Publications by authors named "Laetitia Castelnau-Ptakhine"

4 Publications

  • Page 1 of 1

Mutations in the neuronal ß-tubulin subunit TUBB3 result in malformation of cortical development and neuronal migration defects.

Hum Mol Genet 2010 Nov 9;19(22):4462-73. Epub 2010 Sep 9.

Institut Cochin, Université Paris-Descartes, CNRS (UMR 8104), 24 rue du Faubourg St Jacques, Paris, France.

Mutations in the TUBB3 gene, encoding β-tubulin isotype III, were recently shown to be associated with various neurological syndromes which all have in common the ocular motility disorder, congenital fibrosis of the extraocular muscle type 3 (CFEOM3). Surprisingly and in contrast to previously described TUBA1A and TUBB2B phenotypes, no evidence of dysfunctional neuronal migration and cortical organization was reported. In our study, we report the discovery of six novel missense mutations in the TUBB3 gene, including one fetal case and one homozygous variation, in nine patients that all share cortical disorganization, axonal abnormalities associated with pontocerebellar hypoplasia, but with no ocular motility defects, CFEOM3. These new findings demonstrate that the spectrum of TUBB3-related phenotype is broader than previously described and includes malformations of cortical development (MCD) associated with neuronal migration and differentiation defects, axonal guidance and tract organization impairment. Complementary functional studies revealed that the mutated βIII-tubulin causing the MCD phenotype results in a reduction of heterodimer formation, yet produce correctly formed microtubules (MTs) in mammalian cells. Further to this, we investigated the properties of the MT network in patients' fibroblasts and revealed that MCD mutations can alter the resistance of MTs to depolymerization. Interestingly, this finding contrasts with the increased MT stability observed in the case of CFEOM3-related mutations. These results led us to hypothesize that either MT dynamics or their interactions with various MT-interacting proteins could be differently affected by TUBB3 variations, thus resulting in distinct alteration of downstream processes and therefore explaining the phenotypic diversity of the TUBB3-related spectrum.
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http://dx.doi.org/10.1093/hmg/ddq377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298850PMC
November 2010

Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria.

Nat Genet 2009 Jun 24;41(6):746-52. Epub 2009 May 24.

Institut Cochin, Université Paris Descartes CNRS (UMR 8104), Paris, France.

Polymicrogyria is a relatively common but poorly understood defect of cortical development characterized by numerous small gyri and a thick disorganized cortical plate lacking normal lamination. Here we report de novo mutations in a beta-tubulin gene, TUBB2B, in four individuals and a 27-gestational-week fetus with bilateral asymmetrical polymicrogyria. Neuropathological examination of the fetus revealed an absence of cortical lamination associated with the presence of ectopic neuronal cells in the white matter and in the leptomeningeal spaces due to breaches in the pial basement membrane. In utero RNAi-based inactivation demonstrates that TUBB2B is required for neuronal migration. We also show that two disease-associated mutations lead to impaired formation of tubulin heterodimers. These observations, together with previous data, show that disruption of microtubule-based processes underlies a large spectrum of neuronal migration disorders that includes not only lissencephaly and pachygyria, but also polymicrogyria malformations.
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http://dx.doi.org/10.1038/ng.380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2883584PMC
June 2009

Neuroanatomical distribution of ARX in brain and its localisation in GABAergic neurons.

Brain Res Mol Brain Res 2004 Mar;122(1):35-46

Laboratoire de Génétique et de Physiopathologie des Retards Mentaux, Institut Cochin. Inserm U567, Université Paris V. 24, rue du Faubourg Saint Jacques, 75014 Paris, France.

Recent human genetics approaches identified the Aristaless-related homeobox (ARX) gene as the causative gene in X-linked infantile spasms, Partington syndrome, and non-syndromic mental retardation as well as in forms of lissencephaly with abnormal genitalia. The ARX predicted protein belongs to a large family of homeoproteins and is characterised by a C-terminal Aristaless domain and an octapeptide domain near the N-terminus. In order to learn more about ARX function, we have studied in detail Arx expression in the central nervous system during mouse embryonic development as well as in the adult. During early stages of development, Arx is expressed in a significant proportion of neurons in the cortex, the striatum, the ganglionic eminences and also in the spinal cord. In the adult, expression of Arx is still present and restricted to regions that are known to be rich in GABAergic neurons such as the amygdala and the olfactory bulb. A possible role for Arx in this type of neurons is further reinforced by the expression of Arx in a subset of GABAergic interneurons in young and mature primary cultures of cortical neuronal cells as well as in vivo. Moreover, these data could explain the occurrence of seizures in the great majority of patients with an ARX mutation, due to mislocalisation or dysfunction of GABAergic neurons. We also performed ARX wild-type and mutant over-expression experiments and found that the different ARX mutations tested did not modify the morphology of the cells. Moreover, no abnormal cell death or protein aggregation was observed, hence suggesting that more subtle pathogenic mechanisms are involved.
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http://dx.doi.org/10.1016/j.molbrainres.2003.11.021DOI Listing
March 2004

In vivo electrotransfer of the cardiotrophin-1 gene into skeletal muscle slows down progression of motor neuron degeneration in pmn mice.

Hum Mol Genet 2002 Jul;11(14):1615-25

Département de Génétique, Développement et Pathologie Moléculaire, Institut Cochin, INSERM, CNRS, Université René Descartes, 24 rue du Faubourg St Jacques, 75014 Paris, France.

Among all vectors designed for gene therapy purposes, adenovirus appears to be the most efficient in vivo vehicle to transduce the broadest spectrum of cellular targets. However, the deleterious immunogenicity of this viral vector impedes its use in chronic diseases. Non-viral vectors, such as naked DNA, are attractive alternatives for safety and technical issues, such as scale-up production. Naked DNA injection, greatly improved when combined with electroporation, showed great potential in adult animals, especially when directed to the muscle. We have recently proven the therapeutic effect of a neonatal single intramuscular injection of a cardiotrophin-1 (CT-1)-encoding adenovirus in a hereditary disease mouse model of human motor neuron disease, the progressive motor neuronopathy (pmn) mutant. We now demonstrate that a single injection/electroporation of a CT-1-encoding plasmid in neonate pmn mice is almost as efficient as adenovirus-mediated gene transfer with respect to survival, muscular function and neuroprotection of the animals. Treated mice gain global weight, their mean lifespan is extended by 25%, all their electromyographic parameters are improved and myelinated axons of their phrenic nerves are protected. Moreover, we show that re-injection/electroporation leads to improvements in this neuroprotection. We therefore demonstrate for the first time the therapeutic efficacy of neonatal intramuscular DNA injection/electroporation in a murine model of a human hereditary disorder.
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http://dx.doi.org/10.1093/hmg/11.14.1615DOI Listing
July 2002