A Pleiotropic Recurrent Dominant Itpr3 Variant Causes a Complex Multisystemic Disease

A Pleiotropic Recurrent Dominant Itpr3 Variant Causes a Complex Multisystemic Disease Publisher Pubmed

Molitor A^{1, 2} ; Lederle A^{1, 2} ; Radosavljevic M^{1, 2, 3} ; Sapuru V^{4, 5} ; Zavorka Thomas ME⁶ ; Yang J^{1, 2} ; Shirin M^{1, 2} ; Collinbund V^{1, 2} ; Jerabkovaroda K^{1, 7} ; Miao Z^{8, 9} ; Bernard A^{1, 2, 3} ; Rolli V^{1, 2, 3} ; Grenot P^{1, 2} ; Castro CN¹⁰ Show All Authors

Molitor A^{1, 2}
Lederle A^{1, 2}
Radosavljevic M^{1, 2, 3}
Sapuru V^{4, 5}
Zavorka Thomas ME⁶
Yang J^{1, 2}
Shirin M^{1, 2}
Collinbund V^{1, 2}
Jerabkovaroda K^{1, 7}
Miao Z^{8, 9}
Bernard A^{1, 2, 3}
Rolli V^{1, 2, 3}
Grenot P^{1, 2}
Castro CN¹⁰
Rosenzwajg M^{11, 12}
Lewis EG¹³
Person R¹⁴
Esperonmoldes US¹⁵
Kaare M¹⁵
Nokelainen PT¹⁵
Batzir NA¹⁶
Hoffer GZ¹⁶
Paul N^{1, 2}
Stemmelen T^{1, 2, 3}
Naegely L^{1, 2}
Hanauer A^{1, 2}
Bibitriki S^{1, 2}
Grun S^{10, 17}
Jung S^{1, 18}
Busnelli I¹
Tripolszki K¹⁹
Alali R¹⁹
Ordonez N¹⁹
Bauer P¹⁹
Song E²⁰
Zajo K²¹
Partidasanchez S²²
Robledoavila F²²
Kumanovics A²³
Louzoun Y²⁴
Hirschler A²⁵
Pichot A^{1, 2}
Toker O^{26, 27}
Munoz Mejia CA²⁸
Parvaneh N²⁹
Knapp E¹³
Hersh JH¹³
Kenney H³⁰
Delmonte OM³⁰
Notarangelo LD³⁰
Goetz JG^{1, 7}
Kahwash SB⁶
Carapito C²⁵
Bajwa RPS³¹
Thomas C³²
Ehl S¹⁰
Isidor B³³
Carapito R^{1, 2, 3}
Abraham RS⁶
Hite RK⁴
Marcus N^{34, 35, 36}
Bertoliavella A¹⁹
Bahram S^{1, 2, 3}

Show Affiliations

1. Laboratoire d’ImmunoRhumatologie Moleculaire, Institut national de la sante et de la recherche medicale (INSERM) UMR_S 1109, Plateforme GENOMAX, Centre de Recherche d’Immunologie et d’Hematologie, Centre de Recherche en Biomedecine de Strasbourg (CRBS), Faculte de Medecine, Federation Hospitalo, Universitaire OMICARE, Federation de Medecine Translationnelle de Strasbourg (FMTS), Universite de Strasbourg, Strasbourg, France
2. Institut Thematique Interdisciplinaire (ITI) Transplantex NG de Medecine de Precision de Strasbourg, Faculte de Medecine, Universite de Strasbourg, Strasbourg, France
3. Laboratoire d’Immunologie, Plateau Technique de Biologie, Pole de Biologie, Nouvel Hopital Civil, Hopitaux Universitaires de Strasbourg, Strasbourg, France
4. Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States
5. Physiology, Biophysics, and Systems Biology (PBSB) Program, Weill Cornell Graduate School of Biomedical Sciences, New York, NY, United States
6. Departmen of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
7. Equipe labellisee, Ligue nationale Contre le Cancer, Strasbourg, France
8. Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, China
9. Translational Research Institute of Brain and Brain-Like Intelligence and Deartment of Anesthesiology, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
10. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
11. Assistance Publique Hopitaux de Paris, Hopital Pitie-Salpetriere, Clinical Investigation Center for Biotherapies (CIC-BTi), Immunology-Inflammation-Infectiology and Dermatology Department (3iD), Paris, France
12. Sorbonne Universite, INSERM UMR_S 959, Immunology-Immunopathology-Immunotherapy (i3), Paris, France
13. Norton Children’s Medica Group, University of Louisville School of Medicine, Louisville, KY, United States
14. GeneDx, Gaithersburg, MD, United States
15. Blueprint Genetics, A Quest Diagnostics Company, Espoo, Finland
16. Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikvah, Israel
17. Faculty of Biology, University of Freiburg, Freiburg, Germany
18. Centre de Reference des maladies rares orales et dentaires (O-Rares), Pole de Medecine et de Chirurgie bucco-dentaires, Hopitaux Universitaires de Strasbourg Strasbourg, France
19. CENTOGENE GmbH, Rostock, Germany
20. Division of Infectious Diseases and Host Defense, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States
21. Institute of Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
22. Center for Microbial Pathogenesis Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH, United States
23. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
24. Department of Mathematics, Bar-Ilan University, Ramat Gan, Israel
25. Laboratoire de Spectrometrie de Masse Bio-Organique (LSMBO), Institut Pluridisciplinaire Hubert Curien (IPHC), UMR 7178, Universite de Strasbourg, CNRS, Infrastructure Nationale de Proteomique ProFI - FR2048, Strasbourg, France
26. Allergy and Immunology Unit, Shaare Zedek Medical Center, Jerusalem, Israel
27. Faculty of Medicine Hebrew university, Jerusalem, Israel
28. Hospital Infantil Napoleon Franco Pareja, Bolivar, Cartagena de Indias, Colombia
29. Department of Pediatrics, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
30. Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States
31. Division of Pediatric Hematology, Oncology and Bone Marrow Transplantation, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States
32. Service d'Oncologie-Hematologie et Immunologie Pedi atrique, Hopital Enfant-Adolescent, CHU Nantes, Nantes, France
33. Service de Genetique Medicale, Hopital Hotel-Dieu, CHU de Nantes, Nantes, France
34. Allergy and Immunology Unit, Kipper Institute of Immunology, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel
35. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
36. The Jeffrey Modell Foundation Israeli Network for Primary Immunodeficiency, New York, NY, United States

