title: Deficiency of the E3 ubiquitin ligase TRIM2 in early-onset axonal neuropathy.
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.
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, Finland.
authors.forename: Emil
authors.initials: E
authors.lastname: Ylikallio
authors.forename: Rosanna
authors.initials: R
authors.lastname: Pöyhönen
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zimon
authors.forename: Els
authors.initials: E
authors.lastname: De Vriendt
authors.forename: Taru
authors.initials: T
authors.lastname: Hilander
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
authors.forename: Tuula
authors.initials: T
authors.lastname: Lönnqvist
authors.forename: Henna
authors.initials: H
authors.lastname: Tyynismaa
mesh_terms: D000293:Adolescent; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D001706:Biopsy; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D009154:Mutation; D016900:Neurofilament Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency*; D020871:RNA Stability; D017422:Sequence Analysis, DNA; D013497:Sural Nerve / Q000378:metabolism / Q000473:pathology
chemical_list: C400022:NARF protein, human; D016900:Neurofilament Proteins; D009687:Nuclear Proteins