1/3. Complex chromosomal rearrangement and associated counseling issues in a family with pelizaeus-merzbacher disease.We report cytogenetic and molecular findings in a family in which pelizaeus-merzbacher disease has arisen by a sub-microscopic duplication of the proteolipid protein (PLP1) gene involving the insertion of approximately 600 kb from Xq22 into Xq26.3. The duplication arose in an asymptomatic mother on a paternally derived x chromosome and was inherited by her son, the proband, who is affected with pelizaeus-merzbacher disease. The mother also carries a large interstitial deletion of approximately 70 Mb extending from Xq21.1 to Xq27.3, which is present in a mosaic form. In lymphocytes, the mother has no normal cells, having one population with three copies of the PLP1gene (one normal X and one duplication x chromosome) and the other population having only one copy of the PLP1 gene (one normal X and one deleted x chromosome). Her karyotype is 46,XX.ish dup (X) (Xpter --> Xq26.3::Xq22 --> Xq22::Xq26.3 --> Xqter)(PLP )/46,X,del(X)(q21.1q27.3).ish del(X)(q21.1q27.3)(PLP-). Both ends of the deletion have been mapped by fluorescence in situ hybridization using selected dna clones and neither involves the PLP1 gene or are in the vicinity of the duplication breakpoints. prenatal diagnosis was carried out in a recent pregnancy and the complex counseling issues associated with these chromosomal rearrangements are discussed.- - - - - - - - - - ranking = 1keywords = hybridization (Clic here for more details about this article) |
2/3. Three or more copies of the proteolipid protein gene PLP1 cause severe pelizaeus-merzbacher disease.We describe five boys from different families with an atypically severe form of pelizaeus-merzbacher disease (PMD) who have three, and in one case, five copies of the proteolipid protein (PLP1) gene. This is the first report of more than two copies of PLP1 in PMD patients and clearly demonstrates that severe clinical symptoms are associated with increased PLP1 gene dosage. Previously, duplications, deletions and mutations of the PLP1 gene were reported to give rise to this X-linked disorder. patients with PLP1 duplication are usually classified as having either classical or transitional PMD rather than the more rare severe connatal form. The clinical symptoms of the five patients in this study included lack of stable head control and severe mental retardation, with three having severe paroxysmal disorder and two dying before the first year of life. gene dosage was determined using interphase FISH (fluorescence in situ hybridization) and the novel approach of multiple ligation probe amplification (MLPA). We found FISH unreliable for dosage detection above the level of a duplication and MLPA to be more accurate in determination of specific copy number. Our finding that three or more copies of the gene give rise to a more severe phenotype is in agreement with observations in transgenic mice where severity of disease increased with Plp1 gene dosage and level of overexpression. The patient with five copies of PLP1 was not more affected than those with a triplication, suggesting that there is possibly a limit to the level of severity or that other genetic factors influence the phenotype. It highlights the significance of PLP1 dosage in CNS myelinogenesis as well as the importance of accurate determination of PLP1 gene copy number in the diagnosis of PMD and carrier detection.- - - - - - - - - - ranking = 1keywords = hybridization (Clic here for more details about this article) |
3/3. Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect.OBJECTIVE: To report an association between spastic paraplegia type 2 with axonal peripheral neuropathy and apparent proteolipid protein gene (PLP1) silencing in a family. methods: Pulsed-field gel electrophoresis, custom array comparative genomic hybridization, and semi-quantitative multiplex polymerase chain reaction analyses were used to examine the PLP1 genomic region. RESULTS: Electrodiagnostic studies and a sural nerve biopsy showed features of a dystrophic axonal neuropathy. Molecular studies identified a small duplication downstream of PLP1. INTERPRETATION: We propose the duplication to result in PLP1 gene silencing by virtue of a position effect. Our observations suggest that genomic rearrangements that do not include PLP1 coding sequences should be considered as yet another potential mutational mechanism underlying PLP1-related dysmyelinating disorders.- - - - - - - - - - ranking = 1keywords = hybridization (Clic here for more details about this article) |