Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association.
J Allergy Clin Immunol
; 137(3): 879-88.e2, 2016 Mar.
Article
in En
| MEDLINE
| ID: mdl-26476480
ABSTRACT
BACKGROUND:
Coronin-1A (CORO1A) is a regulator of actin dynamics important for T-cell homeostasis. CORO1A deficiency causes T(-)B(+) natural killer-positive severe combined immunodeficiency or T-cell lymphopenia with severe viral infections. However, because all known human mutations in CORO1A abrogate protein expression, the role of the protein's functional domains in host immunity is unknown.OBJECTIVE:
We sought to identify the cause of the primary immunodeficiency in 2 young adult siblings with a history of disseminated varicella, cutaneous warts, and CD4(+) T-cell lymphopenia.METHODS:
We performed immunologic, genetic, and biochemical studies in the patients, family members, and healthy control subjects.RESULTS:
Both patients had CD4(+) T-cell lymphopenia and decreased lymphocyte proliferation to mitogens. IgG, IgM, IgA, and specific antibody responses were normal. Whole-genome sequencing identified a homozygous frameshift mutation in CORO1A disrupting the last 2 C-terminal domains by replacing 61 amino acids with a novel 91-amino-acid sequence. The CORO1A(S401fs) mutant was expressed in the patients' lymphocytes at a level comparable with that of wild-type CORO1A in normal lymphocytes but did not oligomerize and had impaired cytoskeletal association. CORO1A(S401fs) was associated with increased filamentous actin accumulation in T cells, severely defective thymic output, and impaired T-cell survival but normal calcium flux and cytotoxicity, demonstrating the importance of CORO1A oligomerization and subcellular localization in T-cell homeostasis.CONCLUSIONS:
We describe a truncating mutation in CORO1A that permits protein expression and survival into young adulthood. Our studies demonstrate the importance of intact CORO1A C-terminal domains in thymic egress and T-cell survival, as well as in defense against viral pathogens.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cytoskeleton
/
Virus Diseases
/
Protein Multimerization
/
Homozygote
/
Microfilament Proteins
/
Mutation
Type of study:
Diagnostic_studies
/
Prognostic_studies
/
Risk_factors_studies
Language:
En
Journal:
J Allergy Clin Immunol
Year:
2016
Document type:
Article