Article
Biochemistry & Molecular Biology
Lucia Pia Bruno, Gabriella Doddato, Floriana Valentino, Margherita Baldassarri, Rossella Tita, Chiara Fallerini, Mirella Bruttini, Caterina Lo Rizzo, Maria Antonietta Mencarelli, Francesca Mari, Anna Maria Pinto, Francesca Fava, Alessandra Fabbiani, Vittoria Lamacchia, Anna Carrer, Valentina Caputo, Stefania Granata, Elisa Benetti, Kristina Zguro, Simone Furini, Alessandra Renieri, Francesca Ariani
Summary: Intelectual disability (ID) and autism spectrum disorder (ASD) are often associated and characterized by impairments in cognitive processes and daily life tasks. Molecular diagnosis is crucial for improving prognosis and initiating treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Rahul S. Patil, Anita Kovacs-Kasa, Boris A. Gorshkov, David J. R. Fulton, Yunchao Su, Robert K. Batori, Alexander D. Verin
Summary: Vascular barrier dysfunction, characterized by increased permeability and inflammation of endothelial cells, plays a crucial role in acute lung injury, ARDS, sepsis, and COVID-19. Ser/Thr protein phosphatases (PPases), including PP1 and PP2A, are important regulators of endothelial barrier integrity and cytoskeletal remodeling. Understanding the role of PPases in EC barrier regulation can provide insights into the development of therapeutic strategies for these lung diseases.
Article
Biochemistry & Molecular Biology
Kuriko Doi, Hiroto Takeuchi, Hiroshi Sakurai
Summary: The RB tumor suppressor protein, which is involved in cell proliferation and gene expression, is regulated by the phosphorylation state. This study reveals the role of protein phosphatase 2A (PP2A) adapter proteins IER2 and IER5 in RB dephosphorylation, which affects cell proliferation and gene expression. IER2 promotes the dephosphorylation of RB, while IER5 interacts with both RB and RB-like 1 (p107/RBL1) to enhance their dephosphorylation by PP2A.
Article
Plant Sciences
Xunlu Zhu, Guoxin Shen, Inosha Wijewardene, Yifan Cai, Nardana Esmaeili, Li Sun, Hong Zhang
Summary: Ethylene is a key plant hormone that regulates growth, development, and defense responses. The study demonstrates that PP2A-B'zeta positively regulates plant germination and seedling development, while also negatively regulating ethylene signaling pathway through interaction with CTR1. Further research is needed to fully understand the role of PP2A in ethylene responses.
PLANT PHYSIOLOGY AND BIOCHEMISTRY
(2021)
Review
Immunology
Michal Slawomir Barski, Jordan James Minnell, Goedele Noella Maertens
Summary: Protein phosphatase 2A (PP2A) is a vital cellular protein that is targeted by many viruses for their own benefit, particularly oncogenic viruses. Recent research has revealed that various viruses hijack PP2A through molecular mimicry of a B56-specific motif, highlighting potential implications for therapeutic intervention.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Editorial Material
Medicine, General & Internal
Georgeta Cardos, Nicolae Gica, Corina Gica, Anca Maria Panaitescu, Mariana Predescu, Gheorghe Peltecu, Florina Mihaela Nedelea
Summary: MCA, using DNA microarray technology, is a valuable method for diagnosing pathogenic genomic imbalances in patients with MCM, DD/ID, and ASD, with a higher resolution than the traditional G-banded karyotyping.
Article
Cell Biology
Jun Xing, Kehua Chen, Shuaiyun Gao, Melanie Pousse, Yilin Ying, Bo Wang, Lianxiang Chen, Cuicui Wang, Lei Wang, Weiguo Hu, Yiming Lu, Eric Gilson, Jing Ye
Summary: In this study, the researchers found that the relationship between cellular senescence and behavioral changes in the elderly is still unclear. They observed that aging is associated with a decline in protein phosphatase 2A (PP2A) activity in the brains of zebrafish and mice. Furthermore, drugs activating PP2A reversed age-related behavioral changes. The researchers developed a transgenic zebrafish model to decrease PP2A activity in the brain and found that mutant fish exhibited the behavioral phenotype observed in old animals and premature accumulation of neural cells positive for markers of cellular senescence.
