title: Analysis of potential biomarkers and modifier genes affecting the clinical course of CLN3 disease.
abstract: 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 CLN3 patients carry the same 1-kb deletion in the CLN3 gene, their disease phenotype can be variable. The aims of this study were to (i) study the clinical phenotype in CLN3 patients with identical genotype, (ii) identify genes that are dysregulated in CLN3 disease regardless of the clinical course that could be useful as biomarkers, and (iii) find modifier genes that affect the progression rate of the disease. A total of 25 CLN3 patients homozygous for the 1-kb deletion were classified into groups with rapid, average or slow disease progression using an established clinical scoring system. Genome-wide expression profiling was performed in eight CLN3 patients with different disease progression and matched controls. The study showed high phenotype variability in CLN3 patients. Five genes were dysregulated in all CLN3 patients and present candidate biomarkers of the disease. Of those, dual specificity phosphatase 2 (DUSP2) was also validated in acutely CLN3-depleted cell models and in CbCln3(Δex7/8) cerebellar precursor cells. A total of 13 genes were upregulated in patients with rapid disease progression and downregulated in patients with slow disease progression; one gene showed dysregulation in the opposite way. Among these potential modifier genes, guanine nucleotide exchange factor 1 for small GTPases of the Ras family (RAPGEF1) and transcription factor Spi-B (SPIB) were validated in an acutely CLN3-depleted cell model. These findings indicate that differential perturbations of distinct signaling pathways might alter disease progression and provide insight into the molecular alterations underlying neuronal dysfunction in CLN3 disease and neurodegeneration in general.
authors.affiliation: Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Anne-Hélène
authors.initials: AH
authors.lastname: Lebrun
authors.forename: Parisa
authors.initials: P
authors.lastname: Moll-Khosrawi
authors.forename: Sandra
authors.initials: S
authors.lastname: Pohl
authors.forename: Georgia
authors.initials: G
authors.lastname: Makrypidi
authors.forename: Stephan
authors.initials: S
authors.lastname: Storch
authors.forename: Dirk
authors.initials: D
authors.lastname: Kilian
authors.forename: Thomas
authors.initials: T
authors.lastname: Streichert
authors.forename: Benjamin
authors.initials: B
authors.lastname: Otto
authors.forename: Sara E
authors.initials: SE
authors.lastname: Mole
authors.forename: Kurt
authors.initials: K
authors.lastname: Ullrich
authors.forename: Susan
authors.initials: S
authors.lastname: Cotman
authors.forename: Alfried
authors.initials: A
authors.lastname: Kohlschütter
authors.forename: Thomas
authors.initials: T
authors.lastname: Braulke
authors.forename: Angela
authors.initials: A
authors.lastname: Schulz
mesh_terms: D000293:Adolescent; D000328:Adult; D020029:Base Pairing / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D018450:Disease Progression; D054641:Dual Specificity Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D060045:Genes, Modifier / Q000235:genetics*; D056726:Genetic Association Studies; D006367:HeLa Cells; D006720:Homozygote; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D055815:Young Adult
chemical_list: D015415:Biomarkers; C105199:CLN3 protein, human; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C517032:DUSP2 protein, human; D054641:Dual Specificity Phosphatase 2