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Genotype-phenotype correlation in five Pelizaeus-Merzbacher disease patients with PLP1 gene duplications
S Regis1, R Biancheri, E Bertini
1Diagnosi Pre-Postnatale Malattie Metaboliche Laboratory, Children Hospital IRCCS G. Gaslini, Genoa, Italy.
Abstract:
Pelizaeus-Merzbacher disease (PMD) is an X-linked myelination disorder most frequently caused by duplication of a genomic segment of variable length containing the PLP1 gene. We studied five PMD male patients affected by the classic PMD form carrying a PLP1 gene duplication. On the basis of clinical and neuroradiological features, two of the five patients appeared to be the most severely affected. In order to establish a possible genotype-phenotype correlation, the extent of the duplication was determined in each patient and in the respective mother by quantifying the copy number of genomic markers surrounding the PLP1 gene by a real-time PCR-based approach. Duplications, ranging in size from 167-195 to 580-700 kb, were in the same genomic interval of the majority of the reported duplications. The extent of the duplicated genomic segments does not correlate with the clinical severity. Interestingly enough, each duplication had one of the two breakpoints in or near to low copy repeats (LCRs), supporting recent evidence concerning a possible role of LCRs in the generation of the duplications in PMD.
Insights
Pelizaeus-Merzbacher disease (PMD) is an X-linked myelination disorder. The size of the PLP1 gene duplication does not correlate with disease severity in patients, but breakpoints near low copy repeats (LCRs) may be involved.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Pelizaeus-Merzbacher disease (PMD) is a severe X-linked neurological disorder characterized by the absence of myelin in the central nervous system.
- PMD is most commonly caused by duplications of the proteolipid protein 1 (PLP1) gene, a key component of CNS myelin.
Purpose of the Study:
- To investigate the genotype-phenotype correlation in male patients with classic PMD caused by PLP1 gene duplication.
- To determine the size and location of PLP1 duplications and their relationship to clinical severity.
Main Methods:
- Real-time PCR was used to quantify copy numbers of genomic markers surrounding the PLP1 gene in five PMD patients and their mothers.
- Clinical and neuroradiological data were collected to assess disease severity.
Main Results:
- PLP1 gene duplications were identified in all five patients, with sizes ranging from 167-195 kb to 580-700 kb.
- No significant correlation was found between the extent of the PLP1 duplication and the clinical severity of PMD.
- Breakpoints of the duplications were located in or near low copy repeats (LCRs) in all cases.
Conclusions:
- The size of the PLP1 gene duplication does not determine the clinical phenotype in PMD.
- Low copy repeats (LCRs) likely play a role in the mechanism generating PLP1 duplications in PMD.
- Further research into LCRs is warranted to understand PMD pathogenesis.
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