Title
Deficiency of the E3 ubiquitin ligase TRIM2 in early-onset axonal neuropathyDeficiency of the E3 ubiquitin ligase TRIM2 in early-onset axonal neuropathy
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Research group
VIB DMG - Molecular Neurogenomics
Publication type
article
Publication
Oxford,
Subject
Chemistry
Biology
Human medicine
Source (journal)
Human molecular genetics. - Oxford
Volume/pages
22(2013):15, p. 2975-2983
ISSN
0964-6906
ISI
000321452600001
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
Inherited peripheral neuropathies are a heterogeneous group of disorders that can affect patients of all ages. Children with inherited neuropathy often develop severe disability, but the genetic causes of recessive early-onset axonal neuropathies are not fully known. We have taken a whole-exome sequencing approach to identify causative disease mutations in single patients with early-onset axonal neuropathy. Here, we report compound heterozygous mutations in the tripartite motif containing 2 (TRIM2) gene in a patient with childhood-onset axonal neuropathy, low weight and small muscle mass. We show that the patient fibroblasts are practically devoid of TRIM2, through mRNA and protein instability caused by the mutations. TRIM2 is an E3 ubiquitin ligase that ubiquitinates neurofilament light chain, a component of the intermediate filament in axons. Resembling the findings in our patients sural nerve biopsy, Trim2-gene trap mice showed axonopathy with accumulations of neurofilaments inside axons. Our results suggest that loss-of-function mutations in TRIM2 are a cause of axonal neuropathy, which we propose to develop as a consequence of axonal accumulation of neurofilaments, secondary to lack of its ubiquitination by TRIM2.
E-info
https://repository.uantwerpen.be/docman/iruaauth/af1bc7/65c5358.pdf
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