MRI evidence of white matter damage in a mouse model of Nijmegen breakage syndrome

Nijmegen breakage syndrome (NBS) is a genomic instability disease caused by hypomorphic mutations in the NBSI gene encoding the NbsI (nibrin) protein. Nbs I is a component of the Mrel 1/Rad50/NbsI (MRN) complex that acts as a sensor of double strand breaks (DSBs) in the DNA and is critical for proper activation of the broad cellular response to DSBs. Conditional disruption of the murine ortholog of NBS1, Nbn, in the CNS of mice was previously reported to cause microcephaly, severe cerebellar atrophy and ataxia. In this study we used MRI to study the brain morphology and organization of Nbn deleted mice. Using conventional T-2-weighted magnetic resonance, we found that the brains of the mutant mice (NbsI -CNS-del) were significantly smaller than those of the wild-type animals, with marked mal-development of the cerebellum. Region of interest analysis of the T2 maps revealed significant T2 increase in the areas of white matter (corpus callosum, internal capsule and midbrain), with minor changes, if any, in gray matter. Diffusion tensor imaging (DTI) data confirmed that fractional anisotropy values were significantly reduced in these areas, mainly due to increased radial diffusivity (water diffusion perpendicular to neuronal fibers). Biochemical analysis showed low and dispersed staining for MBP and GaIC in Nbs I -CNS-del brains, indicating defects in myelin fort-nation and oligodendrocyte development. Myelin index and protein levels were significantly reduced in these brains. Our results point to a novel function of NbsI in the development and organization of the white matter. (c) 2007 Elsevier Inc. All rights reserved.