Absence of Dystrophin Related Protein-2 disrupts Cajal bands in a patient with Charcot-Marie-Tooth disease.

Abstract

Using exome sequencing in an individual with Charcot-Marie-Tooth disease (CMT) we have identified a mutation in the X-linked dystrophin-related protein 2 (DRP2) gene. A 60-year-old gentleman presented to our clinic and underwent clinical, electrophysiological and skin biopsy studies. The patient had clinical features of a length dependent sensorimotor neuropathy with an age of onset of 50 years. Neurophysiology revealed prolonged latencies with intermediate conduction velocities but no conduction block or temporal dispersion. A panel of 23 disease causing genes was sequenced and ultimately was uninformative. Whole exome sequencing revealed a stop mutation in DRP2, c.805C>T (Q269*). DRP2 interacts with periaxin and dystroglycan to form the periaxin-DRP2-dystroglycan complex which plays a role in the maintenance of the well-characterized Cajal bands of myelinating Schwann cells. Skin biopsies from our patient revealed a lack of DRP2 in myelinated dermal nerves by immunofluorescence. Furthermore electron microscopy failed to identify Cajal bands in the patient's dermal myelinated axons in keeping with ultrastructural pathology seen in the Drp2 knockout mouse. Both the electrophysiologic and dermal nerve twig pathology support the interpretation that this patient's DRP2 mutation causes characteristic morphological abnormalities recapitulating the Drp2 knockout model and potentially represents a novel genetic cause of CMT.

• Authors: Kathryn M Brennan, Yunhong Bai, Chiara Pisciotta, Suola Wang, Shawna M E Feely, Mark Hoegger, Laurie Gutmann, Steven A Moore, Michael Gonzalez, Diane L Sherman, Peter J Brophy, Stephan Züchner, Michael E Shy
• Journal: Neuromuscular disorders : NMD (Neuromuscul Disord) Vol. 25 Issue 10 Pg. 786-93 (Oct 2015) ISSN: 1873-2364 [Electronic] England
• PMID: 26227883 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Cytoskeletal Proteins
• DAG1 protein, human
• Membrane Proteins
• Muscle Proteins
• UCHL1 protein, human
• dystrophin-related protein 2
• Dystroglycans
• Ubiquitin Thiolesterase

Topics

• Charcot-Marie-Tooth Disease (genetics, pathology, physiopathology)
• Cytoskeletal Proteins (genetics)
• Dermis (innervation, ultrastructure)
• Dystroglycans (metabolism)
• Exome
• Humans
• Male
• Membrane Proteins (genetics)
• Middle Aged
• Muscle Proteins (genetics)
• Myelin Sheath (pathology)
• Neural Conduction
• Pedigree
• Ubiquitin Thiolesterase (metabolism)