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

Anne Molitor1,2, Alexandre Lederle1,2, Mirjana Radosavljevic1,2,3

  • 1Laboratoire 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.

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|September 13, 2024
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A novel Inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) variant causes a complex multisystemic disorder with immunodeficiency. This dominant-negative mutation disrupts calcium homeostasis and affects multiple organs, unlike previously identified ITPR1-3 deficiencies.

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Area of Science:

  • Molecular Biology
  • Immunology
  • Genetics

Background:

  • Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), encoded by ITPR1, ITPR2, and ITPR3, are crucial for intracellular calcium release.
  • IP3R deficiencies typically present with neurological phenotypes.

Purpose of the Study:

  • To investigate the genetic basis and clinical manifestations of a complex multisystemic disorder with immunodeficiency.
  • To elucidate the role of a specific ITPR3 variant in disease pathogenesis.

Main Methods:

  • Identified a recurrent de novo ITPR3 variant (NM_002224.3:c.7570C>T, p.Arg2524Cys) in four unrelated patients.
  • Analyzed clinical data including immunophenotyping, calcium homeostasis, and mitochondrial function.
  • Replicated calcium defects in a Jurkat knock-in model and used site-directed mutagenesis.

Main Results:

  • The identified ITPR3 variant causes a dominant-negative effect, leading to defective calcium homeostasis and mitochondrial dysfunction.
  • Patients exhibited severe immunodeficiency, characterized by CD4+ lymphopenia, absence of naïve T cells, and increased memory cells.
  • Variable multisystemic involvements were observed, including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure.

Conclusions:

  • A recurrent dominant ITPR3 variant defines a unique role for IP3R3 in the IP3R complex, causing a multisystemic disease distinct from other ITPR deficiencies.
  • This finding expands the known spectrum of IP3R-associated disorders beyond neurological phenotypes.