Researcher:
Reversade, Bruno

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Bruno

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Reversade

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Reversade, Bruno

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2017 - 2019162020 - 202326

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Researcher Of Publications: search.filters.isAuthorOfPublication.54d74fcc-8c64-4cb4-8483-9a6a28d3e680

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Now showing 1 - 10 of 42
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    Direct identification of A-to-I editing sites with nanopore native RNA sequencing
    (NATURE PORTFOLIO, 2022) Nguyen, Tram Anh; Heng, Jia Wei Joel; Kaewsapsak, Pornchai; Kok, Eng Piew Louis; Stanojevic, Dominik; Liu, Hao; Cardilla, Angelysia; Praditya, Albert; Yi, Zirong; Lin, Mingwan; Aw, Jong Ghut Ashley; Ho, Yin Ying; Peh, Kai Lay Esther; Wang, Yuanming; Zhong, Qixing; Heraud-Farlow, Jacki; Xue, Shifeng; Walkley, Carl; Ho, Ying Swan; Sikic, Mile; Wan, Yue; Tan, Meng How; N/A; Reversade, Bruno; Faculty Member; School of Medicine; 274182
    Inosine is a prevalent RNA modification in animals and is formed when an adenosine is deaminated by the ADAR family of enzymes. Traditionally, inosines are identified indirectly as variants from Illumina RNA-sequencing data because they are interpreted as guanosines by cellular machineries. However, this indirect method performs poorly in protein-coding regions where exons are typically short, in non-model organisms with sparsely annotated single-nucleotide polymorphisms, or in disease contexts where unknown DNA mutations are pervasive. Here, we show that Oxford Nanopore direct RNA sequencing can be used to identify inosine-containing sites in native transcriptomes with high accuracy. We trained convolutional neural network models to distinguish inosine from adenosine and guanosine, and to estimate the modification rate at each editing site. Furthermore, we demonstrated their utility on the transcriptomes of human, mouse and Xenopus. Our approach expands the toolkit for studying adenosine-to-inosine editing and can be further extended to investigate other RNA modifications.
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    Editorial overview: cilia in development and disease
    (Current Biology Ltd, 2019) Ingham, Philip W.; N/A; Reversade, Bruno; Faculty Member; School of Medicine; 274182
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    A deleterious recessive mutation in NUAK2 causes absence of brain in humans
    (Elsevier Science Bv, 2017) Ghosh, Kakaly; Navaratnam, Naveenan; Chan, Puck Wee; Tan, Thong Teck; Ng, Alvin Yu Jin; Tohari, Sumanty; Pomp, Oz; Venkatesh, Byrappa; Altunoglu, Umut; Bonnard, Carine; N/A; Kayserili, Hülya; Reversade, Bruno; Faculty Member; Faculty Member; School of Medicine; School of Medicine; 7945; 274182
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    Loss-of-function mutations in LGI4, a secreted ligand involved in Schwann cell myelination, are responsible for arthrogryposis multiplex congenita
    (Cell Press, 2017) Xue, Shifeng; Maluenda, Jérôme; Marguet, Florent; Shboul, Mohammad; Quevarec, Loïc; Bonnard, Carine; Ng, Alvin Yu Jin; Tohari, Sumanty; Tan, Thong Teck; Kong, Mung Kei; Monaghan, Kristin G.; Cho, Megan T.; Siskind, Carly E.; Sampson, Jacinda B.; Rocha, Carolina Tesi; Alkazaleh, Fawaz; Gonzales, Marie; Rigonnot, Luc; Whalen, Sandra; Gut, Marta; Gut, Ivo; Bucourt, Martine; Venkatesh, Byrappa; Laquerrière, Annie; Melki, Judith; Reversade, Bruno; Faculty Member; School of Medicine; 274182
    Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.
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    Publisher correction: discovery of a genetic module essential for assigning left–right asymmetry in humans and ancestral vertebrates (Nature Genetics, (2022), 54, 1, (62-72), 10.1038/s41588-021-00970-4)
    (Nature Research, 2022) Szenker-Ravi, Emmanuelle; Ott, Tim; Khatoo, Muznah; de Bellaing, Anne Moreau; Goh, Wei Xuan; Chong, Yan Ling; Beckers, Anja; Kannesan, Darshini; Louvel, Guillaume; Anujan, Priyanka; Ravi, Vydianathan; Bonnard, Carine; Moutton, Sébastien; Schoen, Patric; Fradin, Mélanie; Colin, Estelle; Megarbane, André; Daou, Linda; Chehab, Ghassan; Di Filippo, Sylvie; Rooryck, Caroline; Deleuze, Jean-François; Boland, Anne; Arribard, Nicolas; Eker, Rukiye; Tohari, Sumanty; Ng, Alvin Yu-Jin; Rio, Marlene; Lim, Chun Teck; Eisenhaber, Birgit; Eisenhaber, Frank; Venkatesh, Byrappa; Amiel, Jeanne; Crollius, Hugues Roest; Gordon, Christopher T.; Gossler, Achim; Roy, Sydipto; Attie-Bitach, Tania; Blum, Martin; Bouvagnet, Patrice; N/A; Reversade, Bruno; Faculty Member; School of Medicine; 274182
