Isidor, Bertrand
Mayo Clinic
Service de Génétique Médicale, CHU Nantes, Nantes Université, Nantes, France.
Citations 2
Germline mutations in a G protein identify signaling cross-talk in T cells
Ham, Hyoungjun , Jing, Huie , Lamborn, Ian T. , Kober, M. , Anderson, David E. , Druey, Kirk M. , Mandl, Judith N. , Isidor, Bertrand , Freeman, Alexandra F. , Ganesan, Sundar , Karsak, Meliha , Mustillo, Peter , Teo, Juliana , Zolkipli‐Cunningham, Zarazuela , Lecoquierre, François , Schmid, Jana Pachlopnik , Kuhns, Douglas B. , Xu, Xuehua , Al–Herz, Waleed , Terhal, Paulien A., Muurinen, Mari , Barlogis, Vincent , Danielson, Jeffrey J. , Stewart, Helen , Rading, Sebastian, Keren, Boris , Pfundt, Rolph , Potocki, Lorraine , Olivier, Kenneth N., Faivre, Laurence , Wong, Melanie , Puel, Anne , Chou, Janet , Tusseau, Maud, Moutsopoulos, Niki M. , Matthews, Helen, Simons, Cas , Fink, Danielle , Kong, Heidi H. , Kabát, Juraj , Kim, Woo Sung , Bierhals, Tatjana , Meguro, Kazuyuki , Gu, Jingwen , Stoddard, Jennifer , Banos-Pinero, Benito, Slack, Maria A., Trivellin, Giampaolo , Mazel, Benoît , Li, Samuel T. , Watts, Val J. , Rodriguez-Quevedo, Maria F. , Bruel, Ange‐Line , Lehalle, Daphné , Torres, Daniel , Sullivan, Kathleen E. , Duffourd, Yannis, Similuk, Morgan , Blanc, Pierre , Jin, Tian, Geha, Raif S., Casanova, Jean‐Laurent , Mäkitie, Outi , Edery, Patrick , Germain, Ronald N. , Billadeau, Daniel D. , Zhang, Yu , Lenardo, Michael J. , Kober, Megan M , Koval, Alexey , Anderson, D Eric , Druey, Kirk M , Mandl, Judith N , Isidor, Bertrand , Ferreira, Carlos R , Freeman, Alexandra F , Karsak, Meliha , Mustillo, Peter J , Teo, Juliana , Chatron, Nicolas , Lecoquierre, Francois , Oler, Andrew J , Schmid, Jana Pachlopnik , Kuhns, Douglas B , Xu, Xuehua , Hauck, Fabian , Al-Herz, Waleed , Wagner, Matias , Terhal, Paulien A , Muurinen, Mari , Barlogis, Vincent , Loid, Petra , Keren, Boris , Pfundt, Rolph , Zarember, Kol A , Vill, Katharina , Olivier, Kenneth N , Lesca, Gaetan , Faivre, Laurence , Puel, Anne , Chou, Janet , Moutsopoulos, Niki M , Simons, Cas , Soldatos, Ariane , Masle-Farquhar, Etienne , Pittaluga, Stefania , Brink, Robert , Kong, Heidi H , Kabat, Juraj , Bierhals, Tatjana , Hsu, Amy P. , Gu, Jingwen , Trivellin, Giampaolo , Mazel, Benoît , Soomann, Maarja , Li, Samuel , Watts, Val J , Stratakis, Constantine A , Rodriguez-Quevedo, Maria F , Bruel, Ange-Line , Lipsanen-Nyman, Marita , Saultier, Paul , Lehalle, Daphne , Torres, Daniel , Barbarot, Sébastien , Neu, Axel , Similuk, Morgan N , McWalter, Kirsty , Blanc, Pierre , Bézieau, Stéphane , Geha, Raif S , Casanova, Jean Laurent , Makitie, Outi M , Edery, Patrick , Christodoulou, John , Germain, Ronald N , Goodnow, Christopher C , Sakmar, Thomas P , Billadeau, Daniel D , Kury, Sebastien , Katanaev, Vladimir L , Zhang, Yu , Lenardo, Michael J , Su, Helen C , Berchiche, Yamina A. , Wagner, Matias , Cruz, Phillip , Lesca, Gaëtan , Tusseau, Maud , Taft, Ryan J. , Pittaluga, Stefania , Baños-Piñero, Benito, Stratakis, Constantine A. , Jain, Rashmi, Bezieau, Stéphane , Jin, Tian , Kubisch, Christian , Küry, Sébastien , Su, Helen C.
