@article {1003, title = {Inhibition of HECT E3 ligases as potential therapy for COVID-19.}, journal = {Cell Death Dis}, volume = {12}, year = {2021}, month = {2021 03 24}, pages = {310}, abstract = {

SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.

}, keywords = {Adult, Aged, Animals, Antiviral Agents, Chlorocebus aethiops, COVID-19, Endosomal Sorting Complexes Required for Transport, Female, Humans, Indoles, Male, Mice, Mice, Inbred BALB C, Middle Aged, Nedd4 Ubiquitin Protein Ligases, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Ubiquitin-Protein Ligases, Ubiquitination, Vero Cells}, issn = {2041-4889}, doi = {10.1038/s41419-021-03513-1}, author = {Novelli, Giuseppe and Liu, Jing and Biancolella, Michela and Alonzi, Tonino and Novelli, Antonio and Patten, J J and Cocciadiferro, Dario and Agolini, Emanuele and Colona, Vito Luigi and Rizzacasa, Barbara and Giannini, Rosalinda and Bigio, Benedetta and Goletti, Delia and Capobianchi, Maria Rosaria and Grelli, Sandro and Mann, Justin and McKee, Trevor D and Cheng, Ke and Amanat, Fatima and Krammer, Florian and Guarracino, Andrea and Pepe, Gerardo and Tomino, Carlo and Tandjaoui-Lambiotte, Yacine and Uzunhan, Yurdagul and Tubiana, Sarah and Ghosn, Jade and Notarangelo, Luigi D and Su, Helen C and Abel, Laurent and Cobat, Aurelie and Elhanan, Gai and Grzymski, Joseph J and Latini, Andrea and Sidhu, Sachdev S and Jain, Suresh and Davey, Robert A and Casanova, Jean-Laurent and Wei, Wenyi and Pandolfi, Pier Paolo} } @article {928, title = {Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 04 01}, pages = {1114-1126}, abstract = {

Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.

}, keywords = {Adolescent, Animals, Apolipoprotein C-III, Child, Child, Preschool, Developmental Disabilities, Female, Glycosylation, Humans, Loss of Function Mutation, Male, Mice, N-Acetylgalactosaminyltransferases, Pedigree, Rats, Young Adult}, issn = {1460-2156}, doi = {10.1093/brain/awaa063}, author = {Zilmer, Monica and Edmondson, Andrew C and Khetarpal, Sumeet A and Alesi, Viola and Zaki, MAH S and Rostasy, Kevin and Madsen, Camilla G and Lepri, Francesca R and Sinibaldi, Lorenzo and Cusmai, Raffaella and Novelli, Antonio and Issa, Mahmoud Y and Fenger, Christina D and Abou Jamra, Rami and Reutter, Heiko and Briuglia, Silvana and Agolini, Emanuele and Hansen, Lars and Pet{\"a}j{\"a}-Repo, Ulla E and Hintze, John and Raymond, Kimiyo M and Liedtke, Kristen and Stanley, Valentina and Musaev, Damir and Gleeson, Joseph G and Vitali, Cecilia and O{\textquoteright}Brien, W Timothy and Gardella, Elena and Rubboli, Guido and Rader, Daniel J and Schjoldager, Katrine T and M{\o}ller, Rikke S} } @article {728, title = {Pathogenic Variants in GPC4 Cause Keipert Syndrome.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 May 02}, pages = {914-924}, abstract = {

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506 and p.Glu496 were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.02.026}, author = {Amor, David J and Stephenson, Sarah E M and Mustapha, Mirna and Mensah, Martin A and Ockeloen, Charlotte W and Lee, Wei Shern and Tankard, Rick M and Phelan, Dean G and Shinawi, Marwan and de Brouwer, Arjan P M and Pfundt, Rolph and Dowling, Cari and Toler, Tomi L and Sutton, V Reid and Agolini, Emanuele and Rinelli, Martina and Capolino, Rossella and Martinelli, Diego and Zampino, Giuseppe and Dumi{\'c}, Miroslav and Reardon, William and Shaw-Smith, Charles and Leventer, Richard J and Delatycki, Martin B and Kleefstra, Tjitske and Mundlos, Stefan and Mortier, Geert and Bahlo, Melanie and Allen, Nicola J and Lockhart, Paul J} }