A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease

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, throu...

Full description

Saved in:
Bibliographic Details
Published in:Science advances 2024-09, Vol.10 (37), p.eado5545
Main Authors: Molitor, Anne, Lederle, Alexandre, Radosavljevic, Mirjana, Sapuru, Vinay, Zavorka Thomas, Megan E., Yang, Jianying, Shirin, Mahsa, Collin-Bund, Virginie, Jerabkova-Roda, Katerina, Miao, Zhichao, Bernard, Alice, Rolli, Véronique, Grenot, Pierre, Castro, Carla Noemi, Rosenzwajg, Michelle, Lewis, Elyssa G., Person, Richard, Esperón-Moldes, Uxía-Saraiva, Kaare, Milja, Nokelainen, Pekka T., Batzir, Nurit Assia, Hoffer, Gal Zaks, Paul, Nicodème, Stemmelen, Tristan, Naegely, Lydie, Hanauer, Antoine, Bibi-Triki, Sabrina, Grün, Sarah, Jung, Sophie, Busnelli, Ignacio, Tripolszki, Kornelia, Al-Ali, Ruslan, Ordonez, Natalia, Bauer, Peter, Song, Eunkyung, 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, Hersh, Joseph H., Kenney, Heather, 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., Marcus, Nufar, Bertoli-Avella, Aida, Bahram, Seiamak
Format: Article
Language:English
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. A de novo variant in the Ca 2+ modulator ITPR3 causes a pleiotropic multisystemic disease where immunodeficiency is paramount.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.ado5545