title: 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.affiliation: Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA. Electronic address: katiebre@doctors.org.uk.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Brennan
authors.affiliation: Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pisciotta
authors.affiliation: Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Suola
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Shawna M E
authors.initials: SM
authors.lastname: Feely
authors.affiliation: Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Hoegger
authors.affiliation: Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Laurie
authors.initials: L
authors.lastname: Gutmann
authors.affiliation: Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.affiliation: Department of Human Genetics and Hussmann Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gonzalez
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Sherman
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brophy
authors.affiliation: Department of Human Genetics and Hussmann Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.affiliation: Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Shy
mesh_terms: D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D003598:Cytoskeletal Proteins / Q000235:genetics*; D020405:Dermis / Q000294:innervation / Q000648:ultrastructure; D049030:Dystroglycans / Q000378:metabolism; D059472:Exome; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D009186:Myelin Sheath / Q000473:pathology; D009431:Neural Conduction; D010375:Pedigree; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D008565:Membrane Proteins; D009124:Muscle Proteins; C482860:UCHL1 protein, human; C099589:dystrophin-related protein 2; D049030:Dystroglycans; D043222:Ubiquitin Thiolesterase
keywords: Charcot–Marie–Tooth disease; Hereditary motor and sensory neuropathy; Myelin; Nerve conduction studies; Whole exome sequencing