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 patient's 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.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Ylikallio E,Pöyhönen R,Zimon M,De Vriendt E,Hilander T,Paetau A,Jordanova A,Lönnqvist T,Tyynismaa Hdoi
10.1093/hmg/ddt149subject
Has Abstractpub_date
2013-08-01 00:00:00pages
2975-83issue
15eissn
0964-6906issn
1460-2083pii
ddt149journal_volume
22pub_type
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