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Alternative splicing of the proteolipid protein 1 gene ( PLP1 ) produces two forms,  PLP1  and  DM20 , due to alternative use of 5′ splice sites with the same acceptor site in intron 3. The  PLP1  form predominates in central nervous system RNA. Mutations that reduce the ratio of  PLP1  to  DM20 , whether mutant or normal protein is formed, result in the X-linked leukodystrophy Pelizaeus-Merzbacher disease (PMD). We investigated the ability of sequences throughout  PLP1  intron 3 to regulate alternative splicing using a splicing minigene construct transfected into the oligodendrocyte cell line, Oli-neu. Our data reveal that the alternative splice of  PLP1  is regulated by a long-distance interaction between two highly conserved elements that are separated by 581 bases within the 1071-base intron 3. Further, our data suggest that a base-pairing secondary structure forms between these two elements, and we demonstrate that mutations of either element designed to destabilize the secondary structure decreased the  PLP1/DM20  ratio, while swap mutations designed to restore the structure brought the  PLP1/DM20  ratio to near normal levels. Sequence analysis of intron 3 in families with clinical symptoms of PMD who did not have coding-region mutations revealed mutations that segregated with disease in three families. We showed that these patient mutations, which potentially destabilize the secondary structure, also reduced the  PLP1/DM20  ratio. This is the first report of patient mutations causing disease by disruption of a long-distance intronic interaction controlling alternative splicing. This finding has important implications for molecular diagnostics of PMD.

PMD patient mutations reveal a long-distance intronic interaction that regulates PLP1/DM20 alternative splicing