase pre-mRNA in skin melanocytes. In c2j, there results an almost eightfold increase in activation of the 5' splice site located 78 nt downstream, but in c there is no activation of the intact upstream splice site. Although the tyrosinase mRNA levels are similar in c2j and wildtype, the protein is virtually absent in c2j, as in c, possibly due to proteolytic degradation.