Source: Science Advances Published:2024

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 naive 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. © 2024 American Association for the Advancement of Science. All rights reserved.

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Style	Citing Format
MLA	Molitor A, et al.. "A Pleiotropic Recurrent Dominant Itpr3 Variant Causes a Complex Multisystemic Disease." Science Advances, vol. 10, no. 37, 2024, pp. -.
APA	Molitor A, Lederle A, Radosavljevic M, Sapuru V, Zavorka Thomas ME, Yang J, Shirin M, Collinbund V, Jerabkovaroda K, Miao Z, Bernard A, Rolli V, Grenot P, Castro CN, Rosenzwajg M, Lewis EG, Person R, Esperonmoldes US, Kaare M, ... Bahram S (2024). A Pleiotropic Recurrent Dominant Itpr3 Variant Causes a Complex Multisystemic Disease. Science Advances, 10(37), -.
Chicago	Molitor A, Lederle A, Radosavljevic M, Sapuru V, Zavorka Thomas ME, Yang J, Shirin M, et al.. "A Pleiotropic Recurrent Dominant Itpr3 Variant Causes a Complex Multisystemic Disease." Science Advances 10, no. 37 (2024): -.
Harvard	Molitor A et al. (2024) 'A Pleiotropic Recurrent Dominant Itpr3 Variant Causes a Complex Multisystemic Disease', Science Advances, 10(37), pp. -.
Vancouver	Molitor A, Lederle A, Radosavljevic M, Sapuru V, Zavorka Thomas ME, Yang J, et al.. A Pleiotropic Recurrent Dominant Itpr3 Variant Causes a Complex Multisystemic Disease. Science Advances. 2024;10(37):-.
BibTex	@article{ author = {Molitor A and Lederle A and Radosavljevic M and Sapuru V and Zavorka Thomas ME and Yang J and Shirin M and Collinbund V and Jerabkovaroda K and Miao Z and Bernard A and Rolli V and Grenot P and Castro CN and Rosenzwajg M and Lewis EG and Person R and Esperonmoldes US and Kaare M and Nokelainen PT and Batzir NA and Hoffer GZ and Paul N and Stemmelen T and Naegely L and Hanauer A and Bibitriki S and Grun S and Jung S and Busnelli I and Tripolszki K and Alali R and Ordonez N and Bauer P and Song E and Zajo K and Partidasanchez S and Robledoavila F and Kumanovics A and Louzoun Y and Hirschler A and Pichot A and Toker O and Munoz Mejia CA and Parvaneh N and Knapp E and Hersh JH and Kenney H and Delmonte OM and Notarangelo LD and Goetz JG and Kahwash SB and Carapito C and Bajwa RPS and Thomas C and Ehl S and Isidor B and Carapito R and Abraham RS and Hite RK and Marcus N and Bertoliavella A and Bahram S}, title = {A Pleiotropic Recurrent Dominant Itpr3 Variant Causes a Complex Multisystemic Disease}, journal = {Science Advances}, volume = {10}, number = {37}, pages = {-}, year = {2024} }
RIS	TY - JOUR AU - Molitor A AU - Lederle A AU - Radosavljevic M AU - Sapuru V AU - Zavorka Thomas ME AU - Yang J AU - Shirin M AU - Collinbund V AU - Jerabkovaroda K AU - Miao Z AU - Bernard A AU - Rolli V AU - Grenot P AU - Castro CN AU - Rosenzwajg M AU - Lewis EG AU - Person R AU - Esperonmoldes US AU - Kaare M AU - Nokelainen PT AU - Batzir NA AU - Hoffer GZ AU - Paul N AU - Stemmelen T AU - Naegely L AU - Hanauer A AU - Bibitriki S AU - Grun S AU - Jung S AU - Busnelli I AU - Tripolszki K AU - Alali R AU - Ordonez N AU - Bauer P AU - Song E AU - Zajo K AU - Partidasanchez S AU - Robledoavila F AU - Kumanovics A AU - Louzoun Y AU - Hirschler A AU - Pichot A AU - Toker O AU - Munoz Mejia CA AU - Parvaneh N AU - Knapp E AU - Hersh JH AU - Kenney H AU - Delmonte OM AU - Notarangelo LD AU - Goetz JG AU - Kahwash SB AU - Carapito C AU - Bajwa RPS AU - Thomas C AU - Ehl S AU - Isidor B AU - Carapito R AU - Abraham RS AU - Hite RK AU - Marcus N AU - Bertoliavella A AU - Bahram S TI - A Pleiotropic Recurrent Dominant Itpr3 Variant Causes a Complex Multisystemic Disease JO - Science Advances VL - 10 IS - 37 SP - EP - PY - 2024 ER -

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