Insertion of mutant proteolipid protein results in missorting of myelin proteins
- 26 November 2003
- journal article
- research article
- Published by Wiley in Annals of Neurology
- Vol. 54 (6), 769-780
- https://doi.org/10.1002/ana.10762
Abstract
Two brothers with a leukodystrophy, progressive spastic diplegia, and peripheral neuropathy were found to have proteinaceous aggregates in the peripheral nerve myelin sheath. The patients' mother had only subclinical peripheral neuropathy, but the maternal grandmother had adult‐onset leukodystrophy. Sequencing of the proteolipid protein (PLP) gene showed a point mutation IVS4 + 1 G→A within the donor splice site of intron 4. We identified one transcript with a deletion of exon 4 (Δex4, 169bp) encoding for PLP and DM20 proteins and lacking two transmembrane domains, and a second transcript with exon 4 + 10bp encoding three transmembrane domains. Immunohistochemistry showed abnormal aggregation in the myelin sheath of MBP and P0. Myelin‐associated glycoprotein was present in the Schmidt–Lanterman clefts but significantly reduced in the periaxonal region. Using immunogold electron microscopy, we demonstrated the presence of mutated PLP/DM20 and the absence of the intact protein in the patient peripheral myelin sheath. We conclude that insertion of mutant PLP/DM20 with resulting aberrant distribution of other myelin proteins in peripheral nerve may constitute an important mechanism of dysmyelination in disorders associated with PLP mutations. Ann Neurol 2003;54:769–780Keywords
This publication has 55 references indexed in Scilit:
- Overexpression of the myelin proteolipid protein leads to accumulation of cholesterol and proteolipid protein in endosomes/lysosomesThe Journal of cell biology, 2002
- Genotype–phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutationsEuropean Journal of Human Genetics, 2000
- Altered molecular architecture of peripheral nerves in mice lacking the peripheral myelin protein 22 or connexin32Journal of Neuroscience Research, 1999
- Distinct Phenotypes Associated with Increasing Dosage of the PLP Gene: Implications for CMT1A Due to PMP22 Gene DuplicationAnnals of the New York Academy of Sciences, 1999
- Proteolipid Protein: Is It More than Just a Structural Component of Myelin?Developmental Neuroscience, 1996
- Novel Nonsense Proteolipid Protein Gene Mutation as a Cause of X-Linked Spastic Paraplegia in Twin MalesBiochemical and Biophysical Research Communications, 1995
- A novel insertional mutation at exon VII of the myelin proteolipid protein gene in Pelizaeus — Merzbacher diseaseHuman Molecular Genetics, 1993
- Mouse P0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axonsCell, 1992
- Prenatal diagnosis in Pelizaeus‐Merzbacher disease using RFLP analysisClinical Genetics, 1990
- Expression of Myelin Proteolipid Protein and Basic Protein in Normal and Dysmyelinating Mutant MiceJournal of Neurochemistry, 1986