Splice-site contribution in alternative splicing of PLP1 and DM20: molecular studies in oligodendrocytes.
Mutations in the proteolipid protein 1 (PLP1) gene cause the X-linked dysmyelinating diseases Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia 2 (SPG2). We examined the severity of the following mutations that were suspected of affecting levels of PLP1 and DM20 RNA, the alternatively spliced products of PLP1: c.453G>A, c.453G>T, c.453G>C, c.453+2T>C, c.453+4A>G, c.347C>A, and c.453+28_+46del (the old nomenclature did not include the methionine codon: G450A, G450T, G450C, IVS3+2T>C, IVS3+4A>G, C344A, and IVS3+28-+46del). These mutations were evaluated by information theory-based analysis and compared with mRNA expression of the alternatively spliced products. The results are discussed relative to the clinical severity of disease. We conclude that the observed PLP1 and DM20 splicing patterns correlated well with predictions of information theory-based analysis, and that the relative strength of the PLP1 and DM20 donor splice sites plays an important role in PLP1 alternative splicing.
Hobson
Grace M
GM
Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Nemours Children's Clinic, Wilmington, Delaware, USA. ghobson@nemours.org
Huang
Zhong
Z
Sperle
Karen
K
Sistermans
Erik
E
Rogan
Peter K
PK
Garbern
James Y
JY
Kolodny
Edwin
E
Naidu
Sakkubai
S
Cambi
Franca
F
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D005091:Exons / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007257:Information Theory; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D018991:Myelin Proteolipid Protein / Q000235:genetics*; D009836:Oligodendroglia / Q000378:metabolism*; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000166:cytology
D008565:Membrane Proteins; D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human; D022821:RNA Splice Sites; D012333:RNA, Messenger