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Pelizaeus-Merzbacher disease: tight linkage to proteolipid protein gene exon variant
J A Trofatter1, S R Dlouhy, W DeMyer
1Department of Medical Genetics, Indiana University Medical Center, Indianapolis 46223.
Abstract:
Pelizaeus-Merzbacher disease (PMD) is a human X chromosome-linked dysmyelination disorder of the central nervous system for which the genetic defect has not yet been established. The jimpy mutation jp of the mouse is an X chromosome-linked disorder of myelin formation. The mutation is at an intron/exon splice site in the mouse gene for proteolipid protein (PLP). With the jimpy mouse mutation as a precedent, we focused our attention on the human PLP gene, which is found at Xq22. The polymerase chain reaction was used to amplify the exons of the PLP gene of an affected male from a large Indiana PMD kindred. DNA sequencing showed a C----T transition at nucleotide 40 of the second exon. An affected third cousin also showed this sequence variation, while two unaffected male relatives (sons of an obligate carrier female) had the normal cytidine nucleotide. Allele-specific oligonucleotides were used to generate data for linkage studies on the above mentioned PMD kindred. Our results show tight linkage (theta = 0) of PMD to PLP with a lod (logarithm of odds) score of 4.62. In six other unrelated PMD kindreds, only the normal-sequence oligonucleotide hybridized, which indicates genetic heterogeneity. The radical nature of the predicted amino acid change (proline to leucine), suggests that the PMD-causing defect may have been delineated in one kindred.
Insights
Pelizaeus-Merzbacher disease (PMD), a central nervous system disorder, is linked to the proteolipid protein (PLP) gene. A specific mutation in the PLP gene was identified in one kindred, suggesting a cause for this dysmyelination disorder.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Pelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelination disorder affecting the central nervous system.
- The genetic basis of PMD has remained elusive.
- The mouse jimpy (jp) mutation, affecting myelin formation, provided a model, as it is located at an intron/exon splice site in the proteolipid protein (PLP) gene.
Observation:
- The human PLP gene is located at Xq22.
- DNA sequencing of the PLP gene in an affected male from an Indiana PMD kindred revealed a C-to-T transition at nucleotide 40 of the second exon.
- This specific sequence variation was also found in an affected cousin but not in unaffected relatives.
Findings:
- Linkage analysis demonstrated a tight linkage (lod score of 4.62) between PMD and the PLP gene in the studied kindred.
- The identified mutation predicts a proline-to-leucine amino acid change.
- Genetic heterogeneity was observed in six other unrelated PMD kindreds, where only normal PLP gene sequences hybridized.
Implications:
- The identified PLP gene mutation is strongly associated with PMD in the Indiana kindred.
- This finding suggests that mutations in the PLP gene are a cause of PMD.
- The observed genetic heterogeneity indicates that other genes may also be involved in causing PMD in different families.