We propose to test an exciting new hypothesis regarding the causes and molecular mechanisms of a devastating childhood neurodevelopmental progeria known as Cockayne syndrome (CS). If our hypothesis is correct, it will open up new therapeutic options for this currently untreatable disease. CS has long been thought to be a disease of DNA repair because all 5 genes that can cause CS (CSA, CSB, XPB, XPD, and XPG) are essential for transcription-coupled nucleotide excision repair (TC-NER). Yet CS patients usually present with myelin defects and brain calcifications resembling those seen in Aicardi- Goutires syndrome (AGS), a childhood neurodevelopmental leukodystrophy caused by constitutive activation of an innate antiviral interferon response in the absence of viral infection. We recently discovered that the CSB gene, which causes over two thirds of all known cases of CS, contains a piggyBac transposon (PGBD3). As a result, the human CSB locus generates not one but two CSB-related proteins: functional CSB, and a CSB-PGBD3 fusion protein joining the N-terminal domain of CSB to a C-terminal PGBD3 transposase domain (Newman et al., 2008). Most surprisingly, we found that expression of the CSB-PGBD3 fusion protein in CSB-null cells induces a powerful interferon-like innate immune response, and that loss of CSB from normal cells also induces an innate antiviral response (Bailey et al., 2012). Our data suggest that the fusion protein may contribute to CS disease, and could provide an entry point for intervention to delay or ameliorate CS symptoms. We propose two complementary aims to determine whether CS patients display a similar interferon, antiviral, inflammatory, or autoimmune response:
(Aim 1) Using Affymetrix microarrays, we will compare mRNA expression in peripheral blood mononuclear cells (PBMCs) of CS patients to our published data for CSB-null cells that stably express the CSB-PGBD3 fusion protein. Microarrays will enable us to detect an interferon, antiviral, or inflammatory gene expression signature, even if the genes are downregulated in patients by SOCS1 or related regulatory pathways.
(Aim 2) Using Luminex bead-based assays and cell-based reporter assays, we will examine expression of interferons, cytokines, and chemokines at the protein level in CS serum and PBMCs. We will also use Invitrogen ProtoArray v5.0 protein arrays that display >9,000 human proteins to search for CS serum autoantibodies. Our proposal is high risk because the interferon-like response seen in CS cells may be muted in CS patients;however, the rewards could be high because confirmation of an interferon or autoimmune response would justify the use of immunomodulatory or anti-inflammatory biologicals and drugs for treating CS and related conditions.

Public Health Relevance

Cockayne syndrome (CS) is a devastating childhood neurodevelopmental progeria most often caused by defects in the CSB gene. Our new data suggest that the heterogeneous clinical presentation of CS may reflect an innate interferon-like response in the absence of infection. We will test this hypothesis directly with the ultimate goal of identifying novel therapeutic modalities for this currently untreatable disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
Schools of Medicine
United States
Zip Code