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Frappart, P O; Tong, W M; Demuth, I; Radovanovic, I; Herceg, Z; Aguzzi, A; Digweed, M; Wang, Z Q (2005). An essential function for NBS1 in the prevention of ataxia and cerebellar defects. Nature Medicine, 11(5):538-544.

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Abstract

Nijmegen breakage syndrome (NBS), ataxia telangiectasia and ataxia telangiectasia-like disorder (ATLD) show overlapping phenotypes such as growth retardation, microcephaly, cerebellar developmental defects and ataxia. However, the molecular pathogenesis of these neurological defects remains elusive. Here we show that inactivation of the Nbn gene (also known as Nbs1) in mouse neural tissues results in a combination of the neurological anomalies characteristic of NBS, ataxia telangiectasia and ATLD, including microcephaly, growth retardation, cerebellar defects and ataxia. Loss of Nbn causes proliferation arrest of granule cell progenitors and apoptosis of postmitotic neurons in the cerebellum. Furthermore, Nbn-deficient neuroprogenitors show proliferation defects (but not increased apoptosis) and contain more chromosomal breaks, which are accompanied by ataxia telangiectasia mutated protein (ATM)-mediated p53 activation. Notably, depletion of p53 substantially rescues the neurological defects of Nbn mutant mice. This study gives insight into the physiological function of NBS1 (the Nbn gene product) and the function of the DNA damage response in the neurological anomalies of NBS, ataxia telangiectasia and ATLD.

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Additional indexing

Item Type:Journal Article, refereed
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:1 May 2005
Deposited On:11 Feb 2008 12:26
Last Modified:27 Nov 2013 18:59
Publisher:Nature Publishing Group
ISSN:1078-8956
Publisher DOI:10.1038/nm1228
PubMed ID:15821748

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