Since 2005, we have identified several mutations in the sub-domains of this protein. Until then, we only observed mutations associated with classic centronuclear myopathy (CNM) in the “middle domain”; at the end of the PH domain, there were only mutations resulting in the severe form of muscular dystrophy that affect children, and in the first half of the PH domain, only the group of mutations associated with Charcot-Marie-Tooth (CMT) neuropathy. The new mutation that we have identified and which is reported in this article is located in the middle of the group of mutations giving neuropathies. We found that mutation of the amino acid 559 is associated with a distinct neuropathy with no effect on the muscle (Charcot-Marie-Tooth type 2 **) and that the mutation of the following amino acid 560 leads to a myopathy with both a morphologically typical CNM phenotype and a specific phenotype regarding clinical symptoms. This phenotype does not resemble mild forms of the adult or neonatal severe forms, but it is intermediate: late onset of the disease in children (~ 10 years of age) but very rapid progression (loss of ambulation before 30 years of age).
 
What is the role of dynamin 2?
DNM2 is a high molecular weight GTPase, it therefore hydrolyzes GTP, whose main function studied so far is its role in endocytosis. The plasma membrane invaginates with vesicle formation and dynamin forms a helix around the neck of the budding vesicle. Hydrolysis of GTP will induce the release of the vesicle either by lengthwise extension or scission of the vesicle neck (according to models).
 
How is it that two mutations so close result in two such different diseases?
We do not yet know the spatial conformation of the sub-domains and interaction sites with other partners or between them, with the exception of the PH domain that has been crystallized. We positioned the mutations on the three-dimensional structure of the PH domain, the neuropathy is associated with a deletion of the amino acid and in the case of congenital myopathy a charged amino acid is transformed into a neutral amino acid, thus changing the charge of the protein. This can have very different consequences, even if the mutations are very similar. Furthermore, there are several isoforms of the protein of which it is not clear if all are present in the muscle and the nervous system, or the impact of the mutations on these isoforms. There is much work to do concerning the understanding of the protein and the potential impact that these changes may have before trying to think of hypotheses to explain why one gives a myopathy and the other a neuropathy!
 
So what are the next steps?
We will continue to look for new mutations, with the aim of trying to identify a genotype-phenotype relationship. In parallel, we will seek to understand the impact of mutations on the pathophysiology by developing in vitro models (cells in patients already expressing the mutation or cells transfected with the mutant gene) and in vivo (transgenic mice expressing the mutation or electro-transfer of the mutant protein in a mouse muscle then follow-up of the impact on the muscle), after which we will look at their impact on the two hypotheses currently considered, endocytosis and membrane trafficking on the one hand and the relationship with the cytoskeleton on the other.
 
 
* A new centronuclear myopathy phenotype due to a novel dynamin 2 mutation, Bitoun M, Stojkovic T, Prudhon B, Maurage CA, Latour P, Vermersch P, Guicheney P., Neurology. 2009 Jan 6;72(1):93-5.
** A novel mutation in the dynamin 2 gene in a Charcot-Marie-Tooth type 2 patient: clinical and pathological findings, Bitoun M, Stojkovic T, Prudhon B, Maurage CA, Latour P, Vermersch P, Guicheney P., Neuromuscul Disord. 2008 Apr;18(4):334-8.
 
Interview by Anne Berthomier, translation by Racquel N. Cooper