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2. Erratum

Author

Korff, Ane, Yang, Xiaojing, O'Donovan, Kevin, Gonzalez, Abner, Teubner, Brett J.W., Nakamura, Haruko, Messing, James, Yang, Fen, Carisey, Alexandre F., Wang, Yong-Dong, Patni, Tushar, Sheppard, Heather, Zakharenko, Stanislav S., Chook, Yuh Min, Taylor, J. Paul, and Kim, Hong Joo

Subjects
Health care industry
Abstract

Original citation: J Clin Invest. 2023;133(14):e160309. https://doi.org/10.1172/JCI160309. Citation for this erratum: J Clin Invest. 2024;134(8):e181331. https://doi.org/10.1172/JCI181331. During the preparation of this manuscript, a text error was introduced during copyediting by [...]

Published
2024
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3. Sonic Hedgehog activates prostaglandin signaling to stabilize primary cilium length

Author

Ansari, Shariq S., primary, Dillard, Miriam E., additional, Zhang, Yan, additional, Austria, Mary Ashley, additional, Boatwright, Naoko, additional, Shelton, Elaine L., additional, Stewart, Daniel P., additional, Johnson, Amanda, additional, Wang, Christina E., additional, Young, Brandon M., additional, Rankovic, Zoran, additional, Hansen, Baranda S., additional, Pruett-Miller, Shondra M., additional, Carisey, Alexandre F., additional, Schuetz, John D., additional, Robinson, Camenzind G., additional, and Ogden, Stacey K., additional

Published
2024
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4. A murine model of hnRNPH2-related neurodevelopmental disorder reveals a mechanism for genetic compensation by Hnrnph1

Author

Korff, Ane, primary, Yang, Xiaojing, additional, O’Donovan, Kevin, additional, Gonzalez, Abner, additional, Teubner, Brett J.W., additional, Nakamura, Haruko, additional, Messing, James, additional, Yang, Fen, additional, Carisey, Alexandre F., additional, Wang, Yong-Dong, additional, Patni, Tushar, additional, Sheppard, Heather, additional, Zakharenko, Stanislav S., additional, Chook, Yuh Min, additional, Taylor, J. Paul, additional, and Kim, Hong Joo, additional

Published
2024
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6. Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome

Author

Poli, M. Cecilia, Ebstein, Frédéric, Nicholas, Sarah K., de Guzman, Marietta M., Forbes, Lisa R., Chinn, Ivan K., Mace, Emily M., Vogel, Tiphanie P., Carisey, Alexandre F., Benavides, Felipe, Coban-Akdemir, Zeynep H., Gibbs, Richard A., Jhangiani, Shalini N., Muzny, Donna M., Carvalho, Claudia M.B., Schady, Deborah A., Jain, Mahim, Rosenfeld, Jill A., Emrick, Lisa, Lewis, Richard A., Lee, Brendan, Zieba, Barbara A., Küry, Sébastien, Krüger, Elke, Lupski, James R., Bostwick, Bret L., and Orange, Jordan S.

Published
2018
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8. A murine model of hnRNPH2-related neurodevelopmental disorder reveals a mechanism for genetic compensation by Hnrnph1

Author

Korff, Ane, primary, Yang, Xiaojing, additional, O’Donovan, Kevin, additional, Gonzalez, Abner, additional, Teubner, Brett J.W., additional, Nakamura, Haruko, additional, Messing, James, additional, Yang, Fen, additional, Carisey, Alexandre F., additional, Wang, Yong-Dong, additional, Patni, Tushar, additional, Sheppard, Heather, additional, Zakharenko, Stanislav S., additional, Chook, Yuh Min, additional, Taylor, J. Paul, additional, and Kim, Hong Joo, additional

Published
2023
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12. A Versatile Oblique Plane Microscope for Large-Scale and High-Resolution Imaging of Subcellular Dynamics - Public Data

Author

Sapoznik, Etai, Chang, Bo-Jui, Huh, Jaewon, Ju, Robert, Azarova, Evgenia V., Pohlkamp, Theresa, Welf, Erik S., Broadbent, David, Carisey, Alexandre F., Stehbens, Samantha J., Lee, Kyung-Min, Marin, Arnoldo, Hanker, Ariella B., Schmidt, Jens C., Arteaga, Carlos L., Yang, Bin, Koboyashi, Yoshihiko, Tata, Purushothama R., Kruithoff, Rory, Doubrovinski, Konstantin, Shepherd, Doug P., York, Andrew G., Millet-Sikking, Alfred, Dean, Kevin M., and Fiolka, Reto P.

