Human Molecular Genetics Advance Access published online on May 4, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp207
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Increased chromosome instability dramatically disrupts neural genome integrity and mediates cerebellar degeneration in the ataxia-telangiectasia brain
1 National Research Center of Mental Health, RAMS, Moscow, Russia 2 Institute of Paediatrics and Paediatric Surgery, Rosmedtehnlogii, Moscow, Russia 3 Institute of Human Genetics and Anthropology, Jena, Germany
* Corresponding author: Yuri B. Yurov, Professor National Research Center of Mental Health Russian Academy of Medical Sciences Zagorodnoe sh. 2, Moscow 119152, Russia E-mail: y_yurov{at}yahoo.com
Received March 29, 2009; Revised April 28, 2009; Accepted April 28, 2009
Ataxia telangiectasia (AT) is a chromosome instability (CIN) neurological syndrome arising from DNA damage response defects due to ATM gene mutations. The hallmark of AT is progressive cerebellar degeneration. However, the intrinsic cause of the neurodegeneration remains poorly understood. To highlight the relationship between CIN and neurodegeneration in AT, we monitored aneuploidy and interphase chromosome breaks (chromosomal biomarkers of genomic instability) in the normal and diseased brain. We observed a 2-3 fold increase of stochastic aneuploidy affecting different chromosomes in the cerebellum and the cerebrum of the AT brain. The global aneuploidization of the brain is, therefore, a new genetic phenomenon featuring AT. Degenerating cerebellum in AT was remarkably featured by a dramatic 5-20 fold increase of non-random DNA double-strand breaks and aneuploidy affecting chromosomes 14 and, to a lesser extend, chromosomes 7 and X. Novel recurrent chromosome hot spots associated with cerebellar degeneration were mapped within 14q12. In silico analysis has revealed that this genomic region contains two candidate genes (FOXG1B and NOVA1). The existence of non-random breaks disrupting specific chromosomal loci in neural cells with DNA repair deficiency supports the hypothesis that neuronal genome may undergo programmed somatic rearrangements. Investigating chromosome integrity in neural cells, we provide the first evidence that increased CIN can result into neurodegeneration, while it is generally assumed to be associated with cancer. Our data suggest that mosaic instability of somatic genome in cells of the central nervous system is more significant genetic factor predisposing to the brain pathology than previously recognized.