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Background  The breadth of the clinical spectrum underlying Pelizaeus-Merzbacher disease and spastic paraplegia type 2 is due to the extensive allelic heterogeneity in the X-linked  PLP1  gene encoding myelin proteolipid protein (PLP).  PLP1  mutations range from gene duplications of variable size found in 60-70% of patients to intragenic lesions present in 15-20% of patients.    Methods  Forty-eight male patients from 38 unrelated families with a PLP1-related disorder were studied. All DNA samples were screened for  PLP1  gene duplications using real-time PCR.  PLP1  gene sequencing analysis was performed on patients negative for the duplication. The mutational status of all 14 potential carrier mothers of the familial  PLP1  gene mutation was determined as well as 15/24 potential carrier mothers of the  PLP1  duplication.    Results and Conclusions   PLP1  gene duplications were identified in 24 of the unrelated patients whereas a variety of intragenic  PLP1  mutations were found in the remaining 14 patients. Of the 14 different intragenic lesions, 11 were novel; these included one nonsense and 7 missense mutations, a 657-bp deletion, a microdeletion and a microduplication. The functional significance of the novel  PLP1  missense mutations, all occurring at evolutionarily conserved residues, was analysed by the  MutPred  tool whereas their potential effect on splicing was ascertained using the  Skippy  algorithm and a neural network. Although  MutPred  predicted that all 7 novel missense mutations would be likely to be deleterious,  in silico  analysis indicated that four of them (p.Leu146Val, p.Leu159Pro, p.Thr230Ile, p.Ala247Asp) might cause exon skipping by altering exonic splicing elements. These predictions were then investigated  in vitro  for both p.Leu146Val and p.Thr230Ile by means of RNA or minigene studies and were subsequently confirmed in the case of p.Leu146Val. Peripheral neuropathy was noted in four patients harbouring intragenic mutations that altered RNA processing, but was absent from all  PLP1 -duplication patients. Unprecedentedly, family studies revealed the  de novo  occurrence of the  PLP1  duplication at a frequency of 20%.

orphanet journal of rare diseases

Molecular Genetic Analysis of the PLP1 Gene in 38 Families with PLP1-related disorders: Identification and Functional Characterization of 11 Novel PLP1 Mutations