Browsing by Author "Wentzensen, Ingrid M."

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    Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum
    (Elsevier, 2020-09-03) Motta, Marialetizia; Pannone, Luca; Pantaleoni, Francesca; Bocchinfuso, Gianfranco; Radio, Francesca Clementina; Cecchetti, Serena; Ciolfi, Andrea; Di Rocco, Martina; Elting, Mariet W.; Brilstra, Eva H.; Boni, Stefania; Mazzanti, Laura; Tamburrino, Federica; Walsh, Larry; Payne, Katelyn; Fernández-Jaén, Alberto; Ganapathi, Mythily; Chung, Wendy K.; Grange, Dorothy K.; Dave-Wala, Ashita; Reshmi, Shalini C.; Bartholomew, Dennis W.; Mouhlas, Danielle; Carpentieri, Giovanna; Bruselles, Alessandro; Pizzi, Simone; Bellacchio, Emanuele; Piceci-Sparascio, Francesca; Lißewski, Christina; Brinkmann, Julia; Waclaw, Ronald R.; Waisfisz, Quinten; van Gassen, Koen; Wentzensen, Ingrid M.; Morrow, Michelle M.; Álvarez, Sara; Martínez-García, Mónica; De Luca, Alessandro; Memo, Luigi; Zampino, Giuseppe; Rossi, Cesare; Seri, Marco; Gelb, Bruce D.; Zenker, Martin; Dallapiccola, Bruno; Stella, Lorenzo; Prada, Carlos E.; Martinelli, Simone; Flex, Elisabetta; Tartaglia, Marco; Medical and Molecular Genetics, School of Medicine
    Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies.
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    Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome
    (Elsevier, 2022) 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; Zeev, Bruria Ben; Barel, Ortal; Moutton, Sebastien; Morice-Picard, Fanny; Carmignac, Virginie; Cornaton, Jenny; Marle, Nathalie; Devinsky, Orrin; Stimach, Chandler; Burns Wechsler, Stephanie; 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; Suk-Ying Goh, Elaine; 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; Medical and Molecular Genetics, School of Medicine
    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.
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    Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia
    (Elsevier, 2021-05) Muir, Alison M.; Gardner, Jennifer F.; van Jaarsveld, Richard H.; de Lange, Iris M.; van der Smagt, Jasper J.; Wilson, Golder N.; Dubbs, Holly; Goldberg, Ethan M.; Zitano, Lia; Bupp, Caleb; Martinez, Jose; Srour, Myriam; Accogli, Andrea; Alhakeem, Afnan; Meltzer, Meira; Gropman, Andrea; Brewer, Carole; Caswell, Richard C.; Montgomery, Tara; McKenna, Caoimhe; McKee, Shane; Powell, Corinna; Vasudevan, Pradeep C.; Brady, Angela F.; Joss, Shelagh; Tysoe, Carolyn; Noh, Grace; Tarnopolsky, Mark; Brady, Lauren; Zafar, Muhammad; Schrier Vergano, Samantha A.; Murray, Brianna; Sawyer, Lindsey; Hainline, Bryan E.; Sapp, Katherine; DeMarzo, Danielle; Huismann, Darcy J.; Wentzensen, Ingrid M.; Schnur, Rhonda E.; Monaghan, Kristin G.; Juusola, Jane; Rhodes, Lindsay; Dobyns, William B.; Lecoquierre, Francois; Goldenberg, Alice; Polster, Tilman; Axer-Schaefer, Susanne; Platzer, Konrad; Klöckner, Chiara; Hoffman, Trevor L.; MacArthur, Daniel G.; O'Leary, Melanie C.; VanNoy, Grace E.; England, Eleina; Varghese, Vinod C.; Mefford, Heather C.; Medical and Molecular Genetics, School of Medicine
    Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.