A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease

Anne Molitor, Alexandre Lederle, Mirjana Radosavljevic, Vinay Sapuru, Megan E. Zavorka Thomas, Jianying Yang, Mahsa Shirin, Virginie Collin-Bund, Katerina Jerabkova-Roda, Zhichao Miao, Alice Bernard, Véronique Rolli, Pierre Grenot, Carla Noemi Castro, Michelle Rosenzwajg, Elyssa G. Lewis, Richard Person, Uxía Saraiva Esperón-Moldes, Milja Kaare, Pekka T. NokelainenNurit Assia Batzir, Gal Zaks Hoffer, Nicodème Paul, Tristan Stemmelen, Lydie Naegely, Antoine Hanauer, Sabrina Bibi-Triki, Sarah Grün, Sophie Jung, Ignacio Busnelli, Kornelia Tripolszki, Ruslan Al-Ali, Natalia Ordonez, Peter Bauer, Eunkyung Song, Kristin Zajo, Santiago Partida-Sanchez, Frank Robledo-Avila, Attila Kumanovics, Yoram Louzoun, Aurélie Hirschler, Angélique Pichot, Ori Toker, Cesar Andrés Muñoz Mejía, Nima Parvaneh, Esther Knapp, Joseph H. Hersh, Heather Kenney, Ottavia M. Delmonte, Luigi D. Notarangelo, Jacky G. Goetz, Samir B. Kahwash, Christine Carapito, Rajinder P.S. Bajwa, Caroline Thomas, Stephan Ehl, Bertrand Isidor, Raphael Carapito, Roshini S. Abraham, Richard K. Hite, Nufar Marcus, Aida Bertoli-Avella, Seiamak Bahram*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 Arg2524 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.

Original languageEnglish
Article numbereado5545
JournalScience advances
Volume10
Issue number37
DOIs
StatePublished - 13 Sep 2024

Funding

FundersFunder number
R&D Programs of Guangzhou LaboratoryYW-YFYJ0102, SRPG22-006, SRPG22-003, SRPG22-007
Nanotumor Consortium
France’s national Research Agency
Association pour la Recherche contre le Cancer
Institut national de la santé et de la recherche médicale
National Institutes of Health
Division of Intramural Research
European Commission
Fédération Hospitalo-Universitaire3.2 tRidiAG, P30 cA008748, R01-GM13230704
National Institute of Allergy and Infectious Diseases
ARC
MSD Avenir
European Regional Development Fund
National Institute of General Medical SciencesR01-GM13230704
Fondation pour la Recherche MédicaleProFi FR2048, SPF202004011876, AnR-10-inBS-08-03
LabexANR-11-LABX-0070_TRANSPLANTEX
National Key Research and Development Program of China2021YFF1200903, 2021YFF1200900
Agence Nationale de la RechercheAnR-20-SFRi-0012, AnR-11-lABX-0070_tRAnSPlAnteX, AnR-10-ideX-0002, UMR_S 1109
IdEx UnistraANR-10-IDEX-0002, ANR-20-SFRI-0012
French Proteomic InfrastructureANR-10-INBS-08-03, ProFI FR2048
NIH NCIP30 CA008748
National Natural Science Foundation of China32270707
INTERREG V program3.2 TRIDIAG

    Fingerprint

    Dive into the research topics of 'A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease'. Together they form a unique fingerprint.

    Cite this