Analysis of Potential Biomarkers and Modifier Genes Affecting the Clinical Course of CLN3 Disease

摘要: Mutations in the CLN3 gene lead to juvenile neuronal ceroid lipofuscinosis, a pediatric neurodegenerative disorder characterized by visual loss, epilepsy and psychomotor deterioration. Although most patients carry same 1-kb deletion gene, their disease phenotype can be variable. The aims of this study were (i) clinical with identical genotype, (ii) identify genes that are dysregulated regardless course could useful as biomarkers, (iii) find modifier affect progression rate disease. A total 25 homozygous for classified into groups rapid, average or slow using an established scoring system. Genome-wide expression profiling was performed eight different matched controls. showed high variability patients. Five all present candidate biomarkers Of those, dual specificity phosphatase 2 (DUSP2) also validated acutely CLN3-depleted cell models CbCln3Δex7/8 cerebellar precursor cells. 13 upregulated rapid downregulated progression; one dysregulation opposite way. Among these potential genes, guanine nucleotide exchange factor 1 small GTPases Ras family (RAPGEF1) transcription Spi-B (SPIB) model. These findings indicate differential perturbations distinct signaling pathways might alter provide insight molecular alterations underlying dysfunction neurodegeneration general.