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Molecular Medicine

, Volume 17, Issue 11–12, pp 1253–1261 | Cite as

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

  • Anne-Hélène Lebrun
  • Parisa Moll-Khosrawi
  • Sandra Pohl
  • Georgia Makrypidi
  • Stephan Storch
  • Dirk Kilian
  • Thomas Streichert
  • Benjamin Otto
  • Sara E. Mole
  • Kurt Ullrich
  • Susan Cotman
  • Alfried Kohlschütter
  • Thomas Braulke
  • Angela Schulz
Research Article

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 CbCln3Δex7/8 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.

Notes

Acknowledgments

We thank the affected and control families for participating in this study and Johannes Brand for technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (grant SCHU1597/2–1) and the parent organizations Nächstenliebe e.V. and NCL-Gruppe Deutschland e.V.

Supplementary material

10020_2011_17111253_MOESM1_ESM.pdf (1.8 mb)
Supplementary material, approximately 1833 KB.

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Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Anne-Hélène Lebrun
    • 1
  • Parisa Moll-Khosrawi
    • 1
  • Sandra Pohl
    • 1
  • Georgia Makrypidi
    • 1
  • Stephan Storch
    • 1
  • Dirk Kilian
    • 1
  • Thomas Streichert
    • 2
  • Benjamin Otto
    • 2
  • Sara E. Mole
    • 3
  • Kurt Ullrich
    • 1
  • Susan Cotman
    • 4
  • Alfried Kohlschütter
    • 1
  • Thomas Braulke
    • 1
  • Angela Schulz
    • 1
  1. 1.Children’s HospitalUniversity Medical Center Hamburg-Eppendorf Martinistrasse 52HamburgGermany
  2. 2.Array Service CenterUniversity Medical Center Hamburg-EppendorfHamburgGermany
  3. 3.Medical Research Council Laboratory for Molecular Cell Biology, Molecular Medicine Unit, UCL Institute of Child Health and Department of Genetics, Evolution and EnvironmentUniversity College LondonLondonUK
  4. 4.Center for Human Genetic ResearchMassachusetts General HospitalBostonUSA

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