PMP22 exon 4 deletion causes ER retention of PMP22 and a gain‐of‐function allele in CMT1E

David S Wang; Xingyao Wu; Yunhong Bai; Craig Zaidman; Tiffany Grider; John Kamholz; James R Lupski; Anne M Connolly; Michael E Shy

doi:10.1002/acn3.395

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PMP22 exon 4 deletion causes ER retention of PMP22 and a gain‐of‐function allele in CMT1E

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PMP22 exon 4 deletion causes ER retention of PMP22 and a gain‐of‐function allele in CMT1E

David S Wang, Xingyao Wu, Yunhong Bai, Craig Zaidman, Tiffany Grider, John Kamholz, James R Lupski, Anne M Connolly and Michael E Shy

Annals of clinical and translational neurology, Vol.4(4), pp.236-245

04/2017

DOI: 10.1002/acn3.395

PMCID: PMC5376752

PMID: 28382305

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Abstract

Objective To determine whether predicted fork stalling and template switching (FoSTeS) during mitosis deletes exon 4 in peripheral myelin protein 22 KD (PMP22) and causes gain‐of‐function mutation associated with peripheral neuropathy in a family with Charcot–Marie–Tooth disease type 1E. Methods Two siblings previously reported to have genomic rearrangements predicted to involve exon 4 of PMP22 were evaluated clinically and by electrophysiology. Skin biopsies from the proband were studied by RT‐PCR to determine the effects of the exon 4 rearrangements on exon 4 mRNA expression in myelinating Schwann cells. Transient transfection studies with wild‐type and mutant PMP22 were performed in Cos7 and RT4 cells to determine the fate of the resultant mutant protein. Results Both affected siblings had a sensorimotor dysmyelinating neuropathy with severely slow nerve conduction velocities (<10 m/sec). RT‐PCR studies of Schwann cell RNA from one of the siblings demonstrated a complete in‐frame deletion of PMP22 exon 4 (PMP22Δ4). Transfection studies demonstrated that PMP22Δ4 protein is retained within the endoplasmic reticulum and not transported to the plasma membrane. Conclusions Our results confirm that that FoSTeS‐mediated genomic rearrangement produced a deletion of exon 4 of PMP22, resulting in expression of both PMP22 mRNA and protein lacking this sequence. In addition, we provide experimental evidence for endoplasmic reticulum retention of the mutant protein suggesting a gain‐of‐function mutational mechanism consistent with the observed CMT1E in this family. PMP22Δ4 is another example of a mutated myelin protein that is misfolded and contributes to the pathogenesis of the neuropathy.

Details

Title: Subtitle: PMP22 exon 4 deletion causes ER retention of PMP22 and a gain‐of‐function allele in CMT1E
Creators: David S Wang - University of Iowa Hospitals and Clinics
Xingyao Wu - University of Iowa Hospitals and Clinics
Yunhong Bai - University of Iowa Hospitals and Clinics
Craig Zaidman - Washington University School of Medicine
Tiffany Grider - University of Iowa Hospitals and Clinics
John Kamholz - University of Iowa Hospitals and Clinics
James R Lupski - Baylor College of Medicine
Anne M Connolly - Washington University School of Medicine
Michael E Shy - University of Iowa Hospitals and Clinics
Resource Type: Journal article
Publication Details: Annals of clinical and translational neurology, Vol.4(4), pp.236-245
DOI: 10.1002/acn3.395
PMID: 28382305
PMCID: PMC5376752
NLM abbreviation: Ann Clin Transl Neurol
ISSN: 2328-9503
eISSN: 2328-9503
Number of pages: 10
Grant note: National Institute of Neurological Disorders and Stroke (R01 NS058529; R01NS075764) Charcot‐Marie‐Tooth Association Muscular Dystrophy Association National Center for Advancing Translational Sciences (2U54NS065712)
Language: English
Date published: 04/2017
Academic Unit: Neurology; Molecular Physiology and Biophysics; Psychiatry; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
Record Identifier: 9984072077402771

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