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

Abstract

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. To describe five patients with PMD who have mutations in noncoding regions of the PLP gene. 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. 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. Mutations in introns of the PLP gene, even at positions that are not 100% conserved at splice sites, are an important cause of PMD.