Speaker
Description
SUMOylation pathway is a post-translational modification process that regulates the function of hundreds of proteins by SUMO protein attachment. This three-step pathway requires activation of SUMO proteins by the E1 enzyme, transfer to the E2 conjugating enzyme and SUMO-protein ligation directly or through E3 ligase. Defects in SUMOylation are being linked to abnormal neuronal development and synaptic function. This study focuses on UBE2I, which encodes the sole human E2 enzyme (UBC9); the goal is to evaluate the role of UBE2I in neurodevelopmental disorders (NDDs). Trio-exome sequencing of a cohort of >600 NDD families led to the identification of a de novo (dn) missense variant in UBE2I [NM_194260.3:p.(Asn124Ile)] in a pediatric patient with a syndromic phenotype. In GeneMatcher, we found three further NDD patients harboring UBE2I variants (p.Val25Met dn; p.Trp53Leu dn; p.Glu143Gly). All have shared clinical features, such as neurodevelopmental delay, hypertelorism/telecanthus, almond-shaped eyes, thick eyebrows, and hand anomalies. All variants are absent in GnomAD ver 4.0. The substituted amino acids are evolutionarily conserved from C.elegans to humans and the changes are predicted to be highly damaging by multiple bioinformatic tools (CADD ≥26). All variants destabilize protein structure according to 3D modelling predictions (ΔΔG ≤ 0.5 kcal/mol). When stable cell lines expressing either WT or variant UBC9-mCherry fusion proteins were analyzed by western blot and flow cytometry, expression of the UBC9 variants was found to be reduced by ⁓50% with respect to WT. Proteasome inhibition significantly restored expression of the UBC9 variant proteins, indicating they likely destabilize protein structure, leading to proteasomal degradation. Moreover, reduced UBC9 expression was observed in one patient’s lymphoblastic line, corroborating the results obtained before.
In conclusion, we propose that UBE2I be considered as a candidate gene for a novel NDD, a finding that will provide insights into the role of SUMOylation in brain function and development.
| Author(s) | Verdiana Pullano*1, Slavica Trajkova1, Alessandra Aulino1, Matteo Rossi Sebastiano2, Elena Sukarova-Angelovska3, Erika Ortolan4, Henrike Sczakiel5,6, Susan Hiatt7, Anna C.E. Hurst8, Benjamin Cogne9,10, Isidor Bertrand9,10, Karishma Bakshi11, Andrea Pichler11,12, Tommaso Pippucci13, Paola Dimartino14, Simona Cardaropoli15, Roberto Piva16, Enza Ferrero4, Alessandro Mussa15, Silvia De Rubeis17, Joseph Buxbaum17, Giovanni Battista Ferrero18, Alfredo Brusco1 |
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| Affiliation(s) | "1) Department of Neurosciences Rita Levi-Montalcini, University of Turin, Turin, Italy, 2) Department of Molecular Biotechnology and Health Sciences, University of Turin, MedChemBeyondLab, Turin, Italy, 3) University Clinic for Children's Diseases, Faculty of Medicine, University ""Sv. Kiril I Metodij"" , Department of Endocrinology and Genetics, Skopje, Macedonia, 4) Department of Medical Sciences, University of Turin, Turin, Italy 5) Institute of Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, 6) BIH Biomedical Innovation Academy, Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany, 7) HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States, 8) Department of Genetics, University of Alabama, Birmingham, AL, United States, 9) Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, 10) Université de Nantes, Inserm UMR 1087 / CNRS UMR 6291, Institut du thorax, Nantes, France, 11) Institute of Biochemistry, ETH Zürich , Zürich, Switzerland, 12) Max Planck Institute of Immunobiology and Epigenetics, Department of Epigenetics, Freiburg, Germany, 13) IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy, 14) Department of Molecular Medicine, University of Pavia, Pavia, Italy, 15) Department of Public Health and Pediatrics, University of Turin, Turin, Italy, 16) Department of Molecular Biotechnology and Health Sciences, University of Turin Turin, Italy, 17) Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, United States, 18) Department of Clinical and Biological Sciences, University of Turin, Turin, Italy," |
