American journal of human genetics · 2022

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

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

Аннотация

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.

Предметные рубрики MeSH

F-Box-WD Repeat-Containing Protein 7 Germ Cells Germ-Line Mutation Humans Neurodevelopmental Disorders Proteasome Endopeptidase Complex Ubiquitin-Protein Ligases Ubiquitination

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

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Аннотация

Предметные рубрики MeSH