Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

Sarah E.M. Stephenson; Gregory Costain; Laura E.R. Blok; Michael Silk; Thanh Binh Nguyen; Xiaomin Dong; Dana Alhuzaimi; James Dowling; Susan Walker; Kimberly Amburgey; Robin Hayeems; Lance Rodan; Marc Schwartz; Jonathan Picker; Sally Lynch; Aditi Gupta; Kristen Rasmussen; Lisa Schimmenti; Eric Klee; Zhiyv Niu; Katherine Agre; Ilana Chilton; Wendy Chung; Anya Revah-Politi; P.Y. Billie Au; Christopher Griffith; Melissa Racobaldo; Annick Raas-Rothschild; Bruria Ben Zeev; Ortal Barel; Sebastien Moutton; Fanny Morice-Picard; Virginie Carmignac; Jenny Cornaton; Nathalie Marle; Orrin Devinsky; Chandler Stimach; Stephanie Burns Wechsler; Bryan Hainline; Katie Sapp; Marjolaine Willems; Ange-Line Bruel; Kerith-Rae Dias; Carey-Anne Evans; Tony Roscioli; Rani Sachdev; Suzanna E.L. Temple; Ying Zhu; Joshua Baker; Ingrid Scheffer; Fiona Gardiner; Amy Schneider; Alison Muir; Heather Mefford; Amy Crunk; Elizabeth Heise; Francisca Millan; Kristin Monaghan; Richard Person; Lindsay Rhodes; Sarah Richards; Ingrid Wentzensen; Benjamin Cogné; Bertrand Isidor; Mathilde Nizon; Marie Vincent; Thomas Besnard; Amelie Piton; Carlo Marcelis; Kohji Kato; Norihisa Koyama; Tomoo Ogi; Elaine Suk-Ying Goh; Christopher Richmond; David Amor; Jessica Boyce; Angela Morgan; Michael Hildebrand; Antony Kaspi; Melanie Bahlo; Rún Friðriksdóttir; Hildigunnur Katrínardóttir; Patrick Sulem; Kári Stefánsson; Hans Tómas Björnsson; Simone Mandelstam; Manuela Morleo; Milena Mariani; Marcello Scala; Andrea Accogli; Annalaura Torella; Valeria Capra; Mathew Wallis; Sandra Jansen; Quinten Waisfisz; Hugoline de Haan; Simon Sadedin; Sze Chern Lim; Susan White; David Ascher; Annette Schenck; Paul Lockhart; John Christodoulou; Tiong Yang Tan

doi:10.1016/j.ajhg.2022.03.002

Back

Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

Journal article

Peer reviewed

Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

Sarah E.M. Stephenson, Gregory Costain, Laura E.R. Blok, Michael Silk, Thanh Binh Nguyen, Xiaomin Dong, Dana Alhuzaimi, James Dowling, Susan Walker, Kimberly Amburgey, …

American Journal of Human Genetics, Vol.109(4), pp.601-617

04/2022

DOI: https://doi.org/10.1016/j.ajhg.2022.03.002

PMCID: PMC9069070

PMID: 35395208

Abstract

F-box protein

FBXW7

Neurodevelopment

brain malformation

epilepsy

gastrointestinal issues

global developmental delay

hypotonia

intellectual disability

macrocephaly.

F-box protein

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.

Files and links (2)

