Dynamin 2 mutations associated with human diseases impair clathrin-mediated rece

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Hum Mutat. 2009 Jul 7.

Dynamin 2 mutations associated with human diseases impair clathrin-mediated

receptor endocytosis.

Bitoun M, Durieux AC, Prudhon B, Bevilacqua JA, Herledan A, Sakanyan V,

Urtizberea A, Cartier L, Romero NB, Guicheney P.

Institut National de la Santé et de la Recherche Médicale (INSERM), U582,

Institut de Myologie, Paris, France.

Dynamin 2 (DNM2) is a large GTPase involved in the release of nascent vesicles

during endocytosis and intracellular membrane trafficking. Distinct DNM2

mutations, affecting the middle domain (MD) and the Pleckstrin homology domain

(PH), have been identified in autosomal dominant centronuclear myopathy (CNM)

and * in the intermediate and axonal forms of the Charcot-Marie-Tooth

peripheral neuropathy (CMT)*.

We report here the first CNM mutation (c.1948G>A, p.E650 K) in the DNM2 GTPase

effector domain (GED), leading to a slowly progressive moderate myopathy. COS7

cells transfected with DNM2 constructs harboring a disease-associated mutation

in MD, PH, or GED show a reduced uptake of transferrin and low-density

lipoprotein (LDL) complex, two markers of clathrin-mediated receptor

endocytosis. A decrease in clathrin-mediated endocytosis was also identified in

skin fibroblasts from one CNM patient.

We studied the impact of DNM2 mutant overexpression on epidermal growth factor

(EGF)-induced extracellular signal-regulated kinase 1 (ERK1) and ERK2

activation, known to be an endocytosis- and DNM2-dependent process. Activation

of ERK1/2 was impaired for all the transfected mutants in COS7 cells, but not in

CNM fibroblasts.

Our results indicate that impairment of clathrin-mediated endocytosis may play a

role in the pathophysiological mechanisms leading to DNM2-related diseases, but

the tissue-specific impact of DNM2 mutations in both diseases remains unclear.