156 research outputs found
Myotubularines et maladie de Charcot-Marie-Tooth
No full textLa maladie de Charcot Marie Tooth (CMT) est la neuropathie périphérique héréditaire la plus commune chez l'homme ; elle affecte environ une personne sur 2500. A ce jour, plus de 20 gènes ont été liés à une des formes de CMT et parmi eux, deux sont impliqués dans des formes sévères autosomiques récessives démyélinisantes, les CMT4B1 et CMT4B2. Ces gènes codent pour des protéines de la famille des myotubularines, MTMR2 et MTMR13. Les rôles cellulaires de ces protéines sont aujourd'hui encore largement inconnus. Nous avons étudié les profils d'expression de ces gènes et montré qu'ils s'expriment selon un profil spatio-temporel similaire, mais avec une cinétique différente lors de la myélinisation. Nous avons ensuite établi un modèle in vitro de leur perte de fonction par RNA interférence, et montré qu'elle entraîne une diminution de la densité des cellules de Schwann. De plus, l'inactivation de MTMR2 diminue la survie de ces cellules par un mécanisme apoptotique dépendant des caspases.The Charcot Marie Tooth disease is the most common inherited neuropathy in humans, with a frequency of 1/2500. More than 20 genes have been identified so far, and two of them are involved in the severe autosomal recessives demyelinating forms CMT4B1 and CMT4B2. Those two genes belongs to the myotubularin family, MTMR2 (Myotubularin related 2) and MTMR13, their roles in the physiopathology of the CMT4 being still largely unknown. We established their expression profile during development and showed that they are spatially expressed in a similar way, but differ during the myelination. We then developed a model in which MTMR2 and MTMR13 loss of function was reproduced in Schwann cells by RNA interference. We found that depletion of MTMR2 and MTMR13 cells decreased their rate of proliferation. Furthemore, MTMR2-depletion increased the number of Schwann cells that died by a caspase-dependant apoptosis.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF
PCDH19-related infantile epileptic encephalopathy: an unusual X-linked inheritance disorder.
No full textInternational audiencePCDH19 encodes protocadherin 19 on chromosome Xq22.3. This 1,148-amino-acid protein, highly expressed during brain development, could play significant roles in neuronal migration or establishment of synaptic connections. PCDH19 is composed of six exons, with a large first exon encoding the entire extracellular domain of the protein. Heterozygous PCDH19 mutations were initially identified in epilepsy and mental retardation limited to females, a familial disorder with a singular mode of inheritance as only heterozygous females are affected, whereas hemizygous males are asymptomatic. Yet, mosaic males can also be affected, supporting cellular interference as the pathogenic mechanism. Recently, mutations in PCDH19, mostly occurring de novo, were shown to be a frequent cause of sporadic infantile-onset epileptic encephalopathy in females. PCDH19 mutations were also identified in epileptic females without cognitive impairment. Typical features of this new epileptic syndrome include generalized or focal seizures highly sensitive to fever, and brief seizures occurring in clusters, repeating during several days. Here, we present a review of the published mutations in the PCDH19 gene to date and report on new mutations. PCDH19 has become the second most relevant gene in epilepsy after SCN1A
Caract\ue9risation d'EFHC1, une prot\ue9ine mut\ue9es dans l'\ue9pilepsie myoclonique juv\ue9nile
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Genetic refinement and physical mapping of the CMT4B gene on chromosome 11q22.
No full textCharcot-Marie-Tooth disease type 4B (CMT4B) is a demyelinating autosomal recessive motor and sensory neuropathy characterized by focally folded myelin sheaths in the peripheral nerve. We recently mapped the CMT4B gene to a 5-cM interval on chromosome 11q22, using homozygosity mapping and haplotype sharing analysis on a large inbred pedigree. In the present study, we report the construction of a YAC-based transcript map across the 5-cM critical region, including 26 YACs, 35 STSs, and 52 ESTs. Furthermore, using 15 additional physically ordered microsatellite markers from the 11q22 region on the original inbred family, we were able to narrow the critical interval for the gene to 2 Mb, which is now flanked by markers D11S1757 and CHLC-GATA3B05. Finally, after computer analysis of the 33 ESTs assigned to the 2-Mb interval, we demonstrated that 21 different transcripts as well as 3 known genes might represent potential candidates for the disease
LGI1 acts presynaptically to regulate excitatory synaptic transmission during early postnatal development
No full textInternational audienceThe secreted leucine-rich glioma inactivated 1 (LGI1) protein is an important actor for human seizures of both genetic and autoimmune etiology: mutations in LGI1 cause inherited temporal lobe epilepsy, while LGI1 is involved in antibody-mediated encephalitis. Remarkably, Lgi1-deficient (Lgi1 −/−) mice recapitulate the epileptic disorder and display early-onset spontaneous seizures. To understand how Lgi1-deficiency leads to seizures during postnatal development, we here investigated the early functional and structural defects occurring before seizure onset in Lgi1 −/− mice. We found an increased excitatory synaptic transmission in hippocampal slices from Lgi1 −/− mice. No structural alteration in the morphology of pyramidal cell dendrites and synapses was observed at this stage, indicating that Lgi1-deficiency is unlikely to trigger early developmental abnormalities. Consistent with the presynaptic subcellular localization of the protein, Lgi1-deficiency caused presynaptic defects, with no alteration in postsynaptic AMPA receptor activity in Lgi1 −/− pyramidal cells before seizure onset. Presynaptic dysfunction led to increased synaptic glutamate levels, which were associated with hyperexcitable neuronal networks. Altogether, these data show that Lgi1 acts presynaptically as a negative modulator of excitatory synaptic transmission during early postnatal development. We therefore here reveal that increased presynaptic glutamate release is a key early event resulting from Lgi1-deficiency, which likely contributes to epileptogenesis
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