Article
Biochemistry & Molecular Biology
Zhigang Liu, Baozhong Xin, Iris N. Smith, Valerie Sency, Julia Szekely, Anna Alkelai, Alan Shuldiner, Stephanie Efthymiou, Farrah Rajabi, Stephanie Coury, Catherine A. Brownstein, Sabine Rudnik-Schoeneborn, Ange-Line Bruel, Julien Thevenon, Shimriet Zeidler, Parul Jayakar, Axel Schmidt, Kirsten Cremer, Hartmut Engels, Sophia O. Peters, Maha S. Zaki, Ruizhi Duan, Changlian Zhu, Yiran Xu, Chao Gao, Tania Sepulveda-Morales, Reza Maroofian, Issam A. Alkhawaja, Mariam Khawaja, Hunaida Alhalasah, Henry Houlden, Jill A. Madden, Valentina Turchetti, Dana Marafi, Pankaj B. Agrawal, Ulrich Schatz, Ari Rotenberg, Joshua Rotenberg, Grazia M. S. Mancini, Somayeh Bakhtiari, Michael Kruer, Isabelle Thiffault, Steffen Hirsch, Maja Hempel, Lara G. Stuehn, Tobias B. Haack, Jennifer E. Posey, James R. Lupski, Hyunpil Lee, Nicholas B. Sarn, Charis Eng, Claudia Gonzaga-Jauregui, Bin Zhang, Heng Wang
Summary: This study identified hemizygous variants in the PPP1R3F gene associated with a novel X-linked recessive neurodevelopmental disorder. Patients with this disorder exhibit developmental delay, mild intellectual disability, neurobehavioral issues, and other neurological abnormalities. Functional studies revealed defects in PP1 binding, protein stability, subcellular localization, and glycogen metabolism regulation caused by variants in PPP1R3F.
HUMAN MOLECULAR GENETICS
(2023)
Article
Biochemistry & Molecular Biology
Xiuke Ouyang, Zhuqing Wang, Bingtong Wu, Xiuxia Yang, Bo Dong
Summary: This study demonstrates that the C-terminal of ascidian DYRK1 possesses transcriptional activation activity independent of its kinase function, and this activity can be repressed by a domain in the N-terminal. In humans, the activation and repression domains are retained in HsDYRK1A. Genes activated by HsDYRK1A are involved in ion transport and neuroactive ligand-receptor interaction. The presence of mutation sites in the C-terminal of HsDYRK1A suggests the potential involvement of its transcriptional activation ability in synaptic transmission and neuronal function related to intellectual disability syndrome.
Article
Biochemistry & Molecular Biology
Simona Amenta, Giuseppe Marangi, Daniela Orteschi, Silvia Frangella, Fiorella Gurrieri, Elisa Paccagnella, Marcello Scala, Ferruccio Romano, Valeria Capra, Vincenzo Nigro, Marcella Zollino
Summary: Loss-of-function variants in CHAMP1 cause intellectual disability, autism, and distinctive facial characteristics, possibly through haploinsufficiency or a dominant negative effect. In addition, a deletion and a missense variant in CHAMP1 are associated with borderline neurodevelopmental impairment and refractory seizures, respectively. This study suggests that loss-of-function variants in CHAMP1 lead to a severe phenotype, while haploinsufficiency may result in milder impairment and missense variants are associated with severe epileptic encephalopathy.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Neurosciences
Benedetta Kassabian, Christina Duhring Fenger, Marjolaine Willems, Angel Aledo-Serrano, Tarja Linnankivi, Pamela Pojomovsky McDonnell, Laina Lusk, Birgit Susanne Jepsen, Michael Bayat, Anja Kattentidt, Anna Abuli Vidal, Gabriel Valero-Lopez, Helena Alarcon-Martinez, Kimberly Goodspeed, Marjon van Slegtenhorst, Tahsin Stefan Barakat, Rikke S. Moller, Katrine M. Johannesen, Guido Rubboli
Summary: The phenotypic spectrum of SLC6A1-related neurodevelopmental disorders (SLC6A1-NDD) includes intellectual disability (ID), autistic spectrum disorders (ASD), epilepsy, developmental delay, and other neurological features. Our study aimed to investigate intrafamilial phenotypic variability in families with SLC6A1 variants and found that relatives presented with a less severe phenotype compared to probands.
