HGNC Approved Gene Symbol: DRP2
Cytogenetic location: Xq22.1 Genomic coordinates (GRCh38): X:101,219,786-101,264,502 (from NCBI)
The DRP2 gene encodes dystrophin-related protein-2, which forms part of the periaxin (PRX; 605725)-DRP2-dystroglycan (PDG) complex in myelinating Schwann cells of the peripheral nervous system. The PDG complex is concentrated at zones of adhesion on the abaxonal surface and defines the boundaries of cytoplasm-filled channels called Cajal bands (summary by Sherman et al., 2012).
During the course of a phylogenetic study of sequences encoding the characteristic C-terminal domains of dystrophin-related proteins, Roberts et al. (1996) identified a vertebrate dystrophin-related gene class. They termed this class dystrophin-related protein-2 (DRP2) and suggested that utrophin/DRP (128240) be designated DRP1 to simplify future nomenclature. By Northern analysis Roberts et al. (1996) showed that the DRP2 gene is expressed principally in the brain and spinal cord.
Roberts et al. (1996) determined that the DRP2 gene contains 24 exons distributed over approximately 45 kb. It is similar in overall structure to the Dp116 dystrophin isoform (300377).
Roberts et al. (1996) mapped the human DRP2 gene to chromosome Xq22. The gene was localized to a 6.5-Mb YAC contig, approximately 300 kb proximal to the gene encoding the BTK gene (300300), defective in X-linked agammaglobulinemia.
Sherman et al. (2001) found that rodent Drp2 interacted and colocalized with periaxin (PRX; 605725) within a dystroglycan complex localized to the plasma membrane of Schwann cells. In Prx-null mice, who develop a severe late-onset demyelinating neuropathy in which the myelin sheath becomes unstable (Gillespie et al., 2000), Sherman et al. (2001) found mislocalization and concomitant loss of Drp2, suggesting that periaxin stabilizes the Drp2-dystroglycan complex. Sherman et al. (2001) concluded that the periaxin-Drp2-dystroglycan complex is important in regulating the terminal stages of myelination.
Associations Pending Confirmation
For discussion of a possible association between variation in the DRP2 gene and an X-linked intermediate form of Charcot-Marie-Tooth disease (see, e.g., CMTX1, 302800), see 300052.0001.
Sherman et al. (2012) found that targeted deletion of the Drp2 gene in Schwann cells in mice resulted in mislocalization of periaxin and disruption of both the PDG complex and of the abaxonal appositions that define the boundary of Cajal bands. Although Drp2 mutants had normal internodal lengths, conduction velocities, and motor behavior, they developed age-dependent peripheral nerve abnormalities, including myelin outfoldings, focal hypermyelination, and onion bulbs with remyelination. These changes were different from those observed in Prx-null mice. Sherman et al. (2012) concluded that the primary role of the PDG complex in peripheral nerve appositions is to stabilize and limit the radial growth of myelin.
This variant is classified as a variant of unknown significance because its contribution to a late-onset peripheral neuropathy consistent with an X-linked intermediate form of Charcot-Marie-Tooth disease (see, e.g., CMTX1, 302800) has not been confirmed.
In a 60-year-old man with an intermediate form of Charcot-Marie-Tooth disease, Brennan et al. (2015) identified a hemizygous c.805C-T transition in exon 5 of the DRP2 gene, resulting in a gln269-to-ter (Q269X) substitution. The mutation was predicted to result in nonsense-mediated mRNA decay or rapid degradation of a truncated protein, resulting in a loss of function. The variant, which was found by whole-exome sequencing, was not found in the Exome Variant Server database or in an unaffected family member. Skin biopsy from the patient showed lack of DRP2 immunostaining in myelinated nerves. Electron microscopy of dermal nerves showed no distinct abaxonal appositions, with most myelinated axons demonstrating a circumferential band of Schwann cell cytoplasm surrounding the abaxonal myelin. In contrast, control dermal nerved showed abaxonal appositions. The patient first developed distal muscle weakness and atrophy associated with distal sensory impairment of the lower limbs at age 50. He also had pes cavus. He had a wide-based gait and was unable to walk on his heels or toes. Electrophysiologic studies showed intermediate nerve conduction velocities.
Brennan, K. M., Bai, Y., Pisciotta, C., Wang, S., Feely, S. M. E., Hoegger, M., Gutmann, L., Moore, S. A., Gonzalez, M., Sherman, D. L., Brophy, P. J., Zuchner, S., Shy, M. E. Absence of dystrophin related protein-2 disrupts Cajal bands in a patient with Charcot-Marie-Tooth disease. Neuromusc. Disord. 25: 786-793, 2015. [PubMed: 26227883] [Full Text: https://doi.org/10.1016/j.nmd.2015.07.001]
Gillespie, C. S., Sherman, D. L., Fleetwood-Walker, S. M., Cottrell, D. F., Tait, S., Garry, E. M., Wallace, V. C. J., Ure, J., Griffiths, I. R., Smith, A., Brophy, P. J. Peripheral demyelination and neuropathic pain behavior in periaxin-deficient mice. Neuron 26: 523-531, 2000. [PubMed: 10839370] [Full Text: https://doi.org/10.1016/s0896-6273(00)81184-8]
Roberts, R. G., Freeman, T. C., Kendall, E., Vetrie, D. L. P., Dixon, A. K., Shaw-Smith, C., Bone, Q., Bobrow, M. Characterization of DRP2, a novel human dystrophin homologue. Nature Genet. 13: 223-226, 1996. [PubMed: 8640231] [Full Text: https://doi.org/10.1038/ng0696-223]
Sherman, D. L., Fabrizi, C., Gillespie, C. S., Brophy, P. J. Specific disruption of a schwann cell dystrophin-related protein complex in a demyelinating neuropathy. Neuron 30: 677-687, 2001. [PubMed: 11430802] [Full Text: https://doi.org/10.1016/s0896-6273(01)00327-0]
Sherman, D. L., Wu, L. M. N., Grove, M., Gillespie, C. S., Brophy, P. J. Drp2 and periaxin form Cajal bands with dystroglycan but have distinct roles in Schwann cell growth. J. Neurosci. 32: 9419-9428, 2012. [PubMed: 22764250] [Full Text: https://doi.org/10.1523/JNEUROSCI.1220-12.2012]