A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease

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.