Presentation at the American Neurology Association, Plenary Session on October 15, 2002, NY, NY.
Cambi, F., Huang, Z., Rogan, P., Svojanovsky, S., Davis-Williams, A., Sperle, K., Lewis, D., and Hobson, G.
Mutations in the proteolipid protein gene (PLP) cause a spectrum of disorders from Pelizaeus-Merzbacher Disease to X-linked spastic parapareses. PLP and DM20 are generated from the same primary transcript by alternative splicing of 105 bp of exon 3. PLP is preferentially expressed by oligodendrocytes, whereas DM20 is more broadly expressed. We describe two mutations that specifically affect PLP splicing. A 19-bp deletion in intron 3 is associated with mild developmental delay and progressive loss of acquired motor milestones. A transition, G450A, in the DM20 specific portion of exon 3 is associated with a rather severe developmental delay. Neither mutation causes amino acid changes. In both patients, MRS studies show high choline peak and low NAA peak consistent with myelin membrane remodeling and axonal loss. Transfections of chimeric constructs containing the 19-bp deletion into oligodendrocytes demonstrated a reduction in PLP splice site selection. The G450A mutation reduces the information content of the adjacent splice donor site from 5.8 to 2.8 bits, which corresponds to at least an 8-fold reduction (or <13% of wild type) in binding strength by the U1 splicesome. The data suggest that alteration of PLP-specific splicing results in disorders characterized by myelin instability and axonal loss.
origin: 2002 June 27
updated: 2002 June 27