Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway deregulation and cause periventricular nodular heterotopia

被引：93

作者：

Broix, Loic ^{[1
,2
,3
,4
,5
]}

Jagline, Helene ^{[1
,2
,3
,4
]}

Ivanova, Ekaterina L. ^{[1
,2
,3
,4
]}

Schmucker, Stephane ^{[1
,2
,3
,4
]}

Drouot, Nathalie ^{[1
,2
,3
,4
]}

Clayton-Smith, Jill ^{[6
]}

Pagnamenta, Alistair T. ^{[7
]}

Metcalfe, Kay A. ^{[6
]}

Isidor, Bertrand ^{[8
]}

Louvier, Ulrike Walther ^{[9
]}

Poduri, Annapurna ^{[10
]}

Taylor, Jenny C. ^{[7
]}

Tilly, Peggy ^{[1
,2
,3
,4
]}

Poirier, Karine ^{[5
]}

Saillour, Yoann ^{[5
]}

Lebrun, Nicolas ^{[5
]}

Stemmelen, Tristan ^{[1
,2
,3
,4
]}

Rudolf, Gabrielle ^{[1
,2
,3
,4
]}

Muraca, Giuseppe ^{[5
]}

Saintpierre, Benjamin ^{[5
]}

Elmorjani, Adrienne ^{[5
]}

Moise, Martin ^{[11
]}

Weirauch, Nathalie Bednarek ^{[12
]}

Guerrini, Renzo ^{[13
]}

Boland, Anne ^{[14
]}

Olaso, Robert ^{[14
]}

Masson, Cecile ^{[15
]}

Tripathy, Ratna ^{[16
]}

Keays, David ^{[16
]}

Beldjord, Cherif ^{[17
]}

Nguyen, Laurent ^{[11
]}

Godin, Juliette ^{[1
,2
,3
,4
]}

Kini, Usha ^{[18
]}

Nischke, Patrick ^{[15
]}

Deleuze, Jean-Francois ^{[14
]}

Bahi-Buisson, Nadia ^{[19
]}

Sumara, Izabela ^{[1
,2
,3
,4
]}

Hinckelmann, Maria-Victoria ^{[1
,2
,3
,4
]}

Chelly, Jamel ^{[1
,2
,3
,4
,20
]}

机构：

[1] Inst Genet & Biol Mol & Cellulaire, Illkirch Graffenstaden, France

[2] CNRS, U7104, Illkirch Graffenstaden, France

[3] INSERM, U964, Illkirch Graffenstaden, France

[4] Univ Strasbourg, Illkirch Graffenstaden, France

[5] Paris Descartes Univ, CNRS, INSERM, Inst Cochin,U1016,U8104, Paris, France

[6] Cent Manchester Univ Hosp NHS Trust, Manchester Acad Hlth Sci Ctr, Manchester Ctr Genom Med, Manchester, Lancs, England

[7] Univ Oxford, Wellcome Trust Ctr Human Genet, NIHR Biomed Res Ctr, Oxford, England

[8] Univ Hosp Nantes, Serv Genet Med, Nantes, France

[9] Univ Hosp Montpellier, Unite Neuropediat & Epileptol Infantile, Montpellier, France

[10] Boston Childrens Hosp, Dept Neurol, Div Epilepsy & Clin Neurophysiol, Epilepsy Genet Program, Boston, MA USA

[11] Univ Liege, Grappe Interdisciplinaire Genoproteom Appl Neuros, Liege, Belgium

[12] Univ Hosp Reims, Hop Maison Blanche, Reims, France

[13] Univ Florence, A Meyer Childrens Hosp, Paediat Neurol Unit, Florence, Italy

[14] CEA, Inst Genom, Ctr Natl Genotypage, Evry, France

[15] Paris Descartes Univ, Inst Imagine, Bioinformat Platform, Paris, France

[16] Inst Mol Pathol, Vienna, Austria

[17] Hop Cochin, Lab Biochim & Genet Mol, Paris, France

[18] Oxford Univ Hosp NHS Trust, Dept Clin Genet, Oxford, England

[19] Paris Descartes Univ, Hop Necker Enfants Malades, INSERM, Inst Imagine,U1163, Paris, France

[20] Hop Univ Strasbourg, Hop Civil Strasbourg, Serv Diagnost Genet, Strasbourg, France

来源：

NATURE GENETICS | 2016年 / 48卷 / 11期

关键词：

UBIQUITIN LIGASE NEDD4L; CORTICAL DEVELOPMENT; NEURONAL MIGRATION; C2; DOMAIN; FILAMIN-A; MALFORMATIONS; NEOCORTEX; PHOSPHORYLATION; ACTIVATION; MECHANISMS;

D O I：

10.1038/ng.3676

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Neurodevelopmental disorders with periventricular nodular heterotopia (PNH) are etiologically heterogeneous, and their genetic causes remain in many cases unknown. Here we show that missense mutations in NEDD4L mapping to the HECT domain of the encoded E3 ubiquitin ligase lead to PNH associated with toe syndactyly, cleft palate and neurodevelopmental delay. Cellular and expression data showed sensitivity of PNH-associated mutants to proteasome degradation. Moreover, an in utero electroporation approach showed that PNH-related mutants and excess wild-type NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Further investigations, including rapamycin-based experiments, found differential deregulation of pathways involved. Excess wild-type NEDD4L leads to disruption of Dab1 and mTORC1 pathways, while PNH-related mutations are associated with deregulation of mTORC1 and AKT activities. Altogether, these data provide insights into the critical role of NEDD4L in the regulation of mTOR pathways and their contributions in cortical development.

引用

页码：1349 / 1358

页数：10

共 37 条

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