Browsing by Author "Prada, Carlos E."

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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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    Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15
    (Oxford University Press, 2019-05-01) Cheng, Hanyin; Gottlieb, Leah; Marchi, Elaine; Kleyner, Robert; Bhardwaj, Puja; Rope, Alan F.; Rosenheck, Sarah; Moutton, Sébastien; Philippe, Christophe; Eyaid, Wafaa; Alkuraya, Fowzan S.; Toribio, Janet; Mena, Rafael; Prada, Carlos E.; Stessman, Holly; Bernier, Raphael; Wermuth, Marieke; Kauffmann, Birgit; Blaumeiser, Bettina; Kooy, R Frank; Baralle, Diana; Mancini, Grazia M. S.; Conway, Simon J.; Xia, Fan; Chen, Zhao; Meng, Linyan; Mihajlovic, Ljubisa; Marmorstein, Ronen; Lyon, Gholson J.; Pediatrics, School of Medicine
    N-alpha-acetylation is one of the most common co-translational protein modifications in humans and is essential for normal cell function. NAA10 encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. The auxiliary and regulatory subunits of the NatA complex are NAA15 and Huntington-interacting protein (HYPK), respectively. Through a genotype-first approach with exome sequencing, we identified and phenotypically characterized 30 individuals from 30 unrelated families with 17 different de novo or inherited, dominantly acting missense variants in NAA10 or NAA15. Clinical features of affected individuals include variable levels of intellectual disability, delayed speech and motor milestones and autism spectrum disorder. Additionally, some subjects present with mild craniofacial dysmorphology, congenital cardiac anomalies and seizures. One of the individuals is an 11-year-old boy with a frameshift variant in exon 7 of NAA10, who presents most notably with microphthalmia, which confirms a prior finding with a single family with Lenz microphthalmia syndrome. Biochemical analyses of variants as part of the human NatA complex, as well as enzymatic analyses with and without the HYPK regulatory subunit, help to explain some of the phenotypic differences seen among the different variants.
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    Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15
    (Oxford University Press, 2020-03-27) Cheng, Hanyin; Gottlieb, Leah; Marchi, Elaine; Kleyner, Robert; Bhardwaj, Puja; Rope, Alan F.; Rosenheck, Sarah; Moutton, Sébastien; Philippe, Christophe; Eyaid, Wafaa; Alkuraya, Fowzan S.; Toribio, Janet; Mena, Rafael; Prada, Carlos E.; Stessman, Holly; Bernier, Raphael; Wermuth, Marieke; Kauffmann, Birgit; Blaumeiser, Bettina; Kooy, R. Frank; Baralle, Diana; Mancini, Grazia M. S.; Conway, Simon J.; Xia, Fan; Chen, Zhao; Meng, Linyan; Mihajlovic, Ljubisa; Marmorstein, Ronen; Lyon, Gholson J.; Medicine, School of Medicine
    In the original version of this article, Ezzat El-Akkad’s name was misspelled in the acknowledgements section; this has now been corrected. The authors apologize for this error.