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    Elabela deficiency promotes preeclampsia and cardiovascular malformations in mice
    (American Association for the Advancement of Science (AAAS), 2017) Ho, Lena; van Dijk, Marie; Chye, Sam Tan Jian; Messerschmidt, Daniel M.; Chng, Serene C.; Ong, Sheena; Yi, Ling Ka; Boussata, Souad; Goh, Grace Hui-Yi; Afink, Gijs B.; Lim, Chin Yan; Dunn, N. Ray; Solter, Davor; Knowles, Barbara B.; N/A; Reversade, Bruno; Faculty Member; School of Medicine; 274182
    Preeclampsia (PE) is a gestational hypertensive syndrome affecting between 5 and 8% of all pregnancies. Although PE is the leading cause of fetal and maternal morbidity and mortality, its molecular etiology is still unclear. Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta. Elabela but not Apelin knockout pregnant mice exhibit PE-like symptoms, including proteinuria and elevated blood pressure due to defective placental angiogenesis. In mice, infusion of exogenous ELA normalizes hypertension, proteinuria, and birth weight. ELA, which is abundant in human placentas, increases the invasiveness of trophoblast-like cells, suggesting that it enhances placental development to prevent PE. The ELA-APLNR signaling axis may offer a new paradigm for the treatment of common pregnancy-related complications, including PE.
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    DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling
    (American Association for the Advancement of Science (AAAS), 2022) Harapas, Cassandra R.; Robinson, Kim S.; Lay, Kenneth; Wong, Jasmine; Traspas, Ricardo Moreno; Nabavizadeh, Nasrin; Rass-Rothschild, Annick; Boisson, Bertrand; Drutman, Scott B.; Laohamonthonkul, Pawat; Bonner, Devon; Xiong, Jingwei Rachel; Gorrell, Mark D.; Davidson, Sophia; Yu, Chien-Hsiung; Fleming, Mark D.; Gudera, Jonas; Stein, Jerry; Ben-Harosh, Miriam; Groopman, Emily; Shimamura, Akiko; Tamary, Hannah Hatipoglu; Nevin; Casanova, Jean-Laurent; Bernstein, Jonathan A.; Zhong, Franklin L.; Masters, Seth L.; N/A; Kayserili, Hülya; Reversade, Bruno; Faculty Member; Faculty Member; School of Medicine; School of Medicine; 7945; 274182
    Dipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it affects inflammasome regulation in vivo is not yet established. Here, we report three families with immune-associated defects, poor growth, pancytopenia, and skin pigmentation abnormalities that segregate with biallelic DPP9 rare variants. Using patient-derived primary cells and biochemical assays, these variants were shown to behave as hypomorphic or knockout alleles that failed to repress NLRP1. The removal of a single copy of Nlrp1a/b/c, Asc, Gsdmd, or Il-1r, but not Il-18, was sufficient to rescue the lethality of Dpp9 mutant neonates in mice. Similarly, dpp9 deficiency was partially rescued by the inactivation of asc, an obligate downstream adapter of the NLRP1 inflammasome, in zebrafish. These experiments suggest that the deleterious consequences of DPP9 deficiency were mostly driven by the aberrant activation of the canonical NLRP1 inflammasome and IL-1 ss signaling. Collectively, our results delineate a Mendelian disorder of DPP9 deficiency driven by increased NLRP1 activity as demonstrated in patient cells and in two animal models of the disease.
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    A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI-NET sequencing
    (John Wiley and Sons Inc, 2023) Bressin, Annkatrin; Shboul, Mohammad; Moreno Traspas, Ricardo; Chia, Poh Hui; Bonnard, Carine; Szenker-Ravi, Emmanuelle; Beillard, Emmanuel; Hojati, Zohreh; Drutman, Scott; Freier, Susanne; El-Khateeb, Mohammad; Fathallah, Rajaa; Casanova, Jean-Laurent; Soror, Wesam; Arafat, Alaa; Mayer, Andreas; Altunoğlu, Umut; Reversade, Bruno; Nabavizadeh, Nasrinsadat; Sarıbaş, Burak; Faculty Member; Faculty Member; Researcher; Researcher; Master Student; School of Medicine; School of Medicine; School of Medicine; N/A; Graduate School of Health Sciences; 126174; 274182; N/A; N/A; N/A
