A pleiotropic recurrent dominant <i>ITPR3</i> variant causes a complex multisystemic disease

Inositol 1,4,5-trisphosphate (IP3) receptor type 1 (<i>ITPR1</i>), <i>2</i> (<i>ITPR2</i>), and <i>3</i> (<i>ITPR3</i>) encode the IP3 receptor (IP3R), a key player in intracellular calcium release. In four unrelated patients, we report that an identical <i>ITPR3</i> 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<sup>+</sup> lymphopenia, a quasi-absence of naïve CD4<sup>+</sup> and CD8<sup>+</sup> 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<sup>2524</sup> 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 <i>ITPR1-3</i> deficiencies leading to narrow, mainly neurological phenotypes, a recurrent dominant <i>ITPR3</i> variant leads to a multisystemic disease, defining a unique role for IP3R3 in the tetrameric IP3R complex.

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Publication Details

Journal
Science Advances
Published
2024-09-13
DOI
https://doi.org/10.1126/sciadv.ado5545
Citations
5
Primary Topic
Calcium signaling and nucleotide metabolism
Type
article
Field-Weighted Citation Impact
2.01
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article

A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease

Heather Kenney, Nurit Assia Batzir, Rajinder Bajwa, Mahsa Shirin et al.
5 citations
Science Advances
Calcium signaling and nucleotide metabolism
2.01
article

A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease

Heather Kenney, Nurit Assia Batzir, Rajinder Bajwa, Mahsa Shirin, Sabrina Bibi‐Triki, Jacky G. Goetz, Nufar Marcus, Eunkyung Song, Milja Kaare, Caroline Thomas, Pierre Grenot, Kateřina Jeřábková, Natalia Ordoñez, Frank Robledo‐Avila, Sarah Grün, Ruslan Al‐Ali, Tristan Stemmelen, Luigi Daniele Notarangelo, Richard K. Hite, Nima Parvaneh, Kornélia Tripolszki, Ottavia M. Delmonte, Mirjana Radosavljevic, Véronique Rolli, Seiamak Bahram, Roshini S. Abraham, Megan E. Zavorka Thomas, Vinay Sapuru, Santiago Partida‐Sánchez, Stephan Ehl, Sophie Jung, Michèlle Rosenzwajg, Virginie Collin-Bund, César Mejía, Angélique Pichot, Zhichao Miao, Aurélie Hirschler, Ignacio Busnelli, Antoine Hanauer, Carla N. Castro, Samir B. Kahwash, Bertrand Isidor, Jianying Yang, Kristin Zajo, Raphaël Carapito, Anne Molitor, Ori Toker, Pekka Nokelainen, Alexandre Lederle, Aida M. Bertoli‐Avella, Attila Kumánovics, Yoram Louzoun, Christine Carapito, Peter Bauer, Nicodème Paul, Lydie Naegely, Esther Knapp, Gal Zaks Hoffer, Joseph H. Hersh, Uxía-Saraiva Esperón-Moldes, Richard Person, Elyssa G. Lewis, Alice Bernard
article en
5 citations

Abstract

Inositol 1,4,5-trisphosphate (IP3) receptor type 1 (<i>ITPR1</i>), <i>2</i> (<i>ITPR2</i>), and <i>3</i> (<i>ITPR3</i>) encode the IP3 receptor (IP3R), a key player in intracellular calcium release. In four unrelated patients, we report that an identical <i>ITPR3</i> 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<sup>+</sup> lymphopenia, a quasi-absence of naïve CD4<sup>+</sup> and CD8<sup>+</sup> 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<sup>2524</sup> 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 <i>ITPR1-3</i> deficiencies leading to narrow, mainly neurological phenotypes, a recurrent dominant <i>ITPR3</i> variant leads to a multisystemic disease, defining a unique role for IP3R3 in the tetrameric IP3R complex.

Science AdvancesVol. 10(37)
Tongji University (CN), Centre National de la Recherche Scientifique (FR), National Institutes of Health (US), Nationwide Children's Hospital (US), Memorial Sloan Kettering Cancer Center (US), Bar-Ilan University (IL), University of Louisville (US), Inserm (FR), University of Freiburg (DE), Tel Aviv University (IL), Hebrew University of Jerusalem (IL), Norton Healthcare (US), Cornell University (US), Shaare Zedek Medical Center (IL), Institut Pluridisciplinaire Hubert Curien (FR), Centre Hospitalier Universitaire de Nantes (FR), Sorbonne Université (FR), La Ligue Contre le Cancer (FR), Assistance Publique – Hôpitaux de Paris (FR), Schneider Children's Medical Center (IL), Children's Medical Center (IR), Blueprint Genetics (Finland) (FI), Bipar (FR), Mayo Clinic in Arizona (US), Centre d'Immunologie et des Maladies Infectieuses (FR), Hôpital Mère-Enfant (FR), National Institute of Allergy and Infectious Diseases (US), Centogene (Germany) (DE), Casa del Niño Hospital Infantil (CO), Hôpitaux Universitaires de Strasbourg (FR), Jeffrey Modell Foundation (US), Hôpital Civil, Strasbourg (FR), Immunologie - Immunopathologie - Immunothérapie (FR), Université de Strasbourg (FR), Tehran University of Medical Sciences (IR), Nelson Mandela University (ZA)
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Openalex Percentile: Top 14%
Calcium signaling and nucleotide metabolism
2.01
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