Science | September 19, 2024 | Volume: 385 | Issue: 6715 | Pages: No page available
Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2 , which encodes G αi2 , a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase–mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating G αi2 mutations had clinical presentations that included impaired immunity. Mutant G αi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G αi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)–activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal–regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)–AKT S6 signaling to drive cellular growth and proliferation.
A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease
Molitor, Anne , Lederle, Alexandre , Radosavljevic, Mirjana , Sapuru, Vinay , Thomas, Megan E. Zavorka, Yang, Jianying , Shirin, Mahsa , Collin-Bund, Virginie , Jeřábková, Kateřina , Miao, Zhichao , Bernard, Alice , Grenot, Pierre , Lewis, Elyssa G., Person, Richard, Esperón-Moldes, Uxía-Saraiva, Kaare, Milja, Nokelainen, Pekka, Batzir, Nurit Assia , Hoffer, Gal Zaks, Stemmelen, Tristan , Naegely, Lydie , Hanauer, Antoine , Bibi‐Triki, Sabrina , Grün, Sarah, Jung, Sophie , Busnelli, Ignacio, Tripolszki, Kornélia , Ordoñez, Natalia, Song, Eunkyung , Zajo, Kristin , Partida‐Sánchez, Santiago , Robledo‐Avila, Frank , Kumánovics, Attila , Pichot, Angélique , Toker, Ori , Mejía, César , Parvaneh, Nima , Knapp, Esther , Hersh, Joseph H., Kenney, Heather , Bajwa, Rajinder , Thomas, Caroline , Ehl, Stephan , Isidor, Bertrand , Abraham, Roshini S. , Hite, Richard K. , Bertoli‐Avella, Aida M. , Bahram, Seiamak , Zavorka Thomas, Megan E , Jerabkova-Roda, Katerina , Rolli, Véronique , Grenot, Pierre , Castro, Carla Noemi , Rosenzwajg, Michelle , Person, Richard , Batzir, Nurit Assia , Hoffer, Gal Zaks , Paul, Nicodème , Stemmelen, Tristan , Naegely, Lydie , Hanauer, Antoine , Bibi-Triki, Sabrina , Jung, Sophie , Bauer, Peter , Zajo, Kristin , Partida-Sanchez, Santiago , Robledo-Avila, Frank , Kumanovics, Attila , Louzoun, Yoram , Hirschler, Aurélie , Pichot, Angélique , Toker, Ori , Mejía, Cesar Andrés Muñoz , Parvaneh, Nima , Knapp, Esther , Delmonte, Ottavia M , Notarangelo, Luigi D , Goetz, Jacky G , Kahwash, Samir B , Carapito, Christine , Bajwa, Rajinder P S , Thomas, Caroline , Ehl, Stephan , Isidor, Bertrand , Carapito, Raphael , Abraham, Roshini S , Hite, Richard K , Bahram, Seiamak , Esperón-Moldes, Uxia , Al‐Ali, Ruslan , Kenney, Heather , Kahwash, Samir B. , Marcus, Nufar
Science Advances | September 13, 2024 | Volume: 10 | Issue: 37 | Pages: No page available
Inositol 1,4,5-trisphosphate (IP3) receptor type 1 ( ITPR1 ), 2 ( ITPR2 ), and 3 ( ITPR3 ) encode the IP3 receptor (IP3R), a key player in intracellular calcium release. In four unrelated patients, we report that an identical ITPR3 de novo variant—NM_002224.3:c.7570C>T, p.Arg2524Cys—causes, through a dominant-negative effect, a complex multisystemic disorder with immunodeficiency. This leads to defective calcium homeostasis, mitochondrial malfunction, CD4 + lymphopenia, a quasi-absence of naïve CD4 + and CD8 + cells, an increase in memory cells, and a distinct TCR repertoire. The calcium defect was recapitulated in Jurkat knock-in. Site-directed mutagenesis displayed the exquisite sensitivity of Arg 2524 to any amino acid change. Despite the fact that all patients had severe immunodeficiency, they also displayed variable multisystemic involvements, including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. In conclusion, unlike previously reported ITPR1-3 deficiencies leading to narrow, mainly neurological phenotypes, a recurrent dominant ITPR3 variant leads to a multisystemic disease, defining a unique role for IP3R3 in the tetrameric IP3R complex.