Our work in the field of neuronal migration disorders
The deletion of YWHAE causes a brain malformation phenotype.
In order to identify new genetic causes for malformations of cortical development, we have performed a large number of comparative genomic hybridizations using DNA microarrays (see below). In a patient presenting with periventricular heterotopias and marked corpus callosum hypoplasia, we have identified a small 17p13.3 deletion involving the YWHAE gene. We have shown that YWHAE is the only gene to be expressed in the brain in the deleted region and that the other genes are not likely to contribute to the brain malformation phenotype of this patient. Most 17p13.3 deletions are large, such as deletions causing Miller-Dieker syndrome, and they involve several genes that are important for brain development. Hence, it is difficult to determine individual contributions for these genes. In the mouse, the deletion of the Ywhae gene (the homologue of human YWHAE) causes a defect of cortical organization. The corresponding human phenotype was not known. The case that we have identified and studied could represent the human counterpart of the phenotype of the mouse deleted for Ywhae and it documents a new cause for cortical malformations in humans (Mignon-Ravix et al. 2009). Our findings are supported by a similar report of several cases published simultaneously in the same journal(Sreenath Nagamani et al. 2009).
High resolution CGH arrays for NMD patients.
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.
Periventricular nodular heterotopias en France.
In collaboration with colleagues from Bordeaux, we participated in the description of new mutations in the FLNA gene. Mutation frequency, phenotypic heterogeneity and mutation spectrum were studied (Sole et al., 2009). This work lead to the identification of 12 new mutations in 15 patients and sustains the importance of cardiovascular monitoring in FLNA-BPNH patients.
Better knowledge of cortical dysgeneses caused by TUBA1A mutations.
In collaboration with colleagues in Paris, we participated in the identification of several new mutations in the TUBA1A gene (Bahi-Buisson et al., 2008). All together, it emerges that the TUBA1A related lissencephaly spectrum ranges from perisylvian pachygyria, in the less severe form, to posteriorly predominant pachygyria in the most severe, associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia.
Chromosome 5q deletions and bilateral nodular heterotopias.
This work describes 3 patients with with epilepsy, mental retardation, and bilateral PH in the walls of the temporal horns of the lateral ventricles associated with a de novo deletion of the 5q14.3-15 region (Cardoso et al., 2009). It identifies a new syndrome featuring bilateral periventricular heterotopia (PH), mental retardation, and epilepsy, mapping to chromosome 5q14.3-q15. The search for causative genes in underway.
X-linked bilateral perisylvian polymicrogyria.
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.
Involvement of NHEJ1 in a case of diffuse polymicrogyria and nodular heterotopia.
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.