- Balanced translocations and abnormal phenotypes : what is the relationship ?
We have reported a genetic locus for bilateral perisylvian polymicrogyria mapped by linkage analysis using five families (Villard et al., 2002). Linkage places the critical region for BPP to Xq28 (Z=3.08 in Xq28, distal to DXS8103). We suggest that this region contains a gene necessary for correct neuronal organization. The search for mutations in candidate genes of the critical region is still ongoing.
Recent developments in microarray-based technologies allow to achieve exceptional resolutions to detect small chromosomal rearrangements in a number of patients (especially those suffering from a malformation of the cerebral cortex). Several sets of experiments have been performed in our team using Agilent Technologie's "CGH" arrays. These arrays provide an average resolution of 9 kilobases. Several rearrangements were identified in patients suffering from a malformation of the cerebral cortex. Additional analysis are underway to determine the status of these rearrangements and their impact for the expression of the genes involved.
We studied a case presenting a defect of cortical organization consisting of a polymicrogyric cortex and neuronal heterotopia within the white matter. Karyotype analysis revealed a balanced, de novo, chromosomal translocation t(2;7)(q35;p22). Cloning and sequencing of the two translocation breakpoints reveals that the chromosomal rearrangement disrupts the coding region of a single gene, called NHEJ1, Cernunnos or XLF, in 2q35 (Cantagrel et al. 2007). The NHEJ1 gene was recently identified as being responsible for autosomal recessive immunodeficiency with microcephaly ( Ahnesorg et al. 2006 , Buck et al. 2006). Using quantitative PCR experiments, we show that a truncated transcript is expressed in the patient cells suggesting a potential dominant negative effect that could disturb the development of the cerebral cortex. In collaboration with Susan Lindsay and Steven Lisgo at HDBR, we studied the expression of NHEJ1 during human development and showed that the NHEJ1 transcript is preferentially expressed in the telencephalic ventricular and subventricular zones, consistent with the phenotype of the affected individual. In the human adult central nervous system, NHEJ1 is mainly expressed in the cerebral cortex and in the cerebellum. The association of polymicrogyria with the disruption of its transcript suggests that, in addition to its recently uncovered function in the immune system, the NHEJ1 protein may also play a role during development of the human cerebral cortex.