Mutations in the netrin-1 gene cause congenital mirror movements

J Clin Invest. 2017 Nov 1;127(11):3923-3936. doi: 10.1172/JCI95442.

Aurélie Méneret ¹ ², Elizabeth A Franz ³, Oriane Trouillard ¹, Thomas C Oliver ⁴, Yvrick Zagar ⁵, Stephen P Robertson ⁶, Quentin Welniarz ¹ ⁷, R J MacKinlay Gardner ⁶, Cécile Gallea ¹, Myriam Srour ⁸ ⁹, Christel Depienne ¹ ¹⁰ ¹¹, Christine L Jasoni ¹², Caroline Dubacq ⁷, Florence Riant ¹³ ¹⁴, Jean-Charles Lamy ¹, Marie-Pierre Morel ⁷, Raphael Guérois ¹⁵, Jessica Andreani ¹⁵, Coralie Fouquet ⁷, Mohamed Doulazmi ¹⁶, Marie Vidailhet ¹ ², Guy A Rouleau ⁸ ¹⁷ ¹⁸, Alexis Brice ¹ ¹⁹, Alain Chédotal ⁵, Isabelle Dusart ⁷, Emmanuel Roze ¹ ², David Markie ⁴

Affiliations

1 INSERM U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06, UMR S1127, CIC-1422, Institut du Cerveau et de la Moelle épinière (ICM), Paris, France.
2 AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Neurologie, Paris, France.
3 Department of Psychology and fMRIotago, , University of Otago, Dunedin, New Zealand.
4 Pathology Department, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
5 Sorbonne Universités, UPMC Université Paris 06, INSERM, CNRS, Institut de la Vision, Paris, France.
6 Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
7 Sorbonne Universités, UPMC Université Paris 06, INSERM, CNRS, Institut de Biologie Paris Seine, Neuroscience Paris Seine, Paris, France.
8 Department of Neurology and Neurosurgery, and.
9 Department of Paediatrics, McGill University, Montreal, Quebec, Canada.
10 Institut de Génétique et de Biologie moléculaire et cellulaire (IGBMC), CNRS UMR 7104, INSERM U964, Université de Strasbourg, Illkirch, France.
11 Laboratoires de génétique, Institut de génétique médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
12 Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
13 AP-HP, Groupe hospitalier Lariboisière-Fernand Widal, Laboratoire de Génétique, Paris, France.
14 INSERM, UMR S740, Université Paris 7 Denis Diderot, Paris, France.
15 Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris Sud, Université Paris-Saclay, Gif sur Yvette, France.
16 Sorbonne Universités, UPMC Université Paris 06, INSERM, CNRS, Institut de Biologie Paris Seine, Adaptation Biologique et Vieillissement, Paris, France.
17 Montreal Neurological Institute, Montreal, Quebec, Canada.
18 Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
19 AP-HP, Hôpital de la Pitié-Salpêtrière, Fédération de Génétique, Département de Génétique et de Cytogénétique, Paris, France.

PMID: 28945198 DOI: 10.1172/JCI95442

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.

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