Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy

Abstract

Dominant intermediate Charcot-Marie-Tooth neuropathy type B is caused by mutations in dynamin 2. We studied the clinical, haematological, electrophysiological and sural nerve biopsy findings in 34 patients belonging to six unrelated dominant intermediate Charcot-Marie-Tooth neuropathy type B families in whom a dynamin 2 mutation had been identified: Gly358Arg (Spain); Asp551_Glu553del; Lys550fs (North America); Lys558del (Belgium); Lys558Glu (Australia, the Netherlands) and Thr855_Ile856del (Belgium). The Gly358Arg and Thr855_Ile856del mutations were novel, and in contrast to the other Charcot-Marie-Tooth-related mutations in dynamin 2, which are all located in the pleckstrin homology domain, they were situated in the middle domain and proline-rich domain of dynamin 2, respectively. We report the first disease-causing mutation in the proline-rich domain of dynamin 2. Patients with a dynamin 2 mutation presented with a classical Charcot-Marie-Tooth phenotype, which was mild to moderately severe since only 3% of the patients were wheelchair-bound. The mean age at onset was 16 years with a large variability ranging from 2 to 50 years. Interestingly, in the Australian and Belgian families, which carry two different mutations affecting the same amino acid (Lys558), Charcot-Marie-Tooth cosegregated with neutropaenia. In addition, early onset cataracts were observed in one of the Charcot-Marie-Tooth families. Our electrophysiological data indicate intermediate or axonal motor median nerve conduction velocities (NCV) ranging from 26 m/s to normal values in four families, and less pronounced reduction of motor median NCV (41-46 m/s) with normal amplitudes in two families. Sural nerve biopsy in a Dutch patient with Lys558Glu mutation showed diffuse loss of large myelinated fibres, presence of many clusters of regenerating myelinated axons and fibres with focal myelin thickenings--findings very similar to those previously reported in the Australian family. We conclude that dynamin 2 mutations should be screened in the autosomal dominant Charcot-Marie-Tooth neuropathy families with intermediate or axonal NCV, and in patients with a classical mild to moderately severe Charcot-Marie-Tooth phenotype, especially when Charcot-Marie-Tooth is associated with neutropaenia or cataracts.

Dynamin 2–dependent endocytosis is required for normal megakaryocyte development in mice

“…19 In contrast, mutations in the housekeeping DNM2 have been associated with thrombocytopenia and hematopoietic disorders such as neutropenia and early T-cell precursor acute lymphoblastic leukemia. [20][21][22][23] We investigated the role of DNM2 in MK maturation and platelet formation by generating Dnm2 fl/fl Pf4-Cre mice specifically lacking DNM2 in the MK lineage via Cre-loxP recombination. Dnm2 fl/fl impaired in Dnm2-null platelets, causing constitutive phosphorylation of the tyrosine kinase JAK2 and elevated circulating TPO levels.…”

Intermediate Charcot-Marie-Tooth disease

“…The majority of DNM2 mutations are located in the pleckstrin-homology domain, and other mutations with similar phenotypes have been reported in the Pro/ Arg-rich domain and the middle domain [42] . patients are wheel-chair bound [42] . Some patients also have combined nuclear and cortical cataracts that occur in early life.…”

“…Some patients also have combined nuclear and cortical cataracts that occur in early life. In some families with DNM2 mutation, the patients have also been segregated with neutropenia, ptosis, and ophthalmoparesis [42,43] .…”

Identification of a Location at Chromosome 19p in a Big Chinese Family with Charcot-Marie-Tooth Disease

“…Mutations had been identified in DNM2 gene for DI-CMTB [5]. From the previous researches, DNM2 mutations in DI-CMTB mainly located in its PH domain [5,6,16,17].…”