Because the DNM2 gene maps to 19p13.2-p12 and shares domains similar to those of genes known to be involved in axonal Charcot-Marie-Tooth disease (see 118210), Zuchner et al. (2005) considered it a candidate gene for the form of dominant intermediate Charcot-Marie-Tooth disease that maps to chromosome 19p13.2-p12 (DI-CMTB; 606482). They identified 3 unique mutations in the DNM2 pleckstrin homology domain in 3 unrelated families with DI-CMTB. These mutations disturbed the function of DNM2 in a cellular model. DNM2 represented the third protein mutated in CMT that contains a GTPase domain and is related to fusion or fission of cellular membranes. In 2 of the families neutropenia cosegregated with the neuropathy; these families each had a mutation affecting lys558 (602378.0002, 602378.0003), which suggested that this residue has a function in maturation or survival of peripheral blood cells.
Bitoun et al. (2005) carried out genomewide linkage mapping analysis in 2 families with autosomal dominant centronuclear myopathy (CNM1; 160150), narrowing the CNM1 locus to an 11-Mb interval on 19p13.2. The DNM2 gene, which maps to this region, was considered a good candidate. Sequencing of exons and intron-exon boundaries in the probands of 3 families identified heterozygous mutations. Two were located in exon 8 and involved the same arg369 residue, (R369Q, 602378.0004; R369W, 602378.0005), and 1 was in exon 11 and involved an R465W mutation (602378.0006). Another mutation, E368K (602378.0007), was a de novo mutation in 1 family.
Tosch et al. (2006) described a patient with centronuclear myopathy who carried heterozygous mutations in both the DNM2 (E368K; 602378.0007) and MTMR14 (Y462C; 611089.0002) genes. They noted that whereas centronuclear myopathy patients with other characterized mutations in DYN2 usually have an age of onset in childhood or adulthood, the age of onset in their patient was neonatal. The report raised the possibility of MTMR14 being a modifier of the phenotype in some cases of centronuclear myopathy.
Bitoun et al. (2007) identified 4 different de novo heterozygous DNM2 mutations (see, e.g., 602378.0010; 602378.0011) in 5 unrelated patients with sporadic CNM. All mutations were in exon 16 of the DNM2 gene within the pleckstrin homology domain. Three of the patients had a severe disorder with onset at birth.
Using in vitro sedimentation assays, Wang et al. (2010) showed that centronuclear myopathy-associated mutant DNM2 proteins (see, e.g., 602378.0005-602378.0007) formed more stable dynamin polymers in the presence of GTP compared to wildtype, presumably reflecting abnormally strong dynamin-dynamin interactions. The mutant protein aggregates were less sensitive to disassociation by GTP, and retained higher GTPase activities compared to wildtype. The observations suggested that the affected residues, such as glu368, arg369, and arg465, normally function to prevent excessive or prolonged dynamin assembly.
Data extracted from the OMIM database