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Your search keyword '"Klaus Schmitz-Abe"' showing total 5 results
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5 results on '"Klaus Schmitz-Abe"'

1. Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6

Author

Safa Baris, Mehdi Benamar, Qian Chen, Mehmet Cihangir Catak, Mónica Martínez-Blanco, Muyun Wang, Jason Fong, Michel J. Massaad, Asena Pinar Sefer, Altan Kara, Royala Babayeva, Sevgi Bilgic Eltan, Ayse Deniz Yucelten, Emine Bozkurtlar, Leyla Cinel, Elif Karakoc-Aydiner, Yumei Zheng, Hao Wu, Ahmet Ozen, Klaus Schmitz-Abe, Talal A. Chatila, and BARIŞ S., Benamar M., Chen Q., Catak M. C., Martínez-Blanco M., Wang M., Fong J., Massaad M. J., Sefer A. P., Kara A., et al.

Subjects
Immunology, Life Sciences (LIFE), Sağlık Bilimleri, gain-of-function mutation, Clinical Medicine (MED), Yaşam Bilimleri, Health Sciences, ALERJİ, Immunology and Allergy, Klinik Tıp (MED), primary atopic disorders, Jakinibs, STAT6, Janus kinase inhibitors, Klinik Tıp, İmmünoloji, Temel Bilimler, Life Sciences, Inborn errors of immunity, CLINICAL MEDICINE, Tıp, ALLERGY, Yaşam Bilimleri (LIFE), Medicine, İmmünoloji ve Alerji, Natural Sciences
Abstract

Background: Inborn errors of immunity have been implicated in causing immune dysregulation, including allergic diseases. STAT6 is a key regulator of allergic responses. Objectives: This study sought to characterize a novel gain-of-function STAT6 mutation identified in a child with severe allergic manifestations. Methods: Whole-exome and targeted gene sequencing, lymphocyte characterization, and molecular and functional analyses of mutated STAT6 were performed. Results: This study reports a child with a missense mutation in the DNA binding domain of STAT6 (c.1114G>A, p.E372K) who presented with severe atopic dermatitis, eosinophilia, and elevated IgE. Naive lymphocytes from the affected patient displayed increased TH2- and suppressed TH1- and TH17-cell responses. The mutation augmented both basal and cytokine-induced STAT6 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reversed STAT6 hyperresponsiveness to IL-4, normalized TH1 and TH17 cells, suppressed the eosinophilia, and improved the patient\"s atopic dermatitis. Conclusions: This study identified a novel inborn error of immunity due to a STAT6 gain-of-function mutation that gave rise to severe allergic dysregulation. Janus kinase inhibitor therapy could represent an effective targeted treatment for this disorder.

Published
2023

2. De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation

Author

Dongxue Mao, Chloe M. Reuter, Maura R.Z. Ruzhnikov, Anita E. Beck, Emily G. Farrow, Lisa T. Emrick, Jill A. Rosenfeld, Katherine M. Mackenzie, Laurie Robak, Matthew T. Wheeler, Lindsay C. Burrage, Mahim Jain, Pengfei Liu, Daniel Calame, Sébastien Küry, Martin Sillesen, Klaus Schmitz-Abe, Davide Tonduti, Luigina Spaccini, Maria Iascone, Casie A. Genetti, Mary K. Koenig, Madeline Graf, Alyssa Tran, Mercedes Alejandro, Brendan H. Lee, Isabelle Thiffault, Pankaj B. Agrawal, Jonathan A. Bernstein, Hugo J. Bellen, Hsiao-Tuan Chao, Maria T. Acosta, Margaret Adam, David R. Adams, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Raphael Bernier, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Lauren C. Briere, Elly Brokamp, Elizabeth A. Burke, Manish J. Butte, Peter Byers, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Yong-hui Jiang, Jean M. Johnston, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Kimberly LeBlanc, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Genecee Renteria, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Monte Westerfield, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Stephan Zuchner

Subjects
Male, 0301 basic medicine, Proband, Ataxia, Adolescent, Developmental Disabilities, Nervous System Malformations, Leukoencephalopathy, eIF-2 Kinase, 03 medical and health sciences, 0302 clinical medicine, Leukoencephalopathies, Report, Genetics, medicine, Humans, Missense mutation, Kinase activity, Child, Genetics (clinical), biology, Leukodystrophy, Genetic Variation, Infant, medicine.disease, White Matter, Hypotonia, Hereditary Central Nervous System Demyelinating Diseases, 030104 developmental biology, Child, Preschool, eIF2B, Immunology, biology.protein, Female, medicine.symptom, 030217 neurology & neurosurgery
Abstract

EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.

