Carlos Cardoso , PhD Neurogenetics

Course and current status

Present position                                                                                                                

Director of Research INSERM - Co-Team Leader “Cortical development disorders and epilepsy

Institut de Neurobiologie de la Méditerranée – INSERM U901

163, Avenue de Luminy BP 13          F-13273 Marseille cedex 09                                                

Phone: +33 (0)4 91 82 81 30 - Fax: +33 (0)4 91 82 81 01

Email: carlos.cardoso@inserm.fr

 

Education                                                                                                                           

2012             Habilitation to Direct Researches (HDR). Aix-Marseille University.

1999             PhD in Human Genetics. University de la Méditerranée, Marseille, France.

1996             Master in Cellular Biology and Genetics. University de la Méditerranée, Marseille, France.

 

Research Experience                                                                                                                   

 

12/2014        Research Director (DR2). Tenure Permanent Position - INMED, INSERM U901, Marseille, France.

2006-2014    CR1 Assistant Professor. Tenure Permanent Position - INMED, INSERM U901, Marseille, France.

2002-05        CR2 Associate Professor. Tenure Permanent Position - INSERM, Medical School of la Timone, Marseille, France.

2000-01        Post doctoral Fellow - KATZ fellowship. Department of Human Genetics, University of Chicago, USA. Director: Pr. DH. Ledbetter.

1996-99        Phd Student – MRT Fellowship. INSERM U491, Marseille, France. Thesis Supervisor: Dr. L. Colleaux.

 

Scientific summary

Molecular mechanisms and pathophysiology of Periventricular Nodular Heterotopia

Periventricular nodular heterotopia (PNH), the most common form of brain malformation in adulthood, is caused by defective neuronal migration that results in ectopic neuronal nodules lining the walls of the lateral ventricles. Most affected patients have seizures and their cognitive level varies from normal to severely impaired. Mutations in the FLNA gene, on Xq28, are the main cause of PNH and were found in 100% of families with X-linked bilateral PH and in 26% of sporadic patients. However, other genes can cause PNH. A rare recessive form caused by mutations in the ARFGEF2 gene, on 20q13, has been reported in two consanguineous families. PNH has also been observed in patients with chromosomal rearrangements, such as deletions of 5q14.3-15 that we recently identifed. Although the link between FLNArelated PNH and clinical manifestations has been well established, the underlying pathological mechanism remains unknown. Though two FlnA knockout mice strains have been developed, progress has been hindered by the fact that none of them showed the presence of ectopic nodules. Therefore, to recapitulate the loss of FlnA function in the developing rat brain, we used an in utero RNA interference-mediated knockdown approach and successfully reproduced a PNH phenotype in rats comparable to that observed in patients. Using this FlnA knockdown rodent model, we demonstrated that PNH is associated with a disruption in radial glial scaffold integrity in the ventricular zone and also an inability for neuroprogenitor cells to progress adequately through the cell cycle. Consistent with the observations made in rodents, we found similar alterations of radial glia in postmortem brains of two PNH patients harboring distinct FLNA mutations. These data highlights the complexity of the pathogenesis of PNH, the likelihood that several mechanisms are coalescing to lead to disrupted neuronal migration.

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