Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus-Merzbacher disease

Background: Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive dys myelinating disorder of the CNS. Duplications or point mutations in exons o f the proteolipid protein (PLP) gene are found in most patients. Objective: To describe five patients with PMD who have mutations in noncoding regions of the PLP gene. Methods: Quantitative multiplex PCR and Southern blot ana lyses were used to detect duplication of the PLP gene, and DNA sequence ana lysis, including exon-intron borders, was used to detect mutation of the PL P gene. Results: Duplication of the PLP gene was ruled out, and mutations w ere identified in noncoding regions of five patients in four families with PMD. In two brothers with a severe form of PMD, a G to T transversion at IV S6+3 was detected. This mutation resulted in skipping of exon 6 in the PLP mRNA of cultured fibroblasts. A patient who developed nystagmus at 16 month s and progressive spastic ataxia at 18 months was found to have a 19-base p air (bp) deletion of a G-rich region near the 5' end of intron 3 of the PLP gene. A patient with a T to C transition at IVS3+2 and a patient with an A to G transition at IVS3+4 have the classic form of PMD. These, like the 19 -bp deletion, are in intron 3, which is involved in PLP/DM20 alternative sp lice site selection. Conclusions: Mutations in introns of the PLP gene, eve n at positions that are not 100% conserved at splice sites, are an importan t cause of PMD.