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Mutations in the netrin-1 gene cause congenital mirror movements.

Authors :
Méneret A
Franz EA
Trouillard O
Oliver TC
Zagar Y
Robertson SP
Welniarz Q
Gardner RJM
Gallea C
Srour M
Depienne C
Jasoni CL
Dubacq C
Riant F
Lamy JC
Morel MP
Guérois R
Andreani J
Fouquet C
Doulazmi M
Vidailhet M
Rouleau GA
Brice A
Chédotal A
Dusart I
Roze E
Markie D
Source :
The Journal of clinical investigation [J Clin Invest] 2017 Nov 01; Vol. 127 (11), pp. 3923-3936. Date of Electronic Publication: 2017 Sep 25.
Publication Year :
2017

Abstract

Netrin-1 is a secreted protein that was first identified 20 years ago as an axon guidance molecule that regulates midline crossing in the CNS. It plays critical roles in various tissues throughout development and is implicated in tumorigenesis and inflammation in adulthood. Despite extensive studies, no inherited human disease has been directly associated with mutations in NTN1, the gene coding for netrin-1. Here, we have identified 3 mutations in exon 7 of NTN1 in 2 unrelated families and 1 sporadic case with isolated congenital mirror movements (CMM), a disorder characterized by involuntary movements of one hand that mirror intentional movements of the opposite hand. Given the diverse roles of netrin-1, the absence of manifestations other than CMM in NTN1 mutation carriers was unexpected. Using multimodal approaches, we discovered that the anatomy of the corticospinal tract (CST) is abnormal in patients with NTN1-mutant CMM. When expressed in HEK293 or stable HeLa cells, the 3 mutated netrin-1 proteins were almost exclusively detected in the intracellular compartment, contrary to WT netrin-1, which is detected in both intracellular and extracellular compartments. Since netrin-1 is a diffusible extracellular cue, the pathophysiology likely involves its loss of function and subsequent disruption of axon guidance, resulting in abnormal decussation of the CST.

Details

Language :
English
ISSN :
1558-8238
Volume :
127
Issue :
11
Database :
MEDLINE
Journal :
The Journal of clinical investigation
Publication Type :
Academic Journal
Accession number :
28945198
Full Text :
https://doi.org/10.1172/JCI95442