FRONTIERS IN NEUROSCIENCE
(2023)
Article
Genetics & Heredity
Maria Asif, Maryam Anayat, Faiza Tariq, Tanzeela Noureen, Ghulam Naseer Ud Din, Christian Becker, Kerstin Becker, Holger Thiele, Ehtisham ul Haq Makhdoom, Pakeeza Arzoo Shaiq, Shahid M. Baig, Peter Nuernberg, Muhammad Sajid Hussain, Ghazala Kaukab Raja, Uzma Abdullah
Summary: Intellectual disability (ID) is a condition characterized by significant limitations in cognitive functioning and adaptive behavior, with genetic predisposition accounting for 50% of the etiology. In this study, two consanguineous Pakistani families presenting severe ID and developmental delay were recruited. Whole exome sequencing (WES) was performed on the probands and variants were prioritized based on population frequency, predicted pathogenicity, and functional relevance. Homozygous pathogenic variants in the genes MBOAT7 and TRAPPC9 were identified through WES data analysis. The pathogenicity of these variants was supported by co-segregation analysis and in silico tools. This study expands the mutation spectrum and provides additional evidence for the involvement of MBOAT7 and TRAPPC9 in the development of ID.
Review
Cell Biology
Priyanka Sandal, Chian Ju Jong, Ronald A. Merrill, Jianing Song, Stefan Strack
Summary: Mutations in subunits of the PP2A protein phosphatase have been strongly associated with neurodevelopmental disorders, impacting the structure and function of PP2A holoenzymes and contributing to the etiology of NDDs.
JOURNAL OF CELL SCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Jade J. Dyson, Fatima Abbasi, Prajakta Varadkar, Brent McCright
Summary: Knockout experiments of B56 genes suggest that individual B56 genes are not essential for mouse survival, but simultaneous inactivation of B56 delta and B56 gamma can lead to impaired heart development. This indicates a strong genetic interaction between B56 delta and B56 gamma in regulating heart development.
Article
Neurosciences
Xiaozhen Song, Wuhen Xu, Man Xiao, Yanfen Lu, Xiaoping Lan, Xiaojun Tang, Nanjie Xu, Guangjun Yu, Hong Zhang, Shengnan Wu
Summary: Pathogenic variants in the NR4A2 gene cause a neurodevelopmental disorder characterized by developmental delay, language impairment, and attention-deficit hyperactivity disorder. Two novel variants in NR4A2 were identified in two patients using whole exome sequencing. Functional analysis revealed that these variants affect protein expression and splicing differently. The study highlights the potential link between NR4A2 mutations and phenotypic variability.
FRONTIERS IN NEUROSCIENCE
(2022)
Article
Geriatrics & Gerontology
Vienna E. Brunt, Akpevweoghene P. Ikoba, Brian P. Ziemba, Dov B. Ballak, Alexander Hoischen, Charles A. Dinarello, Marissa A. Ehringer, Douglas R. Seals
Summary: The study investigates the role of interleukin (IL)-37 in biological aging in humans. They found that plasma IL-37 levels are lower in older adults, despite elevations in pro-inflammatory markers. The ratios of circulating IL-37 to pro-inflammatory markers were also considerably lower in older adults, indicating impaired IL-37 responsiveness to a pro-inflammatory state with aging. The study provides novel insights into the potential role of IL-37 in aging.
