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

Broix, Loïc; Jagline, Hélène; Ivanova, Ekaterina; Schmucker, Stéphane; Drouot, Nathalie; Clayton‐Smith, Jill; Pagnamenta, Alistair T.; Metcalfe, Kay; Isidor, Bertrand; Louvier, U. Walther; Poduri, Annapurna; Taylor, Jenny C.; Tilly, Peggy; Poirier, Karine; Saillour, Yoann; Lebrun, Nicolas; Stemmelen, Tristan; Rudolf, Gabrielle; Muraca, Giuseppe; Saintpierre, Benjamin; Elmorjani, Adrienne; Moïse, Martin; Weirauch, Nathalie Bednarek; Guerrini, Renzo; Boland, Anne; Olaso, Robert; Masson, Cécile; Tripathy, Ratna; Keays, David A.; Beldjord, Chérif; Nguyen, Laurent; Godin, Juliette D.; Kini, Usha; Nischké, Patrick; Deleuze, Jean‐François; Bahi‐Buisson, Nadia; Sumara, Izabela; Hinckelmann, María-Victoria; Chelly, Jamel

doi:10.1038/ng.3676

Cited by 105 publications

(115 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…More recently, mutations were also found in several patients in the NEDD4L gene, which codes for the E3 ubiquitin ligase. This work suggested that disruption of mTOR and AKT signaling pathways is involved in the neurodevelopment of this pathology [189]. Defects in progenitor cells, neuronal positioning and terminal translocation were identified by in utero electroporation.…”

Section: 23b Animal Models and Functional Studiesmentioning

confidence: 99%

“…In PVH, some neurons fail to migrate to their proper position and form nodules of grey matter located around the walls of the lateral ventricles, associated with breaks of the VL, disrupting the integrity of the neuroependyma [188]. Amongst neuronal migration MCDs, PVH may represent up to 31% of cases [189]. This disorder can occur as an isolated malformation or associated with other brain malformations, such as e.g.…”

Section: A Periventricular Nodular Heterotopias (Pvh) and Ventricularmentioning

confidence: 99%

See 1 more Smart Citation

Genetics and mechanisms leading to human cortical malformations

Romero

Bahi‐Buisson

Francis

2018

Seminars in Cell & Developmental Biology

Self Cite

100

109

View full text Add to dashboard Cite

Section: 23b Animal Models and Functional Studiesmentioning

confidence: 99%

Section: A Periventricular Nodular Heterotopias (Pvh) and Ventricularmentioning

confidence: 99%

Genetics and mechanisms leading to human cortical malformations

Romero

Bahi‐Buisson

Francis

2018

Seminars in Cell & Developmental Biology

Self Cite

100

109

View full text Add to dashboard Cite

“…The HECT thioester intermediate directly ubiquitinates target proteins and itself on Lys residues. Because of their direct role in catalysis, it is presumed that HECT E3 ligases must be held in check to prevent both excessive target ubiquitination as well as self-destruction by autoubiquitination (Broix et al, 2016; Buetow and Huang, 2016). …”

mentioning

confidence: 99%

“…Members of the NEDD4 family include WWP2, WWP1, ITCH, and NEDD4-1 and these E3 ligases target for destruction key signaling molecules and transcription factors (Aki et al, 2015; Buetow and Huang, 2016; Chen et al, 2014; Scheffner and Kumar, 2014; Zhi and Chen, 2012). Abnormal activities of NEDD4 E3 ligases are connected to cancer, immune disorders, and other diseases (Aki et al, 2015; Broix et al, 2016; Buetow and Huang, 2016; Chen et al, 2014; Scheffner and Kumar, 2014; Zhi and Chen, 2012). The NEDD4 family proteins each contain an N-terminal C2 domain followed by two to four WW domains and culminate in a C-terminal catalytic HECT domain (Figure 1A and Figure S1A) (Buetow and Huang, 2016).…”

mentioning

confidence: 99%

A Tunable Brake for HECT Ubiquitin Ligases

et al. 2017

View full text Add to dashboard Cite

The HECT E3 ligases ubiquitinate numerous transcription factors and signaling molecules and their activity must be tightly controlled to prevent cancer, immune disorders, and other diseases. In this study we have found unexpectedly that peptide linkers tethering WW domains in several HECT family members are key regulatory elements of their catalytic activities. Biochemical, structural, and cellular analysis has revealed that the linkers can lock the HECT domain in an inactive conformation and block the proposed allosteric ubiquitin binding site. Such linker-mediated autoinhibition of the HECT domain can be relieved by linker post-translational modifications, but complete removal of the brake can induce hyperactive autoubiquitination and E3 self-destruction. These results clarify the mechanisms of several HECT protein cancer associated mutations and provide a new framework for understanding how HECT ubiquitin ligases must be finely tuned to ensure normal cellular behavior.

show abstract

“…Heterozygous mutations in the NEDD4L gene have recently been identified to cause a novel syndromic form of periventricular nodular heterotopia in humans (PVNH7; OMIM #617201) (Broix et al, ). PVNH describes the nodular accumulation of neuronal precursor cells at the site of their origin along the lateral walls of both lateral ventricles, most likely resulting from failed initiation of neuronal migration (Ferland & Guerrini, ; Lange et al, ).…”

Section: Introductionmentioning

confidence: 99%

Familial NEDD4L variant in periventricular nodular heterotopia and in a fetus with hypokinesia and flexion contractures

Elbracht

Kraft

Begemann

et al. 2018

Molec Gen & Gen Med

View full text Add to dashboard Cite

BackgroundMutations in the HECT domain of NEDD4L have recently been identified in a cohort of eight patients with a syndromic form of bilateral periventricular nodular heterotopia (PVNH) in association with neurodevelopmental delay, cleft palate, and toe syndactyly (PVNH7).MethodsCase report based on NGS sequencing.ResultsHere, we describe a girl with a novel heterozygous NEDD4L missense variant, p.Tyr679His, and characteristic clinical findings, including bilateral periventricular nodular heterotopia, cleft palate and mild toe syndactyly. Molecular testing from peripheral blood identified the healthy father to carry the NEDD4L variant in mosaic state. Notably, a previous pregnancy of the couple had been terminated due to a complex fetal developmental disorder, including hypokinesia and flexion contractures. Upon review, this affected fetus was also shown to carry the familial NEDD4L variant.ConclusionOur findings may suggest a broader spectrum of NEDD4L‐associated phenotypes, including severe prenatal neurodevelopmental manifestations, which might represent yet another genetic form of fetal hypokinesia with flexion contractures.

show abstract

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

Cited by 105 publications

References 40 publications

Genetics and mechanisms leading to human cortical malformations

Genetics and mechanisms leading to human cortical malformations

A Tunable Brake for HECT Ubiquitin Ligases

Familial NEDD4L variant in periventricular nodular heterotopia and in a fetus with hypokinesia and flexion contractures

Contact Info

Product

Resources

About