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Communicated by Christine Van BroeckhovenThe proteolipid protein 1 (PLP1) gene encodes the two major proteins of the central nervous system (CNS) myelin: PLP and DM20. PLP1 gene mutations are associated with a large spectrum of X-linked dysmyelinating disorders ranging from hypomyelinating leukodystrophy, Pelizaeus-Merzbacher disease (PMD), to spastic paraplegia (SPG2) according to the nature of the mutation. Genetic heterogeneity exists and mutations in the gap-junction alpha 12 (GJA12) gene have been related to PMD. About 20% of patients with the PMD phenotype remain without mutation in these two genes and are classified as affected by Pelizaeus-Merzbacherlike disease (PMLD). To study PLP1 splicing abnormalities, we analyzed PLP/DM20 transcripts from nerves and/or skin cultured fibroblasts of 14 PMD/SPG2 patients carrying different PLP1 mutations and 20 PMLD patients. We found that various types of PLP1 mutations result in missplicing, including one considered as a missense in exon 2 and a nucleotide substitution in intron 3 outside the classical donor and acceptor splicing sites. Moreover, we demonstrated for two patients that the fibroblast transcript pattern was in accordance with the one observed in the corresponding CNS/peripheral nervous system (PNS) tissues. Finally, we observed no abnormal splicing in fibroblasts of 20 PMLD patients tested; suggesting that PLP1 gene splicing abnormalities, potentially caused by undetected intronic mutations, are either not involved or are very rarely implicated in the PMLD phenotype. These results confirm that fibroblasts are reliable, accessible cells useful in detecting PLP1 transcript abnormalities, better characterizing the functional consequences of PLP1 mutations for genotype-phenotype correlation, characterizing new PLP1 splicing regulatory elements, and identifying PLP1 mutations undetected by conventional PLP1 screening. Hum Mutat 29(8),1028–1036, 2008.