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DOI 10.1126/sciadv.ado5545

Медицинская библиотека · Science advances · 2024

A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease.

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

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПеревод пока не подготовлен

Аннотация

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.

Для цитирования: 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. A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease.. Science advances. 2024. DOI: 10.1126/sciadv.ado5545.

Предметные рубрики MeSH

HumansInositol 1,4,5-Trisphosphate ReceptorsMaleFemaleCalciumChildMutationJurkat CellsChild, PreschoolGenes, DominantPedigreePhenotype
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