A glial origin for periventricular nodular heterotopia caused by impaired expression of Filamin-A

Aurelie Carabalona, Shirley Beguin, Emilie Pallesi-Pocachard, Emmanuelle Buhler, Christophe Pellegrino, Karen Arnaud, Philippe Hubert, Mehdi Oualha, Jean Pierre Siffroi, Sabrina Khantane, Isabelle Coupry, Cyril Goizet, Antoinette Bernabe Gelot, Alfonso Represa, Carlos Cardoso
Human Molecular Genetics. 2011-11-10; 21(5): 1004-1017
DOI: 10.1093/HMG/DDR531

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1. Hum Mol Genet. 2012 Mar 1;21(5):1004-17. doi: 10.1093/hmg/ddr531. Epub 2011 Nov

A glial origin for periventricular nodular heterotopia caused by impaired
expression of Filamin-A.

Carabalona A(1), Beguin S, Pallesi-Pocachard E, Buhler E, Pellegrino C, Arnaud K,
Hubert P, Oualha M, Siffroi JP, Khantane S, Coupry I, Goizet C, Gelot AB, Represa
A, Cardoso C.

Author information:
(1)INMED, Parc Scientifique de Luminy, Marseille, France; Université de la Mé
diterranée, UMR S901 Aix-Marseille 2, Marseille, France; Inserm Unité 901,
Marseille, France.

Periventricular nodular heterotopia (PH) is a human brain malformation caused by
defective neuronal migration that results in ectopic neuronal nodules lining the
lateral ventricles beneath a normal appearing cortex. Most affected patients have
seizures and their cognitive level varies from normal to severely impaired.
Mutations in the Filamin-A (or FLNA) gene are the main cause of PH, but the
underlying pathological mechanism remains unknown. Although two FlnA knockout
mouse strains have been generated, none of them showed the presence of ectopic
nodules. 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 PH phenotype in rats comparable with that observed in human
patients. In FlnA-knockdown rats, we report that PH results from a disruption of
the polarized radial glial scaffold in the ventricular zone altering progression
of neural progenitors through the cell cycle and impairing migration of neurons
into the cortical plate. Similar alterations of radial glia are observed in human
PH brains of a 35-week fetus and a 3-month-old child, harboring distinct FLNA
mutations not previously reported. Finally, juvenile FlnA-knockdown rats are
highly susceptible to seizures, confirming the reliability of this novel animal
model of PH. Our findings suggest that the disorganization of radial glia is the
leading cause of PH pathogenesis associated with FLNA mutations. Rattus
norvegicus FlnA mRNA (GenBank accession number FJ416060).

DOI: 10.1093/hmg/ddr531
PMID: 22076441 [Indexed for MEDLINE]

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