In our current work we have analyzed the clinical phenotypes and MRI scans of 51 male patients with PMD and 10 female carriers for whom the PLP1 genotype had been determined.
Alterations in the myelin proteolipid protein gene ( PLP1) may result in rare X-linked disorders in humans such as Pelizaeus-Merzbacher disease and spastic paraplegia type 2.
As only 10 - 30 % of patients with a Pelizaeus Merzbacher disease (PMD) phenotype carry mutations of the proteolipid protein (PLP) gene, we were interested if the degree and time-dependent progression of abnormal MRI and MRS findings would discriminate patients with mutations of the PLP gene (Pelizaeus Merzbacher disease, PMD) from patients without a defect of the PLP gene (Pelizaeus Merzbacher-like disease, PMLD).
We describe genomic structures of 59 X-chromosome segmental duplications that include the proteolipid protein 1 gene (PLP1) in patients with Pelizaeus-Merzbacher disease.
Long-range polymerase chain reaction (PCR) is a traditional approach to obtain CNV breakpoint junction, but this method is inefficient when challenged by structural complexity such as often found at the PLP1 locus in association with Pelizaeus-Merzbacher disease (PMD).
The complicated form is heterogeneous, caused by mutations of the L1CAM gene at Xq28 (SPG1) or the PLP gene at Xq22 (SPG2) that is allelic to Pelizaeus-Merzbacher disease (PMD).
Although PLP1 expression was confirmed in iPS cells generated from two patients with the entire PLP1 duplication and the missense mutation of PLP1, iPS cells generated from the patient with the partial PLP1 duplication manifesting a milder form of PMD showed null expression.
Duplications of the proteolipid protein (PLP) gene have been found in a proportion of patients, suggesting that, in addition to coding-region or splice-site mutations, overdosage of the gene can cause PMD.
We also examined plasmalogen synthesis in Pelizaeus-Merzbacher disease (PMD) lymphocytes which possess a proteolipid protein-1 (PLP1) missense mutation that results in abnormal PLP1 folding and it's accumulation in the endoplasmic reticulum (ER), the cellular site of the last steps in plasmalogen synthesis.
In investigating genotype-phenotype correlations, we screened five Japanese families with PMD for PLP gene mutations and compared their clinical manifestations.
However, a copy of the PLP1 gene on the derivative chromosome 22, in addition to those on the X and der(X) chromosomes, resulted in two active copies of the gene, irrespective of the X-inactivation pattern, thus causing PMD.
Pelizaeus-Merzbacher disease (PMD) is X-linked hypomyelinating leukodystrophy caused by mutations of the PLP1 gene, which codes the proteolipid protein 1.
Additionally, a single intracerebroventricular injection of MO-PLP into the brains of neonatal mice, carrying a deletion of an intronic splicing enhancer identified in a PMD patient that reduces the Plp1 spliced form, corrected alternative splicing at both RNA and protein levels in the CNS.
Although PLP1 proteins with missense mutations have been shown to accumulate in the rough endoplasmic reticulum (ER) in disease model animals and cell lines transfected with mutant PLP1 genes, the exact pathogenetic mechanism of PMD has not previously been clarified.
The incidence of PMD with PLP1 mutations was estimated to be 1.45 per 100,000 male live births and that for congenital hypomyelinating disorders with unknown cause to be 0.41 per 100,000 live births.