Subjects
Selective plane illumination microscopy, Light-sheet microscopy, Oblique plane microscopy
Abstract

We present an Oblique Plane Microscope that uses a bespoke glass-tipped tertiary objective to improve the resolution, field of view, and usability over previous variants. Owing to its high numerical aperture optics, this microscope achieves lateral and axial resolutions that are comparable to the square illumination mode of Lattice Light-Sheet Microscopy, but in a user friendly and versatile format. Given this performance, we demonstrate high-resolution imaging of clathrin-mediated endocytosis, vimentin, the endoplasmic reticulum, membrane dynamics, and Natural Killer-mediated cytotoxicity. Furthermore, we image biological phenomena that would be otherwise challenging or impossible to perform in a traditional light-sheet microscope geometry, including cell migration through confined spaces within a microfluidic device, subcellular photoactivation of Rac1, diffusion of cytoplasmic rheological tracers at a volumetric rate of 14 Hz, and large field of view imaging of neurons, developing embryos, and centimeter-scale tissue sections.

Published
2020
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13. A Single-Objective Light-Sheet Microscope with 200 nm-Scale Resolution

Author

Sapoznik, Etai, Chang, Bo-Jui, Ju, Robert J., Welf, Erik S., Broadbent, David, Carisey, Alexandre F., Stehbens, Samantha J., Lee, Kyung-min, Marín, Arnaldo, Hanker, Ariella B., Schmidt, Jens C., Arteaga, Carlos L., Yang, Bin, Kruithoff, Rory, Shepherd, Doug P., Millett-Sikking, Alfred, York, Andrew G., Dean, Kevin M., and Fiolka, Reto

Abstract

We present a single-objective light-sheet microscope, also known as an oblique-plane microscope, that uses a bespoke glass-tipped tertiary objective and improves the resolution, field of view, usability, and stability over previous variants. Owing to its high numerical aperture optics, this microscope achieves the highest lateral resolution in light-sheet fluorescence microscopy, and its axial resolution is similar to that of Lattice Light-Sheet Microscopy. Given this performance, we demonstrate high-resolution imaging of clathrin-mediated endocytosis, vimentin, the endoplasmic reticulum, membrane dynamics, and natural killer cell-mediated cell death. Furthermore, we image biological phenomena that would be otherwise challenging or impossible to perform in a traditional light-sheet microscope geometry, including cell migration through a confined space within a microfluidic device, photoactivation of PI3K, and diffusion of cytoplasmic rheological tracers at a volumetric rate of 14 Hz.

Published
2020
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14. A versatile oblique plane microscope for large-scale and high-resolution imaging of subcellular dynamics

Author

Sapoznik, Etai, primary, Chang, Bo-Jui, additional, Huh, Jaewon, additional, Ju, Robert J, additional, Azarova, Evgenia V, additional, Pohlkamp, Theresa, additional, Welf, Erik S, additional, Broadbent, David, additional, Carisey, Alexandre F, additional, Stehbens, Samantha J, additional, Lee, Kyung-Min, additional, Marín, Arnaldo, additional, Hanker, Ariella B, additional, Schmidt, Jens C, additional, Arteaga, Carlos L, additional, Yang, Bin, additional, Kobayashi, Yoshihiko, additional, Tata, Purushothama Rao, additional, Kruithoff, Rory, additional, Doubrovinski, Konstantin, additional, Shepherd, Douglas P, additional, Millett-Sikking, Alfred, additional, York, Andrew G, additional, Dean, Kevin M, additional, and Fiolka, Reto P, additional