Article
Biochemistry & Molecular Biology
Bart P. G. H. van der Sanden, Gaby Schobers, Jordi Corominas Galbany, David A. Koolen, Margje Sinnema, Jeroen van Reeuwijk, Connie T. R. M. Stumpel, Tjitske Kleefstra, Bert B. A. de Vries, Martina Ruiterkamp-Versteeg, Nico Leijsten, Michael Kwint, Ronny Derks, Hilde Swinkels, Amber den Ouden, Rolph Pfundt, Tuula Rinne, Nicole de Leeuw, Alexander P. Stegmann, Servi J. Stevens, Arthur van den Wijngaard, Han G. Brunner, Helger G. Yntema, Christian Gilissen, Marcel R. Nelen, Lisenka E. L. M. Vissers
Summary: Genome sequencing (GS) is a technique that can provide novel diagnoses for patients who remain undiagnosed. In a study involving patients with neurodevelopmental disorders, GS and standard of care (SOC) had similar diagnostic yield, but GS identified two additional conclusive diagnoses and four additional possible diagnoses. GS comprehensively identified all variants in a single experiment, suggesting it is a more efficient genetic diagnostic workflow.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Genetics & Heredity
Nora Oyama, Pieter Vaneynde, Sara Reynhout, Emily M. Pao, Andrew Timms, Xiao Fan, Kimberly Foss, Rita Derua, Veerle Janssens, Wendy Chung, Ghayda M. Mirzaa
Summary: This study delineates the common features of PPP2R5D-related neurodevelopmental disorders, expands the clinical and molecular spectrum, and identifies genotype-phenotype correlations.
JOURNAL OF MEDICAL GENETICS
(2023)
Article
Genetics & Heredity
Laurens Wiel, Juliet E. Hampstead, Hanka Venselaar, Lisenka E. L. M. Vissers, Han G. Brunner, Rolph Pfundt, Gerrit Vriend, Joris A. Veltman, Christian Gilissen
Summary: We developed Meta-Domain HotSpot (MDHS) to identify mutation hotspots in protein domains and found three significantly enriched missense DNM hotspots in the ion transport protein domain family. These hotspots are associated with neurodevelopmental disorders and affect multiple genes.
AMERICAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Biochemistry & Molecular Biology
Lisa U. Teufel, Caspar van der Made, Viola Kluck, Annet Simons, Alexander Hoischen, Vivian Vernimmen, Leo A. B. Joosten, Rob J. W. Arts
Summary: A case study was conducted on a patient with a heterozygous stop-gain variant in the IL37 gene, which did not result in a clear pro-inflammatory phenotype in immune cells.
Article
Oncology
Gerben Lassche, Adriana C. H. van Engen-van Grunsven, Onno van Hooij, Tilly W. Aalders, Jetty A. M. Weijers, Emiliano Cocco, Alexander Drilon, Alexander Hoischen, Kornelia Neveling, Jack A. Schalken, Gerald W. Verhaegh, Carla M. L. van Herpen
Summary: The use of anticancer drugs targeting specific molecular tumor characteristics is increasing, but selecting patients to benefit from these treatments remains challenging. Organoid cultures have been proposed as a suitable method to test drug responses in vitro. This study presents a case of secretory carcinoma of the salivary glands with ETV6-NTRK3 gene fusion and corresponding organoid cultures. The cultures initially responded to TRK targeting therapy, but later developed resistance. This case highlights the advancements in precision oncology and the limitations of using organoids in predicting treatment response.