Published
2020

3. Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections

Author

Fatma Betul Oktelik, Qian Chen, Metin Yusuf Gelmez, Mehdi Benamar, Ayca Kiykim, Ye Cui, Jason Jun Hung Fong, Achille Broggi, Jonathan Z. Li, Sreya Ghosh, Peggy S. Lai, Hani Harb, Murat Kose, Esin Aktas Cetin, Paola Contini, Jason W. Griffith, Ivan Zanoni, Talal A. Chatila, Lorenzo Berra, Elena Crestani, Ziwei Wang, Novalia Pishesha, Klaus Schmitz-Abe, Louis-Marie Charbonnier, Raffaele De Palma, Günnur Deniz, Gilberto Filaci, Emmanuel Stephen-Victor, Stephen C. Kolifrath, Xu G. Yu, Luca Marri, Hidde L. Ploegh, Genny Del Zotto, Boston Childrens Hosp, Division Immunology, Harvard Med Sch, Department pediatric, Massachusetts General Hospital, Div Pulm & Crit Care, Harvard Medical School - department medical, University Genoa, Dept Internal Medical, IRCCS Ospedale Policlinico San Martino [Genoa, Italy], IRCCS Istituto Giannina Gaslini [Genoa, Italy], Boston Childrens Hospital, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Istanbul Univ, Aziz Sancar Inst Expt Med Aziz Sancar DETAE, Istanbul Univ Cerrahpasa, Fac Med, Div Pediat Allergy & Immunol, Istanbul Univ, Fac Med, Dept Internal Med, Massachusetts Institute of Technology (MIT), Harvard Medical School [Boston] (HMS), and DUMENIL, Anita

Subjects
0301 basic medicine, Il-6, Survival, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Severity of Illness Index, T-Lymphocytes, Regulatory, regulatory T cells, Mice, 0302 clinical medicine, Immunology and Allergy, Receptor, Notch4, Lung, ComputingMilieux_MISCELLANEOUS, Influenza-Virus, Immunity, Cellular, Protection, Immunohistochemistry, [SDV] Life Sciences [q-bio], Infectious Diseases, medicine.anatomical_structure, Cytokine, Influenza A virus, 030220 oncology & carcinogenesis, Host-Pathogen Interactions, Cytokines, Interleukin 18, Disease Susceptibility, amphiregulin, Inflammation Mediators, medicine.symptom, influenza, IL-18, Signal Transduction, Regulatory T cell, Pneumonia, Viral, Immunology, Activation, Mice, Transgenic, Inflammation, Biology, Amphiregulin, Article, Virus, Immunomodulation, 03 medical and health sciences, medicine, Animals, Humans, Interleukin 6, IL-6, Innate immune system, SARS-CoV-2, Notch4, Immunity, COVID-19, Disease Models, Animal, 030104 developmental biology, biology.protein, Biomarkers
Abstract

A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections., Graphical abstract, Harb, Benamar, et al. find that interleukin-6 increases Notch4 expression on lung regulatory T cells, which, in turn, restrains production of the tissue repair cytokine amphiregulin and promotes severe lung inflammation. Their findings have implications for treatment of COVID-19 and other respiratory viral infections.

Published
2021

4. LARS2 variations can cause lethal infantile multisystem failure

Author

Mark D. Fleming, Sandra T. Cooper, Kyriacos Markianos, Carolyn M. Sue, Joëlle Rudinger-Thirion, John Christodoulou, Lisa G. Riley, Susan Arbuckle, Ryan L. Davis, Magali Frugier, Klaus Schmitz-Abe, Juliana Teo, and David R. Thorburn

Subjects
Molecular Medicine, Cell Biology, Molecular Biology
Published
2015

5. P.9.5 A novel NEFL gene mutation is identified in a family diagnosed with Nemaline Myopathy

Author

Mugdha Joshi, Klaus Schmitz-Abe, Kyriacos Markianos, U. De Girolami, P.D. Ciarlini, Nicholas S. Marinakis, Alan H. Beggs, and Pankaj B. Agrawal

Subjects
Genetics, Sanger sequencing, Mutation, Gene mutation, Biology, medicine.disease, medicine.disease_cause, Molecular biology, Neurofilament Light Polypeptide, symbols.namesake, Nemaline myopathy, Neurology, Pediatrics, Perinatology and Child Health, medicine, symbols, Missense mutation, Neurology (clinical), medicine.symptom, Myopathy, Exome, Genetics (clinical)
Abstract

We describe a family of four members (a mother and her three sons) diagnosed with a skeletal muscle disease with biopsy findings consistent with nemaline myopathy (NM) in two, one with non-specific myopathy and one with neurogenic atrophy and myopathic features. Interestingly, some of the clinico-pathological findings were consistent with involvement of the peripheral nerves. Sanger sequencing did not identify a pathogenic mutation in genes associated with NM. Given the atypical presentation not attributable to a known NM gene, linkage analysis was performed on DNA samples from the four affected members along with whole genome sequencing (WGS) on mother’s DNA (proband). On bioinformatic analysis, she was identified to carry a heterozygous mutation c.1261C>T in the NEFL gene predicted to cause premature termination of the transcript and a truncated neurofilament light polypeptide protein (p.R421X). This mutation was not present in dbSNP Build 137 or Exome variant server, Washington University, and it was confirmed to be present in all the four affected members of the family by Sanger sequencing. Further, Autosomal dominant mutations in NEFL are associated with Charcot–Marie–Tooth (CMT) disease, subtypes CMT2E/CMT1F. Most of the pathogenic NEFL mutations are missense changes postulated to cause dominant negative effects. Quantitative real-time PCR was performed on cDNA, extracted from muscle samples from an affected family member and an age-matched control, and the mutant transcript was found to be stable. We hypothesize that the mutant transcript does not undergo nonsense-mediated decay, thereby encoding a truncated protein that interferes with the function of the wild type NEFL protein. Further work is underway to understand the molecular basis of the disease. This finding further expands the spectrum of NEFL mutation-associated phenotypes to NM.

Published
2013

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