1. Biallelic PI4KA Mutations Disrupt B-Cell Metabolism and Cause B-Cell Lymphopenia and Hypogammaglobulinemia
- Author
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Saettini, F, Guerra, F, Mauri, M, Salter, C, Adam, M, Adams, D, Baple, E, Barredo, E, Bhatia, S, Borkhardt, A, Brusco, A, Bugarin, C, Chinello, C, Crosby, A, D'Souza, P, Denti, V, Fazio, G, Giuliani, S, Kuehn, H, Amel, H, Elmi, A, Lo, B, Malighetti, F, Mandrile, G, Martín-Nalda, A, Mefford, H, Moratto, D, Emam Mousavi, F, Nelson, Z, Gutiérrez-Solana, L, Macnamara, E, Michaud, V, O'Leary, M, Pagani, L, Pavinato, L, Santamaria, P, Planas-Serra, L, Quadri, M, Raspall-Chaure, M, Rebellato, S, Rosenzweig, S, Roubertie, A, Holzinger, D, Deal, C, Vockley, C, Savino, A, L. Stoddard, J, Uhlig, H, Pujol, A, Magni, F, Paglia, G, Cazzaniga, G, Piazza, R, Barberis, M, Biondi, A, Saettini, Francesco, Guerra, Fabiola, Mauri, Mario, Salter, Claire G., Adam, Margaret P., Adams, David, Baple, Emma L., Barredo, Estibaliz, Bhatia, Sanil, Borkhardt, Arndt, Brusco, Alfredo, Bugarin, Cristina, Chinello, Clizia, Crosby, Andrew H., D'Souza, Precilla, Denti, Vanna, Fazio, Grazia, Giuliani, Silvia, Kuehn, Hye Sun, Amel, Hassan, Elmi, Asha, Lo, Bernice, Malighetti, Federica, Mandrile, Giorgia, Martín-Nalda, Andrea, Mefford, Heather C., Moratto, Daniele, Emam Mousavi, Fatemeh, Nelson, Zoe, Gutiérrez-Solana, Luis González, Macnamara, Ellen, Michaud, Vincent, O'Leary, Melanie, Pagani, Lisa, Pavinato, Lisa, Santamaria, Patricia VVelez, Planas-Serra, Laura, Quadri, Manuel, Raspall-Chaure, Miquel, Rebellato, Stefano, Rosenzweig, Sergio D., Roubertie, Agathe, Holzinger, Dirk, Deal, Christin, Vockley, Catherine Walsh, Savino, Angela Maria, L. Stoddard, Jennifer, Uhlig, Holm H., Pujol, Aurora, Magni, Fulvio, Paglia, Giuseppe, Cazzaniga, Gianni, Piazza, Rocco, Barberis, Matteo, Biondi, Andrea, Saettini, F, Guerra, F, Mauri, M, Salter, C, Adam, M, Adams, D, Baple, E, Barredo, E, Bhatia, S, Borkhardt, A, Brusco, A, Bugarin, C, Chinello, C, Crosby, A, D'Souza, P, Denti, V, Fazio, G, Giuliani, S, Kuehn, H, Amel, H, Elmi, A, Lo, B, Malighetti, F, Mandrile, G, Martín-Nalda, A, Mefford, H, Moratto, D, Emam Mousavi, F, Nelson, Z, Gutiérrez-Solana, L, Macnamara, E, Michaud, V, O'Leary, M, Pagani, L, Pavinato, L, Santamaria, P, Planas-Serra, L, Quadri, M, Raspall-Chaure, M, Rebellato, S, Rosenzweig, S, Roubertie, A, Holzinger, D, Deal, C, Vockley, C, Savino, A, L. Stoddard, J, Uhlig, H, Pujol, A, Magni, F, Paglia, G, Cazzaniga, G, Piazza, R, Barberis, M, Biondi, A, Saettini, Francesco, Guerra, Fabiola, Mauri, Mario, Salter, Claire G., Adam, Margaret P., Adams, David, Baple, Emma L., Barredo, Estibaliz, Bhatia, Sanil, Borkhardt, Arndt, Brusco, Alfredo, Bugarin, Cristina, Chinello, Clizia, Crosby, Andrew H., D'Souza, Precilla, Denti, Vanna, Fazio, Grazia, Giuliani, Silvia, Kuehn, Hye Sun, Amel, Hassan, Elmi, Asha, Lo, Bernice, Malighetti, Federica, Mandrile, Giorgia, Martín-Nalda, Andrea, Mefford, Heather C., Moratto, Daniele, Emam Mousavi, Fatemeh, Nelson, Zoe, Gutiérrez-Solana, Luis González, Macnamara, Ellen, Michaud, Vincent, O'Leary, Melanie, Pagani, Lisa, Pavinato, Lisa, Santamaria, Patricia VVelez, Planas-Serra, Laura, Quadri, Manuel, Raspall-Chaure, Miquel, Rebellato, Stefano, Rosenzweig, Sergio D., Roubertie, Agathe, Holzinger, Dirk, Deal, Christin, Vockley, Catherine Walsh, Savino, Angela Maria, L. Stoddard, Jennifer, Uhlig, Holm H., Pujol, Aurora, Magni, Fulvio, Paglia, Giuseppe, Cazzaniga, Gianni, Piazza, Rocco, Barberis, Matteo, and Biondi, Andrea
- Abstract
Purpose PI4KA-related disorder is a highly clinically variable condition characterized by neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus) and gastrointestinal (inflammatory bowel disease and multiple intestinal atresia) manifestations. Although features consistent with immunodeficiency (autoimmunity/autoinflammation and recurrent infections) have been reported in a subset of patients, the burden of B-cell deficiency and hypogammaglobulinemia has not been extensively investigated. We sought to describe the clinical presentation and manifestations of patients with PI4KA-related disorder and to investigate the metabolic consequences of biallelic PI4KA variants in B cells. Methods Clinical data from patients with PI4KA variants were obtained. Multi-omics analyses combining transcriptome, proteome, lipidome and metabolome analyses in conjunction with functional assays were performed in EBV-transformed B cells. Results Clinical and laboratory data of 13 patients were collected. Recurrent infections (7/13), autoimmune/autoinflammatory manifestations (5/13), B-cell deficiency (8/13) and hypogammaglobulinemia (8/13) were frequently observed. Patients' B cells frequently showed increased transitional and decreased switched memory B-cell subsets. Pathway analyses based on differentially expressed transcripts and proteins confirmed the central role of PI4KA in B cell differentiation with altered B-cell receptor (BCR) complex and signalling. By altering lipids production and tricarboxylic acid cycle regulation, and causing increased endoplasmic reticulum stress, biallelic PI4KA mutations disrupt B cell metabolism inducing mitochondrial dysfunction. As a result, B cells show hyperactive PI3K/mTOR pathway, increased autophagy and deranged cytoskeleton organization. Conclusion By altering lipid metabolism and TCA cycle, impairing mitochondrial activity, hyperactivating mTOR pathway and increasing autophagy, PI4KA-related dis
- Published
- 2025