A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease,Science Advances

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A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease
Science Advances ( IF 11.7 ) Pub Date : 2024-09-13 , DOI: 10.1126/sciadv.ado5545
Anne Molitor _{1,

2} , Alexandre Lederle _{1,

2} , Mirjana Radosavljevic _{1,

2,

3} , Vinay Sapuru _{4,

5} , Megan E Zavorka Thomas ₆ , Jianying Yang _{1,

2} , Mahsa Shirin _{1,

2} , Virginie Collin-Bund _{1,

2} , Katerina Jerabkova-Roda _{1,

7} , Zhichao Miao _{8,

9} , Alice Bernard _{1,

2,

3} , Véronique Rolli _{1,

2,

3} , Pierre Grenot _{1,

2} , Carla Noemi Castro ₁₀ , Michelle Rosenzwajg _{11,

12} , Elyssa G Lewis ₁₃ , Richard Person ₁₄ , Uxía-Saraiva Esperón-Moldes ₁₅ , Milja Kaare ₁₅ , Pekka T Nokelainen ₁₅ , Nurit Assia Batzir ₁₆ , Gal Zaks Hoffer ₁₆ , Nicodème Paul _{1,

2} , Tristan Stemmelen _{1,

2,

3} , Lydie Naegely _{1,

2} , Antoine Hanauer _{1,

2} , Sabrina Bibi-Triki _{1,

2} , Sarah Grün _{10,

17} , Sophie Jung _{1,

18} , Ignacio Busnelli ₁ , Kornelia Tripolszki ₁₉ , Ruslan Al-Ali ₁₉ , Natalia Ordonez ₁₉ , Peter Bauer ₁₉ , Eunkyung Song ₂₀ , Kristin Zajo ₂₁ , Santiago Partida-Sanchez ₂₂ , Frank Robledo-Avila ₂₂ , Attila Kumanovics ₂₃ , Yoram Louzoun ₂₄ , Aurélie Hirschler ₂₅ , Angélique Pichot _{1,

2} , Ori Toker _{26,

27} , Cesar Andrés Muñoz Mejía ₂₈ , Nima Parvaneh ₂₉ , Esther Knapp ₁₃ , Joseph H Hersh ₁₃ , Heather Kenney ₃₀ , Ottavia M Delmonte ₃₀ , Luigi D Notarangelo ₃₀ , Jacky G Goetz _{1,

7} , Samir B Kahwash ₆ , Christine Carapito ₂₅ , Rajinder P S Bajwa ₃₁ , Caroline Thomas ₃₂ , Stephan Ehl ₁₀ , Bertrand Isidor ₃₃ , Raphael Carapito _{1,

2,

3} , Roshini S Abraham ₆ , Richard K Hite ₄ , Nufar Marcus _{34,

35,

36} , Aida Bertoli-Avella ₁₉ , Seiamak Bahram _{1,

2,

3}

Affiliation

Laboratoire d'ImmunoRhumatologie Moléculaire, Institut national de la santé et de la recherche médicale (INSERM) UMR_S 1109, Plateforme GENOMAX, Centre de Recherche d'Immunologie et d'Hématologie and Centre de Recherche en Biomédecine de Strasbourg (CRBS), Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
Institut Thématique Interdisciplinaire (ITI) Transplantex NG de Médecine de Précision de Strasbourg, Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Physiology, Biophysics, and Systems Biology (PBSB) Program, Weill Cornell Graduate School of Biomedical Sciences, New York, NY, USA.
Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
Equipe labellisée, Ligue nationale Contre le Cancer, Strasbourg, France.
Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, China.
Translational Research Institute of Brain and Brain-Like Intelligence and Department of Anesthesiology, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China.
Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Clinical Investigation Center for Biotherapies (CIC-BTi) and Immunology-Inflammation-Infectiology and Dermatology Department (3iD), Paris, France.
Sorbonne Université, INSERM UMR_S 959, Immunology-Immunopathology-Immunotherapy (i3), Paris, France.
Norton Children's Medical Group, University of Louisville School of Medicine, Louisville, KY, USA.
GeneDx, Gaithersburg, MD, USA.
Blueprint Genetics, A Quest Diagnostics Company, Espoo, Finland.
Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikvah, Israel.
Faculty of Biology, University of Freiburg, Freiburg, Germany.
Centre de Référence des maladies rares orales et dentaires (O-Rares), Pôle de Médecine et de Chirurgie bucco-dentaires, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
CENTOGENE GmbH, Rostock, Germany.
Division of Infectious Diseases and Host Defense, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA.
Institute of Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
Center for Microbial Pathogenesis, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN USA.
Department of Mathematics, Bar-Ilan University, Ramat Gan, Israel.
Laboratoire de Spectrométrie de Masse Bio-Organique (LSMBO), Institut Pluridisciplinaire Hubert Curien (IPHC), UMR 7178, Université de Strasbourg, CNRS, Infrastructure Nationale de Protéomique ProFI - FR2048, Strasbourg, France.
Allergy and Immunology Unit, Shaare Zedek Medical Center, Jerusalem, Israel.
Faculty of Medicine Hebrew university, Jerusalem, Israel.
Hospital Infantil Napoleón Franco Pareja, Cartagena de Indias, Bolívar, Colombia.
Department of Pediatrics, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
Division of Pediatric Hematology, Oncology and Bone Marrow Transplantation, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA.
Service d'Oncologie-Hématologie et Immunologie Pédiatrique, Hôpital Enfant-Adolescent, CHU Nantes, Nantes, France.
Service de Génétique Médicale, Hôpital Hôtel-Dieu, CHU de Nantes, Nantes, France.
Allergy and Immunology Unit, Kipper Institute of Immunology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
The Jeffrey Modell Foundation Israeli Network for Primary Immunodeficiency, New York, NY, USA.

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.

中文翻译：

多效性复发性显性 ITPR3 变异导致复杂的多系统疾病

肌醇 1,4,5-三磷酸（IP3）受体 1 型（ITPR1）、2 （ITPR2 ）和 3 型（ITPR3）编码 IP3 受体（IP3R），这是细胞内钙释放的关键参与者。在 4 名无关的患者中，我们报告了相同的 ITPR3 新发变异 — NM_002224.3：c.7570C>T， p.Arg2524Cys — 通过显性阴性效应导致免疫缺陷的复杂多系统疾病。这导致钙稳态缺陷、线粒体功能障碍、CD4 + 淋巴细胞减少、幼稚 CD4 + 和 CD8 + 细胞准缺失、记忆细胞增加和不同的 TCR 库。钙缺陷在 Jurkat 敲入中进行了概括。定点诱变显示 Arg 2524 对任何氨基酸变化都非常敏感。尽管所有患者都患有严重的免疫缺陷，但他们也表现出不同的多系统参与，包括外胚层发育不良、Charcot-Marie-Tooth 病、身材矮小和骨髓衰竭。总之，与先前报道的导致狭窄（主要是神经系统表型）的 ITPR1-3 缺陷不同，复发性显性 ITPR3 变体导致多系统疾病，定义了 IP3R3 在四聚体 IP3R 复合物中的独特作用。

更新日期：2024-09-13

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