Insertion of mutant proteolipid protein results in missorting of myelin proteins.
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 (Deltaex4, 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.
Vaurs-Barriere
Catherine
C
National Institute of Health and Medical Research U384, Clermont-Ferrand, France.
Wong
Kondi
K
Weibel
Thais D
TD
Abu-Asab
Mones
M
Weiss
Michael D
MD
Kaneski
Christine R
CR
Mixon
Tong-Hui
TH
Bonavita
Simona
S
Creveaux
Isabelle
I
Heiss
John D
JD
Tsokos
Maria
M
Goldin
Ehud
E
Quarles
Richard H
RH
Boespflug-Tanguy
Odile
O
Schiffmann
Raphael
R
D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D003711:Demyelinating Diseases / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009185:Myelin Proteins / Q000378:metabolism*; D018991:Myelin Proteolipid Protein / Q000235:genetics*; D009186:Myelin Sheath / Q000235:genetics / Q000473:pathology; D010375:Pedigree; D017354:Point Mutation; D013497:Sural Nerve / Q000473:pathology
D008565:Membrane Proteins; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human