Daniel Hantaï
U582 was closed on January 31st, 2008.
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Development, plasticity and genetic disorders of the neuromuscular synapse
Leader : Daniel Hantaï, director of research
The main objective is the pathophysiological and molecular characterization of congenital myasthenic syndromes (CMS). CMSs are rare genetic diseases which result in neuromuscular transmission dysfunction.
Their clinical expression is characterized by muscular weakness accentuated by effort, usually observed from childhood. CMSs form a group of affections which are heterogeneous, not only at the clinical but also the pathophysiological level (forms with presynaptic, synaptic or postsynaptic anomalies) and the genetic level (sporadic forms, recessive or dominant).
Their clinical expression is characterized by muscular weakness accentuated by effort, usually observed from childhood. CMSs form a group of affections which are heterogeneous, not only at the clinical but also the pathophysiological level (forms with presynaptic, synaptic or postsynaptic anomalies) and the genetic level (sporadic forms, recessive or dominant).
The strategy we adopted rests on:
1) the gathering of clinical data of patients and their families as well as that of their electroneuromyographic examinations;
2) the genetic study allowing identification of the mutations of the key neurotransmission molecules;
3) muscle biopsy analysis which permits the microelectrophysiological study of neurotransmission, the morphological study of neuromuscular junctions, the quantification of acetylcholine receptors and identification of the molecular forms of acetylcholinesterase;
4) the expression of new mutations in cell systems (motoneurone-myotube co-culture) and animal models (electrotransfection into mouse muscle or generation of KI mice) in order to characterise their pathogenic mechanism.
Since this project began four years ago, we have been able to characterise several new mutations in the genes encoding the different subunits of the acetylcholine receptor (AChR), the collagen tail of acetylcholinesterase (ColQ), rapsyn, dok-7 and for the first time we have identified mutations in the agrin receptor gene, MuSK.
In certain cases, this characterisation has allowed us to initiate an appropriate treatment. In certain families for whom the known genes had been excluded, we undertook the identification of the mutations in other genes by linkage analysis and by sequencing the candidate genes. The choice of these candidate genes is determined by comparative analysis of the morphological and molecular modifications of the neuromuscular junctions of patients and murine models. We plan to study the consequences of mutations on the gene and protein expression of the synaptic proteins. This study appears to us as a necessary prelude to any new therapy.
1) the gathering of clinical data of patients and their families as well as that of their electroneuromyographic examinations;
2) the genetic study allowing identification of the mutations of the key neurotransmission molecules;
3) muscle biopsy analysis which permits the microelectrophysiological study of neurotransmission, the morphological study of neuromuscular junctions, the quantification of acetylcholine receptors and identification of the molecular forms of acetylcholinesterase;
4) the expression of new mutations in cell systems (motoneurone-myotube co-culture) and animal models (electrotransfection into mouse muscle or generation of KI mice) in order to characterise their pathogenic mechanism.
Since this project began four years ago, we have been able to characterise several new mutations in the genes encoding the different subunits of the acetylcholine receptor (AChR), the collagen tail of acetylcholinesterase (ColQ), rapsyn, dok-7 and for the first time we have identified mutations in the agrin receptor gene, MuSK.
In certain cases, this characterisation has allowed us to initiate an appropriate treatment. In certain families for whom the known genes had been excluded, we undertook the identification of the mutations in other genes by linkage analysis and by sequencing the candidate genes. The choice of these candidate genes is determined by comparative analysis of the morphological and molecular modifications of the neuromuscular junctions of patients and murine models. We plan to study the consequences of mutations on the gene and protein expression of the synaptic proteins. This study appears to us as a necessary prelude to any new therapy.