Published
2020
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16. A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function

Author

Lam, M. T., Coppola, S., Krumbach, O. H. F., Prencipe, G., Insalaco, A., Cifaldi, C., Brigida, I., Zara, E., Scala, S., Di Cesare, S., Martinelli, S., Di Rocco, M., Pascarella, A., Niceta, M., Pantaleoni, F., Ciolfi, A., Netter, P., Carisey, A. F., Diehl, M., Akbarzadeh, M., Cont, F., Merli, P., Pastore, A., Mortera, S. L., Camerini, S., Farina, L., Buchholzer, M., Pannone, L., Cao, T. N., Coban-Akdemir, Z. H., Jhangiani, S. N., Muzny, D. M., Gibbs, R. A., Basso-Ricci, L., Chiriaco, M., Dvorsky, R., Putignani, L., Carsetti, R., Janning, P., Stray-Pedersen, A., Erichsen, H. C., Horne, A. C., Bryceson, Y. T., Torralba-Raga, L., Ramme, K., Rosti, V., Bracaglia, C., Messia, V., Palma, P., Finocchi, A., Locatelli, Franco, Chinn, I. K., Lupski, J. R., Mace, E. M., Cancrini, C., Aiuti, A., Ahmadian, M. R., Orange, J. S., De Benedetti, F., Tartaglia, M., Locatelli F. (ORCID:0000-0002-7976-3654), Lam, M. T., Coppola, S., Krumbach, O. H. F., Prencipe, G., Insalaco, A., Cifaldi, C., Brigida, I., Zara, E., Scala, S., Di Cesare, S., Martinelli, S., Di Rocco, M., Pascarella, A., Niceta, M., Pantaleoni, F., Ciolfi, A., Netter, P., Carisey, A. F., Diehl, M., Akbarzadeh, M., Cont, F., Merli, P., Pastore, A., Mortera, S. L., Camerini, S., Farina, L., Buchholzer, M., Pannone, L., Cao, T. N., Coban-Akdemir, Z. H., Jhangiani, S. N., Muzny, D. M., Gibbs, R. A., Basso-Ricci, L., Chiriaco, M., Dvorsky, R., Putignani, L., Carsetti, R., Janning, P., Stray-Pedersen, A., Erichsen, H. C., Horne, A. C., Bryceson, Y. T., Torralba-Raga, L., Ramme, K., Rosti, V., Bracaglia, C., Messia, V., Palma, P., Finocchi, A., Locatelli, Franco, Chinn, I. K., Lupski, J. R., Mace, E. M., Cancrini, C., Aiuti, A., Ahmadian, M. R., Orange, J. S., De Benedetti, F., Tartaglia, M., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. CDC42 mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival.

Published
2019

17. A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function

Author

Lam, Michael T., primary, Coppola, Simona, additional, Krumbach, Oliver H.F., additional, Prencipe, Giusi, additional, Insalaco, Antonella, additional, Cifaldi, Cristina, additional, Brigida, Immacolata, additional, Zara, Erika, additional, Scala, Serena, additional, Di Cesare, Silvia, additional, Martinelli, Simone, additional, Di Rocco, Martina, additional, Pascarella, Antonia, additional, Niceta, Marcello, additional, Pantaleoni, Francesca, additional, Ciolfi, Andrea, additional, Netter, Petra, additional, Carisey, Alexandre F., additional, Diehl, Michael, additional, Akbarzadeh, Mohammad, additional, Conti, Francesca, additional, Merli, Pietro, additional, Pastore, Anna, additional, Levi Mortera, Stefano, additional, Camerini, Serena, additional, Farina, Luciapia, additional, Buchholzer, Marcel, additional, Pannone, Luca, additional, Cao, Tram N., additional, Coban-Akdemir, Zeynep H., additional, Jhangiani, Shalini N., additional, Muzny, Donna M., additional, Gibbs, Richard A., additional, Basso-Ricci, Luca, additional, Chiriaco, Maria, additional, Dvorsky, Radovan, additional, Putignani, Lorenza, additional, Carsetti, Rita, additional, Janning, Petra, additional, Stray-Pedersen, Asbjorg, additional, Erichsen, Hans Christian, additional, Horne, AnnaCarin, additional, Bryceson, Yenan T., additional, Torralba-Raga, Lamberto, additional, Ramme, Kim, additional, Rosti, Vittorio, additional, Bracaglia, Claudia, additional, Messia, Virginia, additional, Palma, Paolo, additional, Finocchi, Andrea, additional, Locatelli, Franco, additional, Chinn, Ivan K., additional, Lupski, James R., additional, Mace, Emily M., additional, Cancrini, Caterina, additional, Aiuti, Alessandro, additional, Ahmadian, Mohammad R., additional, Orange, Jordan S., additional, De Benedetti, Fabrizio, additional, and Tartaglia, Marco, additional