url

Find in HALView

url

https://doi.org/10.1016/j.ajhg.2022.03.002View

Published (Version of record) Open

Metrics

1 Record Views

See more details

Details

Title: Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome
Creators - without role: Sarah E.M. Stephenson - Murdoch Children's Research Institute
Gregory Costain - Hospital for Sick Children
Laura E.R. Blok - Radboud University Medical Center
Michael Silk - Australian Cancer Research Foundation
Thanh Binh Nguyen - University of Melbourne
Xiaomin Dong - Murdoch Children's Research Institute
Dana Alhuzaimi - Murdoch Children's Research Institute
James Dowling - Hospital for Sick Children
Susan Walker - Hospital for Sick Children
Kimberly Amburgey - University of Toronto
Robin Hayeems - Institute for Clinical Evaluative Sciences
Lance Rodan - Boston Children's Hospital
Marc Schwartz - Harvard University
Jonathan Picker - Harvard University
Sally Lynch - Children's Health Ireland at Crumlin
Aditi Gupta - Mayo Clinic
Kristen Rasmussen - WinnMed
Lisa Schimmenti - WinnMed
Eric Klee - WinnMed
Zhiyv Niu - Mayo Clinic
Katherine Agre - Mayo Clinic in Florida
Ilana Chilton - Columbia University Irving Medical Center
Wendy Chung - Columbia University Irving Medical Center
Anya Revah-Politi - Columbia University
P.Y. Billie Au - Alberta Children's Hospital
Christopher Griffith - University of South Florida
Melissa Racobaldo - University of South Florida
Annick Raas-Rothschild - Sheba Medical Center
Bruria Ben Zeev - Edmond and Lily Safra Children's Hospital
Ortal Barel - Sheba Medical Center
Sebastien Moutton - Inserm
Fanny Morice-Picard - Génétique des anomalies du développement (CTM UMR 1231)
Virginie Carmignac - Université de Bourgogne
Jenny Cornaton - Maison des Sciences de l’Homme de Dijon
Nathalie Marle - Centre Hospitalier Universitaire Dijon Bourgogne
Orrin Devinsky - NYU Langone Health
Chandler Stimach - Emory Healthcare
Stephanie Burns Wechsler - Emory University
Bryan Hainline - Indiana University – Purdue University Indianapolis
Katie Sapp - Indiana University – Purdue University Indianapolis
Marjolaine Willems - Université de Montpellier
Ange-Line Bruel - Université de Montpellier, Institut des Neurosciences de Montpellier - INM
Kerith-Rae Dias - Prince of Wales Hospital
Carey-Anne Evans - Prince of Wales Hospital
Tony Roscioli - UNSW Sydney
Rani Sachdev - UNSW Sydney
Suzanna E.L. Temple - Sydney Children's Hospital
Ying Zhu - Hunter Genetics
Joshua Baker - Harvard University
Ingrid Scheffer - University of Melbourne
Fiona Gardiner - University of Melbourne
Amy Schneider - University of Melbourne
Alison Muir - University of Washington
Heather Mefford - University of Washington
Amy Crunk - GeneDx [Gaithersburg, MD, USA]
Elizabeth Heise - GeneDx [Gaithersburg, MD, USA]
Francisca Millan - GeneDx [Gaithersburg, MD, USA]
Kristin Monaghan - GeneDx [Gaithersburg, MD, USA]
Richard Person - GeneDx [Gaithersburg, MD, USA]
Lindsay Rhodes - GeneDx [Gaithersburg, MD, USA]
Sarah Richards - GeneDx [Gaithersburg, MD, USA]
Ingrid Wentzensen - GeneDx [Gaithersburg, MD, USA]
Benjamin Cogné - Institut du Thorax
Bertrand Isidor - Inserm
Mathilde Nizon - Institut du Thorax
Marie Vincent - Inserm
Thomas Besnard - Institut du Thorax
Amelie Piton - Inserm
Carlo Marcelis - Radboud University Medical Center
Kohji Kato - Nagoya University
Norihisa Koyama - Toyohashi Municipal Hospital
Tomoo Ogi - Nagoya University
Elaine Suk-Ying Goh - Trillium Health Centre
Christopher Richmond - Victorian Clinical Genetics Services
David Amor - Murdoch Children's Research Institute
Jessica Boyce - Murdoch Children's Research Institute
Angela Morgan - University of Melbourne
Michael Hildebrand - University of Melbourne
Antony Kaspi - University of Melbourne
Melanie Bahlo - University of Melbourne
Rún Friðriksdóttir - deCODE Genetics
Hildigunnur Katrínardóttir - deCODE Genetics
Patrick Sulem - deCODE Genetics
Kári Stefánsson - deCODE Genetics
Hans Tómas Björnsson - Johns Hopkins University
Simone Mandelstam - University of Melbourne
Manuela Morleo - Telethon Institute Of Genetics And Medicine
Milena Mariani - Azienda Socio Sanitaria Territoriale Lariana
Marcello Scala - Istituto Giannina Gaslini
Andrea Accogli - Istituto Giannina Gaslini
Annalaura Torella - Telethon Institute Of Genetics And Medicine
Valeria Capra - Istituto Giannina Gaslini
Mathew Wallis - Royal Hobart Hospital
Sandra Jansen - Amsterdam University Medical Centers
Quinten Waisfisz - Amsterdam University Medical Centers
Hugoline de Haan - Amsterdam University Medical Centers
Simon Sadedin - Murdoch Children's Research Institute
Sze Chern Lim - Murdoch Children's Research Institute
Susan White - University of Melbourne
David Ascher - University of Cambridge
Annette Schenck - Radboud University Medical Center
Paul Lockhart - Murdoch Children's Research Institute
John Christodoulou - University of Melbourne
Tiong Yang Tan - Victorian Clinical Genetics Services
Publication Details: American Journal of Human Genetics, Vol.109(4), pp.601-617
Identifiers: 9933882509311
Academic Unit: Institut des Neurosciences de Montpellier - INM
Language: English
Resource Type: Journal article
Local Fields: inserm-04957364