Kw. Lynch et A. Weiss, A CD45 polymorphism associated with multiple sclerosis disrupts an exonic splicing silencer, J BIOL CHEM, 276(26), 2001, pp. 24341-24347
Previous studies have identified a single nucleotide polymorphism that sign
ificantly increases the splicing of variable exon 4 in transcripts of the h
uman protein-tyrosine phosphatase CD45. Strikingly, the presence of this po
lymorphism correlates with susceptibility to the autoimmune disease multipl
e sclerosis. In this study we investigated the mechanism by which the polym
orphism enhances splicing of CD45 exon 4. We found that at least four disti
nct splicing regulatory elements exist within exon 4 and that the strongest
of these elements is an exonic splicing silencer (designated ESS1), which
is disrupted by the polymorphism. We show that ESS1 normally functions to r
epress the weak 5' splice site (ss) of CD45 exon 4. The ESS1 sequence also
suppresses the splicing of a heterologous 5' ss and associates with a speci
fic complex in nuclear extracts. We further demonstrate that ESS1 is juxtap
osed to a purine-rich enhancer sequence that activates the use of the 5' ss
of exon 4. Thus, proper functioning of the immune system is dependent on a
complex interplay of regulatory activities that mediate the appropriate sp
licing of CD45 exon 4.