Published
2019
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18. Nanoscale Dynamism of Actin Enables Secretory Function in Cytolytic Cells

Author

Carisey, Alexandre F, Mace, Emily M, Saeed, Mezida, Davis, Daniel M, Orange, Jordan S, Carisey, Alexandre F, Mace, Emily M, Saeed, Mezida, Davis, Daniel M, and Orange, Jordan S

Abstract

Natural killer (NK) cells are innate immune effectors that lyse virally infected and tumorigenic cells through the formation of an immunological synapse. Actin remodeling at the lytic immunological synapse is a critical requirement for multiple facets of cytotoxic function. Activating receptor and integrin signaling leads to the regulated turnover and remodeling of actin, which is required for adhesion, sustained receptor signaling, and ultimately exocytosis. NK cells undergo lytic granule exocytosis in hypodense regions of a pervasive actin network. Although these requirements have been well demonstrated, neither the dynamic regulation of synaptic actin nor its specific function, however, has been determined at a nanoscale level. Here, live-cell super-resolution microscopy demonstrates nanoscale filamentous actin dynamism in NK cell lytic granule secretion. Following cell spreading, the overall content of the branched actin network at an immune synapse is stable over time and contains branched actin fibers and discrete actin foci. Similar actin architecture is generated in cytolytic T cells, although the timescale differs from that of NK cells. Individual filament displacement leads to stochastic clearance formation and disappearance, which are independent of lytic granule positioning. Actin dynamism is dependent upon branched network formation mediated by Arp2/3 and contractility generated by myosin IIA. Importantly, the use of small-molecule inhibitors demonstrates that actin dynamism is ultimately needed for granule secretion. Thus, we describe a requirement for nanoscale actin fiber rearrangement in generating the complex actin architecture that enables lytic granule secretion., QC 20240906

Published
2018
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20. NK cells converge lytic granules to promote cytotoxicity and prevent bystander killing

Author

Hsu, Hsiang-Ting, Mace, Emily M., Carisey, Alexandre F., Viswanath, Dixita I., Christakou, Athanasia, Wiklund, Martin, Önfelt, Bjorn, Orange, Jordan S., Hsu, Hsiang-Ting, Mace, Emily M., Carisey, Alexandre F., Viswanath, Dixita I., Christakou, Athanasia, Wiklund, Martin, Önfelt, Bjorn, and Orange, Jordan S.

Abstract

Natural killer (NK) cell activation triggers sequential cellular events leading to destruction of diseased cells. We previously identified lytic granule convergence, a dynein-and integrin signal-dependent movement of lysosome-related organelles to the microtubule-organizing center, as an early step in the cell biological process underlying NK cell cytotoxicity. Why lytic granules converge during NK cell cytotoxicity, however, remains unclear. We experimentally controlled the availability of human ligands to regulate NK cell signaling and promote granule convergence with either directed or nondirected degranulation. By the use of acoustic trap microscopy, we generated specific effector-target cell arrangements to define the impact of the two modes of degranulation. NK cells with converged granules had greater targeted and less nonspecific "bystander" killing. Additionally, NK cells in which dynein was inhibited or integrin blocked under physiological conditions demonstrated increased nondirected degranulation and bystander killing. Thus, NK cells converge lytic granules and thereby improve the efficiency of targeted killing and prevent collateral damage to neighboring healthy cells., QC 20170123

Published
2016
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22. Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia.