Article
Genetics & Heredity
Nina Ishorst, Leonie Henschel, Frederic Thieme, Dmitriy Drichel, Sugirthan Sivalingam, Sarah L. Mehrem, Ariane C. Fechtner, Julia Fazaal, Julia Welzenbach, Andre Heimbach, Carlo Maj, Oleg Borisov, Jonas Hausen, Ruth Raff, Alexander Hoischen, Michael Dixon, Alvaro Rada-Iglesias, Michaela Bartusel, Augusto Rojas-Martinez, Khalid Aldhorae, Bert Braumann, Teresa Kruse, Christian Kirschneck, Gerrit Spanier, Heiko Reutter, Stefanie Nowak, Lina Goelz, Michael Knapp, Andreas Buness, Peter Krawitz, Markus M. Noethen, Michael Nothnagel, Tim Becker, Kerstin U. Ludwig, Elisabeth Mangold
Summary: This study investigates the genetic mechanisms of nonsyndromic cleft lip with/without cleft palate (nsCL/P) and identifies new candidate genes through the detection of highly penetrant de novo variants (DNVs). By conducting a series of analyses and validations on a discovery sample of 50 nsCL/P patient/parent-trios, MDN1 and PAXIP1 were identified as top candidate genes.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2023)
Review
Neurosciences
Sandra Jansen, Lisenka E. L. M. Vissers, Bert B. A. de Vries
Summary: Intellectual disability (ID) affects around 2-3% of the general population and has significant societal impact. The identification of genetic causes for ID has traditionally been challenging, but advancements in genetic diagnostic technologies have greatly improved detection rates. This shift towards a genotype-first approach has revolutionized clinical practice.
Article
Chemistry, Medicinal
Raquel L. Arribas, Lucia Viejo, Isaac Bravo, Minerva Martinez, Eva Ramos, Alejandro Romero, Eva M. Garcia-Frutos, Veerle Janssens, Carmen Montiel, Cristobal de los Rios
Summary: Protein phosphatase 2A (PP2A) plays a crucial role in cellular processes and its deficiency is associated with severe pathologies. In Alzheimer's disease, the hyperphosphorylation of tau protein is linked to the depression of PP2A activity. Researchers have designed new ligands to prevent PP2A inhibition, with compound 10 showing the most promising outcomes.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Medicine, Research & Experimental
Jos van Pelt, Bob Meeusen, Rita Derua, Liesbeth Guffens, Eric Van Cutsem, Veerle Janssens, Chris Verslype
Summary: Pancreatic ductal adenocarcinoma (PDAC) has a low survival and little therapeutic advancements are expected. Epithelial-to-Mesenchymal transition (EMT) and Protein Phosphatase Type 2A (PP2A) play a role in aggressive PDAC. This study investigates the relationship between PP2A expression signature and EMT, and explores treatment implications.
JOURNAL OF TRANSLATIONAL MEDICINE
(2023)
Article
Multidisciplinary Sciences
Karolina Pavic, Nikhil Gupta, Judit Domenech Omella, Rita Derua, Anna Aakula, Riikka Huhtaniemi, Juha A. Maatta, Nico Hofflin, Juha Okkeri, Zhizhi Wang, Otto Kauko, Roosa Varjus, Henrik Honkanen, Daniel Abankwa, Maja Kohn, Vesa P. Hytonen, Wenqing Xu, Jakob Nilsson, Rebecca Page, Veerle Janssens, Alexander Leitner, Jukka Westermarck
Summary: This study reveals the molecular level details and structural mechanisms of PP2A-B56 alpha inhibition by the oncoprotein CIP2A. CIP2A displaces the PP2A-A subunit and forms a pseudotrimer, blocking the B56 alpha substrate binding site and stabilizing CIP2A protein.
NATURE COMMUNICATIONS
(2023)
Article
Genetics & Heredity
Janine Reurink, Nicole Weisschuh, Alejandro Garanto, Adrian Dockery, L. Ingeborgh van den Born, Isabelle Fajardy, Lonneke Haer-Wigman, Susanne Kohl, Bernd Wissinger, G. Jane Farrar, Tamar Ben-Yosef, Fatma Kivrak Pfiffner, Wolfgang Berger, Marianna E. Weener, Lubica Dudakova, Petra Liskova, Dror Sharon, Manar Salameh, Ashley Offenheim, Elise Heon, Giorgia Girotto, Paolo Gasparini, Anna Morgan, Arthur A. Bergen, Jacoline B. ten Brink, Caroline C. W. Klaver, Lisbeth Tranebjaerg, Nanna D. Rendtorff, Sascha Vermeer, Jeroen J. Smits, Ronald J. E. Pennings, Marco Aben, Jaap Oostrik, Galuh D. N. Astuti, Jordi Corominas Galbany, Hester Y. Kroes, Milan Phan, Wendy A. G. van Zelst-Stams, Alberta A. H. J. Thiadens, Joke B. G. M. Verheij, Mary J. van Schooneveld, Suzanne E. de Bruijn, Catherina H. Z. Li, Carel B. Hoyng, Christian Gilissen, Lisenka E. L. M. Vissers, Frans P. M. Cremers, Hannie Kremer, Erwin van Wijk, Susanne Roosing
Summary: Whole genome sequencing combined with an improved variant interpretation pipeline was used to assess individuals suspected of having USH2A-associated disease, leading to the identification of causative variants and providing a conclusive genetic diagnosis for rare genetic conditions.