    Exome sequencing has introduced a paradigm shift for the identification of germline variations responsible for Mendelian diseases. However, non-coding regions, which make up 98% of the genome, cannot be captured. The lack of functional annotation for intronic and intergenic variants makes RNA-seq a powerful companion diagnostic. Here, we illustrate this point by identifying six patients with a recessive Osteogenesis Imperfecta (OI) and neonatal progeria syndrome. By integrating homozygosity mapping and RNA-seq, we delineated a deep intronic TAPT1 mutation (c.1237-52 G>A) that segregated with the disease. Using SI-NET-seq, we document that TAPT1's nascent transcription was not affected in patients' fibroblasts, indicating instead that this variant leads to an alteration of pre-mRNA processing. Predicted to serve as an alternative splicing branchpoint, this mutation enhances TAPT1 exon 12 skipping, creating a protein-null allele. Additionally, our study reveals dysregulation of pathways involved in collagen and extracellular matrix biology in disease-relevant cells. Overall, our work highlights the power of transcriptomic approaches in deciphering the repercussions of non-coding variants, as well as in illuminating the molecular mechanisms of human diseases. © 2023 The Authors. Published under the terms of the CC BY 4.0 license.
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    Dominant-negative NFKBIA mutation promotes IL-1 beta production causing hepatic disease with severe immunodeficiency
    (AMER SOC CLINICAL INVESTIGATION INC, 2020) Tan, Enrica E. K.; Hopkins, Richard A.; Lim, Chrissie K.; Jamuar, Saumya S.; Ong, Christina; Thoon, Koh C.; Koh, Mark J. A.; Shin, Eun Mong; Lian, Derrick W. Q.; Weerasooriya, Madhushanee; Lee, Christopher Z. W.; Soetedjo, Andreas Alvin Pumomo; Lim, Chang Siang; Au, Veonice B.; Chua, Edmond; Lee, Hui Yin; Jones, Leigh Ann; James, Sharmy S.; Kaliaperumal, Nivashini; Kwok, Jeffery; Tan, Ee Shien; Thomas, Biju; Wu, Lynn Xue; Ho, Lena; Fairhurst, Anna Marie; Ginhoux, Florent; Teo, Adrian K. K.; Zhang, Yong Liang; Ong, Kok Huar; Yu, Weimiao; Venkatesh, Byrappa; Tergaonkar, Vinay; Chin, Keh Chuang; Tan, Ah Moy; Liew, Woei Kang; Connolly, John E.; N/A; Reversade, Bruno; Faculty Member; N/A; School of Medicine; N/A; 274182
    Although IKK-beta has previously been shown as a negative regulator of IL-1 beta secretion in mice, this role has not been proven in humans. Genetic studies of NF-kappa B signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-kappa B pathway in suppressing IL-1 beta expression. Here, we report an infant with a clinical pathology comprising neutrophil-mediated autoinflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation of NFKBIA, resulting in a L34P I kappa B alpha variant that severely repressed NF-kappa B activation and downstream cytokine production. Paradoxically, IL-1 beta secretion was elevated in the patient's stimulated leukocytes, in her induced pluripotent stem cell-derived macrophages, and in murine bone marrow-derived macrophages containing the L34P mutation. The patient's hypersecretion of IL-1 beta correlated with activated neutrophilia and liver fibrosis with neutrophil accumulation. Hematopoietic stem cell transplantation reversed neutrophilia, restored a resting state in neutrophils, and normalized IL-1 beta release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1 beta secretion. Our studies reveal a previously unrecognized role of human I kappa B alpha as an essential regulator of canonical NF-kappa B signaling in the prevention of neutrophil-dependent autoinflammatory diseases. These findings also highlight the therapeutic potential of IL-1 inhibitors in treating complications arising from systemic NF-kappa B inhibition.
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    Enteroviral 3C protease activates the human NLRP1 inflammasome in airway epithelia
    (American Association for the Advancement of Science (AAAS), 2020) Robinson, Kim S.; Teo, Daniel Eng Thiam; Tan, Kai Sen; Toh, Gee Ann; Ong, Hsiao Hui; Lim, Chrissie Kaishi; Lay, Kenneth; Au, Bijin Veonice; Lew, Tian Sheng; Chu, Justin Jang Hann; Chow, Vincent Tak Kwong; Wang, De Yun; Zhong, Franklin L.; N/A; Reversade, Bruno; Faculty Member; School of Medicine; 274182
    Immune sensor proteins are critical to the function of the human innate immune system. The full repertoire of cognate triggers for human immune sensors is not fully understood. Here, we report that human NACHT, LRR, and PYD domains-containing protein 1 (NLRP1) is activated by 3C proteases (3Cpros) of enteroviruses, such as human rhinovirus (HRV). 3Cpros directly cleave human NLRP1 at a single site between Glu(130) and Gly(131). This cleavage triggers N-glycine-mediated degradation of the autoinhibitory NLRP1 N-terminal fragment via the cullin(ZER1/ZYG11B) complex, which liberates the activating C-terminal fragment. Infection of primary human airway epithelial cells by live human HRV triggers NLRP1-dependent inflammasome activation and interleukin-18 secretion. Our findings establish 3Cpros as a pathogen-derived trigger for the human NLRP1 inflammasome and suggest that NLRP1 may contribute to inflammatory diseases of the airway.