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Periventricular nodular heterotopia: a new gene involved in this disease

Left panel : normal migration of neurons (yellow).
Right panel : neurons remain blocked around ventricles.

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

Broix L(1,)(2,)(3,)(4,)(5), Jagline H(1,)(2,)(3,)(4), L Ivanova E(1,)(2,)(3,)(4), Schmucker S(1,)(2,)(3,)(4), Drouot N(1,)(2,)(3,)(4), Clayton-Smith J(6), Pagnamenta AT(7), Metcalfe KA(6), Isidor B(8), Louvier UW(9), Poduri A(10), Taylor JC(7), Tilly P(1,)(2,)(3,)(4), Poirier K(5), Saillour Y(5), Lebrun N(5), Stemmelen T(1,)(2,)(3,)(4), Rudolf G(1,)(2,)(3,)(4), Muraca G(5), Saintpierre B(5), Elmorjani A(5); Deciphering Developmental Disorders study, Moïse M(11), Weirauch NB(12), Guerrini R(13), Boland A(14), Olaso R(14), Masson C(15), Tripathy R(16), Keays D(16), Beldjord C(17), Nguyen L(11), Godin J(1,)(2,)(3,)(4), Kini U(18), Nischké P(15), Deleuze JF(14), Bahi-Buisson N(19), Sumara I(1,)(2,)(3,)(4), Hinckelmann MV(1,)(2,)(3,)(4), Chelly J(1,)(2,)(3,)(4,)(20).

Nat Genet nov 2016 2016

Oct. 3, 2016

The team of Jamel Chelly at the IGBMC has recently identified a new gene involved in a malformation resulting from abnormal  brain development named periventricular nodular heterotopia. Their results were published since October 3th, 2016 in the journal Nature Genetics.

When the neurons don’t migrate

Malformations due to abnormal cortical development (MDC) represent a wide spectrum of brain malformations generated during embryogenesis. They are responsible for severe forms of intellectual disability and epilepsy. Among them, periventricular nodular heterotopia (PNH) are mainly characterized by the abnormal presence of clusters (or nodules) of neurons (gray matter) around the ventricles, thought to result from deregulation of neuronal migration process during development. Phenotypes associated with PNH are relatively heterogeneous and their genetic causes are still in many cases unknown. Indeed, only the loss-of-function mutations in one major gene encoding filamine A (FNLA), had been implicated in about half of the PNH cases.


Discovery of a new mutation

In this new study, the team of Jamel Chelly at the IGBMC, in partnership with the Institut Cochin in Paris, shows that mutations in a specific domain (HECT domain) of the E3 ubiquitin ligase enzyme NEDD4L are also responsible for PNH. Using functional approaches, the team also showed that these mutations cause instability NEDD4L protein, which would induce a concomitant degradation of protein partners. This mechanism results in a deregulation of the mTOR signaling pathway which in turn leads to a dysregulated proliferation and neuronal migration.


These results highlight an important new genetic cause of PNH and molecular mechanisms underlying this disorder. Besides their impact in the medical diagnostic field, these data open new perspectives for understanding the critical role of NEDD4L in cortical development.

This study was supported by the Agence Nationale pour la Recherche (ANR), the Fondation pour la recherche médicale (FRM), the University of Strasbourg (Idex and Labex) and the Fondation Maladies rares.

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