Author

Sakthivel, Dharaniya, Brown-Suedel, Alexandra N., Lopez, Karla E., Salgar, Suruchi, Coutinho, Luiza E., Keane, Francesca, Shixia Huang, Mc Sherry, Kenneth, Charendoff, Chloé I., Dunne, Kevin P., Robichaux, Dexter J., Vargas-Hernández, Alexander, Bao Chau Le, Shin, Crystal S., Carisey, Alexandre F., Poreba, Marcin, Flanagan, Jonathan M., and Bouchier-Hayes, Lisa

Subjects
*CASPASES, *ACUTE myeloid leukemia, *CELL cycle regulation, *NUCLEAR proteins, *NUCLEOPHOSMIN, *CELL cycle
Abstract

Mutation in nucleophosmin (NPM1) causes relocalization of this normally nucleolar protein to the cytoplasm (NPM1c+). Despite NPM1 mutation being the most common driver mutation in cytogenetically normal adult acute myeloid leukemia (AML), the mechanisms of NPM1c+-induced leukemogenesis remain unclear. Caspase-2 is a proapoptotic protein activated by NPM1 in the nucleolus. Here, we show that caspase-2 is also activated by NPM1c+ in the cytoplasm and DNA damage-induced apoptosis is caspase-2 dependent in NPM1c+ but not in NPM1wt AML cells. Strikingly, in NPM1c+ cells, caspase-2 loss results in profound cell cycle arrest, differentiation, and down-regulation of stem cell pathways that regulate pluripotency including impairment of the AKT/mTORC1 pathways, and inhibition of Rictor cleavage. In contrast, there were minimal differences in proliferation, differentiation, or the transcriptional profile of NPM1wt cells lacking caspase-2. Our results show that caspase-2 is essential for proliferation and self-renewal of AML cells expressing mutated NPM1. This study demonstrates that caspase-2 is a major effector of NPM1c+ function. [ABSTRACT FROM AUTHOR]

Published
2024
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23. NK cells converge lytic granules to promote cytotoxicity and prevent bystander killing.

Author

Hsiang-Ting Hsu, Mace, Emily M., Carisey, Alexandre F., Viswanath, Dixita I., Christakou, Athanasia E., Wiklund, Martin, Önfelt, Björn, and Orange, Jordan S.

Subjects
*CELL-mediated cytotoxicity, *KILLER cells, *LYSOSOMES
Abstract

Natural killer (NK) cell activation triggers sequential cellular events leading to destruction of diseased cells. We previously identified lytic granule convergence, a dynein- and integrin signal-dependent movement of lysosome-related organelles to the microtubule-organizing center, as an early step in the cell biological process underlying NK cell cytotoxicity. Why lytic granules converge during NK cell cytotoxicity, however, remains unclear. We experimentally controlled the availability of human ligands to regulate NK cell signaling and promote granule convergence with either directed or nondirected degranulation. By the use of acoustic trap microscopy, we generated specific effector-target cell arrangements to define the impact of the two modes of degranulation. NK cells with converged granules had greater targeted and less nonspecific "bystander" killing. Additionally, NK cells in which dynein was inhibited or integrin blocked under physiological conditions demonstrated increased nondirected degranulation and bystander killing. Thus, NK cells converge lytic granules and thereby improve the efficiency of targeted killing and prevent collateral damage to neighboring healthy cells. [ABSTRACT FROM AUTHOR]

Published
2016
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24. A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function

