Journal of Allergy and Clinical Immunology: Global (Feb 2024)

Novel hemizygous CORO1A variant leads to combined immunodeficiency with defective platelet calcium signaling and cell mobility

  • Anna Khoreva, MD,
  • Kirill R. Butov, MD,
  • Elena I. Nikolaeva, MD,
  • Alexey Martyanov, PhD,
  • Elena Kulakovskaya, MD,
  • Dmitry Pershin, MD,
  • Maxim Alexenko, MD,
  • Maria Kurnikova, MD,
  • Ruslan Abasov, MD,
  • Elena Raykina, PhD,
  • Dmitry Abramov, MD,
  • Kristina Arnaudova, PhD,
  • Yulia Rodina, PhD,
  • Natalia Trubina, MD,
  • Yulia Skvortsova, PhD,
  • Dmitry Balashov, PhD,
  • Anastasia Sveshnikova, PhD,
  • Alexey Maschan, PhD,
  • Galina Novichkova, PhD,
  • Mikhail Panteleev, PhD,
  • Anna Shcherbina, PhD

Journal volume & issue
Vol. 3, no. 1
p. 100172

Abstract

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Background: To date, fewer than 20 patients have been identified as having germline biallelic mutations in the coronin-1A gene (CORO1A) and its protein with clinical features of combined immunodeficiency characterized by T-cell lymphopenia ranging from the severe phenotype to the mild phenotype, recurrent infections, and lymphoproliferative disorders. However, the effects of CORO1A protein disruption on actin-dependent functions in primary cells have not been fully delineated. Objective: We sought to characterize the underlying defects of actin-dependent cellular functions in a female patient with combined immunodeficiency caused by a novel missense variant in the CORO1A gene in combination with a de novo heterozygous microdeletion of chromosome 16p11.2 and also to provide evidence of the pathogenicity of this gene mutation. Methods: To identify the genetic defect, next-generation sequencing followed by Sanger confirmation and array comparative genomic hybridization were performed. Western blot and quantitative PCR tests were used to assess the effects on the protein. Flow cytometry and live microscopy were performed to investigate cellular motility and immune cell counts and function. Results: We demonstrated that the CORO1A hemizygous variant c.19C>T, p. A7C induces significant decreases in cellular levels of the CORO1A protein while leaving mRNA concentrations unaffected. The observed mutation resulted in impaired natural killer cell cytotoxicity and platelet calcium signaling. In addition, primary granulocytes and mesenchymal cells showed significant defects in motility. Conclusion: Collectively, we added new data about the CORO1A gene as a key player in actin cytoskeleton dynamics and cell signaling. Our findings expand the clinical spectrum regarding CORO1A protein deficiency and confirm the importance of a personalized therapeutic approach for each patient.

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