HUMAN GENETICS AND GENOMICS ADVANCES
(2023)
Article
Biochemistry & Molecular Biology
Vani Jain, Seow Hoong Foo, Stephen Chooi, Celia Moss, Richard Goodwin, Siren Berland, Angus J. Clarke, Sally J. Davies, Sian Corrin, Oliver Murch, Samantha Doyle, Gail E. Graham, Lynn Greenhalgh, Susan E. Holder, Diana Johnson, Ajith Kumar, Roger L. Ladda, Susan Sell, Amber Begtrup, Sally A. Lynch, Emma Mccann, Rune Ostern, Caroline Pottinger, Miranda Splitt, Andrew E. Fry
Summary: Borjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. In this study, 19 individuals from 15 families carrying likely pathogenic or pathogenic PHF6 variants were analyzed. The study revealed sex-specific differences in PHF6 variant types and locations, with affected males often having missense variants or small in-frame deletions, and affected females tending to have truncating variants or large deletions/duplications. The findings further contribute to the understanding of the genetic and phenotypic spectrum of BFLS.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Immunology
Elif Cakan, Marie Dominique Ah Kioon, Yolanda Garcia-Carmona, Salome Glauzy, David Oliver, Natsuko Yamakawa, Andrea Vega Loza, Yong Du, Jean-Nicolas Schickel, Joshua M. Boeckers, Chao Yang, Alessia Baldo, Lionel B. Ivashkiv, Ryan M. Young, Louis M. Staudt, Krishna L. Moody, Kerstin Nundel, Ann Marshak-Rothstein, Caspar I. van der Made, Alexander Hoischen, Anthony Hayward, Marzia Rossato, Timothy R. D. J. Radstake, Charlotte Cunningham-Rundles, Changwan Ryu, Erica L. Herzog, Franck J. Barrat, Eric Meffre
Summary: TLR9 and CXCL4 play important roles in central B cell tolerance, with TLR9 regulating the removal of autoreactive clones and CXCL4 inhibiting TLR9 function by sequestering its ligands. The findings suggest that correcting defective TLR9 function may be a potential therapeutic strategy for restoring B cell tolerance in SSc patients.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Article
Pediatrics
Richelle A. C. M. Olde Keizer, Abderrahim Marouane, Wilhelmina Kerstjens-Frederikse, A. Chantal Deden, Klaske Lichtenbelt, Tinneke Jonckers, Marieke Vervoorn, Maaike Vreeburg, Lidewij Henneman, Linda de Vries, Richard Sinke, Rolph Pfundt, Servi J. C. Stevens, Peter Andriessen, Richard van Lingen, Marcel Nelen, Hans Scheffer, Daphne Stemkens, Cor Oosterwijk, Hans Kristian Ploos van Amstel, Willem de Boode, Wendy A. G. van Zelst-Stams, Geert W. J. Frederix, Lisenka E. L. M. Vissers
Summary: The introduction of rapid exome sequencing (rES) has improved clinical decision-making for critically ill neonates. A clinical utility study was conducted comparing rES to routine genetic testing, and the results showed that rES detected more conclusive genetic diagnoses in shorter time and reduced genetic diagnostic costs.
EUROPEAN JOURNAL OF PEDIATRICS
(2023)