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

Background: Pelizaeus–Merzbacher disease (PMD) is an X-linked recessive dysmyelinating disorder of the CNS. Duplications or point mutations in exons of 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 analyses were used to detect duplication of the PLP gene, and DNA sequence analysis, including exon-intron borders, was used to detect mutation of the PLP gene. Results: Duplication of the PLP gene was ruled out, and mutations were 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 IVS6+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 months and progressive spastic ataxia at 18 months was found to have a 19–base pair (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 splice site selection. Conclusions: Mutations in introns of the PLP gene, even at positions that are not 100% conserved at splice sites, are an important cause of PMD.