Human Molecular Genetics Advance Access originally published online on January 25, 2008
Human Molecular Genetics 2008 17(10):1349-1362; doi:10.1093/hmg/ddn023
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Variations in the progranulin gene affect global gene expression in frontotemporal lobar degeneration
1 Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine 2 Institute on Aging 3 Department of Neurology 4 Alzheimer’s Disease Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA 5 Department of Biology 6 Center of Excellence for Research on Neurodegenerative Diseases, University of Pennsylvania, Philadelphia, PA 19104, USA
* To whom correspondence should be addressed to: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3rd Floor Maloney, 3600 Spruce Street Philadelphia, PA 19104, USA. Tel: +1 2156624474; Fax: +1 2153495909; Email: vmylee{at}mail.med.upenn.edu
Received October 23, 2007; Accepted January 17, 2008
Frontotemporal lobar degeneration is a fatal neurodegenerative disease that results in progressive decline in behavior, executive function and sometimes language. Disease mechanisms remain poorly understood. Recently, however, the DNA- and RNA-binding protein TDP-43 has been identified as the major protein present in the hallmark inclusion bodies of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), suggesting a role for transcriptional dysregulation in FTLD-U pathophysiology. Using the Affymetrix U133A microarray platform, we profiled global gene expression in both histopathologically affected and unaffected areas of human FTLD-U brains. We then characterized differential gene expression with biological pathway analyses, cluster and principal component analyses, and subgroup analyses based on brain region and progranulin (GRN) gene status. Comparing 17 FTLD-U brains to 11 controls, we identified 414 upregulated and 210 downregulated genes in frontal cortex (P-value < 0.001). Moreover, cluster and principal component analyses revealed that samples with mutations or possibly pathogenic variations in the GRN gene (GRN+, 7/17) had an expression signature that was distinct from both normal controls and FTLD-U samples lacking GRN gene variations (GRN-, 10/17). Within the subgroup of GRN+ FTLD-U, we found >1300 dysregulated genes in frontal cortex (P-value < 0.001), many participating in pathways uniquely dysregulated in the GRN+ cases. Our findings demonstrate a distinct molecular phenotype for GRN+ FTLD-U, not readily apparent on clinical or histopathological examination, suggesting distinct pathophysiological mechanisms for GRN+ and GRN- subtypes of FTLD-U. In addition, these data from a large number of human brains provide a valuable resource for future testing of disease hypotheses.