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. Nokelainen; Nurit 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

doi:10.1126/sciadv.ado5545

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

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	eado5545
Journal	Science advances
Volume	10
Issue number	37
DOIs	https://doi.org/10.1126/sciadv.ado5545
State	Published - 13 Sep 2024

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Molitor, A., Lederle, A., Radosavljevic, M., Sapuru, V., Zavorka Thomas, M. E., Yang, J., Shirin, M., Collin-Bund, V., Jerabkova-Roda, K., Miao, Z., Bernard, A., Rolli, V., Grenot, P., Castro, C. N., Rosenzwajg, M., Lewis, E. G., Person, R., Esperón-Moldes, U. S., Kaare, M., ... Bahram, S. (2024). A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease. Science advances, 10(37), eado5545. https://doi.org/10.1126/sciadv.ado5545

@article{4182b4e78ecd4e918ca14a17f1b5ae4c,

title = "A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease",

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 na{\"i}ve 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.",

author = "Anne Molitor and Alexandre Lederle and Mirjana Radosavljevic and Vinay Sapuru and {Zavorka Thomas}, {Megan E.} and Jianying Yang and Mahsa Shirin and Virginie Collin-Bund and Katerina Jerabkova-Roda and Zhichao Miao and Alice Bernard and V{\'e}ronique Rolli and Pierre Grenot and Castro, {Carla Noemi} and Michelle Rosenzwajg and Lewis, {Elyssa G.} and Richard Person and Esper{\'o}n-Moldes, {Ux{\'i}a Saraiva} and Milja Kaare and Nokelainen, {Pekka T.} and Batzir, {Nurit Assia} and Hoffer, {Gal Zaks} and Nicod{\`e}me Paul and Tristan Stemmelen and Lydie Naegely and Antoine Hanauer and Sabrina Bibi-Triki and Sarah Gr{\"u}n and Sophie Jung and Ignacio Busnelli and Kornelia Tripolszki and Ruslan Al-Ali and Natalia Ordonez and Peter Bauer and Eunkyung Song and Kristin Zajo and Santiago Partida-Sanchez and Frank Robledo-Avila and Attila Kumanovics and Yoram Louzoun and Aur{\'e}lie Hirschler and Ang{\'e}lique Pichot and Ori Toker and Mej{\'i}a, {Cesar Andr{\'e}s Mu{\~n}oz} and Nima Parvaneh and Esther Knapp and Hersh, {Joseph H.} and Heather Kenney and Delmonte, {Ottavia M.} and Notarangelo, {Luigi D.} and Goetz, {Jacky G.} and Kahwash, {Samir B.} and Christine Carapito and Bajwa, {Rajinder P.S.} and Caroline Thomas and Stephan Ehl and Bertrand Isidor and Raphael Carapito and Abraham, {Roshini S.} and Hite, {Richard K.} and Nufar Marcus and Aida Bertoli-Avella and Seiamak Bahram",

year = "2024",

month = sep,

day = "13",

doi = "10.1126/sciadv.ado5545",

language = "אנגלית",

volume = "10",

pages = "eado5545",

journal = "Science advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "37",

}

Molitor, A, Lederle, A, Radosavljevic, M, Sapuru, V, Zavorka Thomas, ME, Yang, J, Shirin, M, Collin-Bund, V, Jerabkova-Roda, K, Miao, Z, Bernard, A, Rolli, V, Grenot, P, Castro, CN, Rosenzwajg, M, Lewis, EG, Person, R, Esperón-Moldes, US, Kaare, M, Nokelainen, PT, Batzir, NA, Hoffer, GZ, Paul, N, Stemmelen, T, Naegely, L, Hanauer, A, Bibi-Triki, S, Grün, S, Jung, S, Busnelli, I, Tripolszki, K, Al-Ali, R, Ordonez, N, Bauer, P, Song, E, Zajo, K, Partida-Sanchez, S, Robledo-Avila, F, Kumanovics, A, Louzoun, Y, Hirschler, A, Pichot, A, Toker, O, Mejía, CAM, Parvaneh, N, Knapp, E, Hersh, JH, Kenney, H, Delmonte, OM, Notarangelo, LD, Goetz, JG, Kahwash, SB, Carapito, C, Bajwa, RPS, Thomas, C, Ehl, S, Isidor, B, Carapito, R, Abraham, RS, Hite, RK, Marcus, N, Bertoli-Avella, A & Bahram, S 2024, 'A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease', Science advances, vol. 10, no. 37, pp. eado5545. https://doi.org/10.1126/sciadv.ado5545

TY - JOUR

T1 - A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease

AU - Molitor, Anne

AU - Lederle, Alexandre

AU - Radosavljevic, Mirjana

AU - Sapuru, Vinay

AU - Zavorka Thomas, Megan E.

AU - Yang, Jianying

AU - Shirin, Mahsa

AU - Collin-Bund, Virginie

AU - Jerabkova-Roda, Katerina

AU - Miao, Zhichao

AU - Bernard, Alice

AU - Rolli, Véronique

AU - Grenot, Pierre

AU - Castro, Carla Noemi

AU - Rosenzwajg, Michelle

AU - Lewis, Elyssa G.

AU - Person, Richard

AU - Esperón-Moldes, Uxía Saraiva

AU - Kaare, Milja

AU - Nokelainen, Pekka T.

AU - Batzir, Nurit Assia

AU - Hoffer, Gal Zaks

AU - Paul, Nicodème

AU - Stemmelen, Tristan

AU - Naegely, Lydie

AU - Hanauer, Antoine

AU - Bibi-Triki, Sabrina

AU - Grün, Sarah

AU - Jung, Sophie

AU - Busnelli, Ignacio

AU - Tripolszki, Kornelia

AU - Al-Ali, Ruslan

AU - Ordonez, Natalia

AU - Bauer, Peter

AU - Song, Eunkyung

AU - Zajo, Kristin

AU - Partida-Sanchez, Santiago

AU - Robledo-Avila, Frank

AU - Kumanovics, Attila

AU - Louzoun, Yoram

AU - Hirschler, Aurélie

AU - Pichot, Angélique

AU - Toker, Ori

AU - Mejía, Cesar Andrés Muñoz

AU - Parvaneh, Nima

AU - Knapp, Esther

AU - Hersh, Joseph H.

AU - Kenney, Heather

AU - Delmonte, Ottavia M.

AU - Notarangelo, Luigi D.

AU - Goetz, Jacky G.

AU - Kahwash, Samir B.

AU - Carapito, Christine

AU - Bajwa, Rajinder P.S.

AU - Thomas, Caroline

AU - Ehl, Stephan

AU - Isidor, Bertrand

AU - Carapito, Raphael

AU - Abraham, Roshini S.

AU - Hite, Richard K.

AU - Marcus, Nufar

AU - Bertoli-Avella, Aida

AU - Bahram, Seiamak

PY - 2024/9/13

Y1 - 2024/9/13

N2 - 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.

AB - 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.

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U2 - 10.1126/sciadv.ado5545

DO - 10.1126/sciadv.ado5545

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C2 - 39270020

AN - SCOPUS:85204167251

SN - 2375-2548

VL - 10

SP - eado5545

JO - Science advances

JF - Science advances

IS - 37

ER -

A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease

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