| Central nervous system (CNS) dysmyelination is a relatively common but nonspecific radiological finding in pediatric patients. To explore the possibility that loss of one copy of the normal Golli-MBP gene product may be responsible for CNS dysmyelination, a cohort of 57 pediatric patients with cytogenetically normal chromosomes and dysmyelination similar to that of patients with cytogenetically visible deletions of 18q were analyzed for mutations and rearrangements of the Golli-MBP gene. Fluorescence in situ hybridization (FISH), direct DNA sequencing of exons, Southern blots and real-time quantitative polymerase chain reaction (RQ-PCR) were performed on patient chromosomes and DNA and correlated to their magnetic resonance imaging (MRI) and clinical presentation.; Of these, only one showed a deletion of Golli-MBP by FISH using probes for both the Golli and MBP portions of the gene complex. FISH with additional genomic probes revealed the patient to have an interstitial deletion spanning approximately 7 Mb. This patient was also analyzed with microarray comparative genomic hybridization (array CGH) to scan his entire genome for additional cryptic chromosomal abnormalities. This confirmed the 7 Mb deletion on chromosome 18q detected by FISH, and in addition showed a gain of 4q material. FISH analysis using probes for 4q showed the chromosomal gained material was translocated to distal 18q.; Molecular mapping of the deleted area shows it to include, in addition to Golli-MBP, several other known genes. Of these MBP is still the most attractive candidate gene for a dysmyelination phenotype but the loss of additional surrounding genes and the gain of 4q material does not allow a definitive genotype-phenotype correlation in this patient.; The criteria for patient recruitment, and methods of mutation analysis used for this study, did not produce a patient with a microdeletion or significant missense mutation that includes only the Golli-MBP gene complex. This was most likely due to the site specificity of the methods used for mutation analysis, and the difficulty of defining a specific dysmyelination phenotype in patients from whom no tissue is available. However, the molecular characterization of the affected patient's cryptic chromosome abnormality by whole genome scanning using microarray CGH and FISH, has provided the most complete and accurate mapping of a submicroscopic rearrangement of chromosome 18 reported in the literature. (Abstract shortened by UMI.)... |
