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

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.

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

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.

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

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.

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

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.

Protective effects of cardiotrophin-1 adenoviral gene transfer on neuromuscular degeneration in transgenic ALS mice.

Amyotrophic lateral sclerosis (ALS) is mainly a sporadic neurodegenerative disorder characterized by loss of cortical and spinal motoneurons. Some familial ALS cases (FALS) have been linked to dominant mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Transgenic mice overexpressing a mutated form of human SOD1 with a Gly93Ala substitution develop progressive muscle wasting and paralysis as a result of spinal motoneuron loss and die at 5 to 6 months.