Author

Immacolata Brigida, Lamberto Torralba-Raga, Radovan Dvorsky, Silvia Di Cesare, Andrea Finocchi, AnnaCarin Horne, Ivan K. Chinn, Serena Scala, Simone Martinelli, Antonia Pascarella, Asbjørg Stray-Pedersen, Erika Zara, Marco Tartaglia, Emily M. Mace, Franco Locatelli, Luca Pannone, Stefano Levi Mortera, Claudia Bracaglia, Giusi Prencipe, Mohammad Akbarzadeh, Paolo Palma, Petra Janning, Anna Pastore, Rita Carsetti, Mohammad Reza Ahmadian, Fabrizio De Benedetti, Michael R. Diehl, Petra Netter, Shalini N. Jhangiani, Richard A. Gibbs, Caterina Cancrini, Tram N. Cao, James R. Lupski, Alexandre F. Carisey, Vittorio Rosti, Pietro Merli, Alessandro Aiuti, Zeynep H. Coban-Akdemir, Donna M. Muzny, Yenan T. Bryceson, Francesca Pantaleoni, Martina Di Rocco, Serena Camerini, Marcello Niceta, Virginia Messia, Cristina Cifaldi, Marcel Buchholzer, Andrea Ciolfi, Michael T. Lam, Hans Christian Erichsen, Antonella Insalaco, Kim Ramme, Oliver H.F. Krumbach, Francesca Conti, Luca Basso-Ricci, Simona Coppola, Jordan S. Orange, Maria Chiriaco, Lorenza Putignani, Luciapia Farina, Lam, M. T., Coppola, S., Krumbach, O. H. F., Prencipe, G., Insalaco, A., Cifaldi, C., Brigida, I., Zara, E., Scala, S., Di Cesare, S., Martinelli, S., Di Rocco, M., Pascarella, A., Niceta, M., Pantaleoni, F., Ciolfi, A., Netter, P., Carisey, A. F., Diehl, M., Akbarzadeh, M., Conti, F., Merli, P., Pastore, A., Levi Mortera, S., Camerini, S., Farina, L., Buchholzer, M., Pannone, L., Cao, T. N., Coban-Akdemir, Z. H., Jhangiani, S. N., Muzny, D. M., Gibbs, R. A., Basso-Ricci, L., Chiriaco, M., Dvorsky, R., Putignani, L., Carsetti, R., Janning, P., Stray-Pedersen, A., Erichsen, H. C., Horne, A., Bryceson, Y. T., Torralba-Raga, L., Ramme, K., Rosti, V., Bracaglia, C., Messia, V., Palma, P., Finocchi, A., Locatelli, F., Chinn, I. K., Lupski, J. R., Mace, E. M., Cancrini, C., Aiuti, A., Ahmadian, M. R., Orange, J. S., De Benedetti, F., and Tartaglia, M.

Subjects
Male, Models, Molecular, 0301 basic medicine, Molecular Conformation, medicine.disease_cause, Mice, 0302 clinical medicine, Immunology and Allergy, Child, cdc42 GTP-Binding Protein, Research Articles, Mutation, Rash, Phenotype, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Cdc42 GTP-Binding Protein, 030220 oncology & carcinogenesis, Female, Disease Susceptibility, biological phenomena, cell phenomena, and immunity, medicine.symptom, Protein Binding, HLH, Genotype, Immunology, Inflammation, macromolecular substances, Lymphohistiocytosis, Hemophagocytic, Article, 03 medical and health sciences, Immune system, Cell Line, Tumor, medicine, Animals, Humans, Alleles, Genetic Association Studies, Cytopenia, Hemophagocytic lymphohistiocytosis, Binding Sites, business.industry, Infant, Immune dysregulation, CDC42, dyshematopoiesis, inflammation, RHO-GTPase, medicine.disease, 030104 developmental biology, Amino Acid Substitution, business
Abstract

Lam et al. characterize a novel hematological/autoinflammatory disorder due to a de novo recurrent missense mutation of CDC42. The authors use in silico, in vitro, and in vivo analyses to correlate the molecular mechanisms altering CDC42 function to the observed phenotype., Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. CDC42 mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival., Graphical Abstract

Published
2019

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