CORO1A – severe combined immunodeficiency due to CORO1A deficiency

Autosomal recessive loss‐of‐function variants in CORO1A underlie a unique form of T(–)B(+)NK(+) severe combined immunodeficiency characterized by profound naïve T‐cell lymphopenia and variable mucocutaneous and infectious phenotypes. Six affected individuals from three unrelated kindreds demonstrate that biallelic CORO1A disruption abrogates Coronin-1A function and impairs T-cell homeostasis ([PMID:25073507]; [PMID:23522482]; [PMID:18836449]).

In the first non‐consanguineous kindred, two siblings harbored compound heterozygous frameshift alleles c.248_249delCT (p.Pro83ArgfsTer10) and c.1077delC (p.Gln360ArgfsTer44), presenting after age 7 y with absent CD4⁺ CD45RA⁺ naïve T cells, low NK counts, double-negative αβ T-cells, epidermodysplasia verruciformis–HPV, molluscum contagiosum, granulomatous leprosy and bronchiectasis; one sibling succumbed to EBV⁺ lymphoma at 16 y ([PMID:25073507]). In a second consanguineous pedigree three siblings were homozygous for a hypomorphic c.400G>A (p.Val134Met) variant leading to near‐absent Coronin-1A expression, early EBV‐associated B‐cell lymphoproliferation and naïve T-cell lymphopenia ([PMID:23522482]). A single patient with a homozygous c.76G>A (p.Glu26Lys) mutation recapitulated the T-cell egress defect in a peripheral T-cell‐deficient mouse strain and human SCID ([PMID:18836449]).

Segregation across three families confirms autosomal recessive inheritance, with all six affected siblings inheriting biallelic CORO1A variants from heterozygous carrier parents and unaffected siblings (affected_relatives = 5).

Functional assays demonstrate complete loss or alteration of Coronin-1A protein. Western blotting in patient cells shows absent or markedly reduced protein for frameshift and missense variants, correlating with impaired T-cell receptor repertoire diversity, diminished invariant NKT and mucosal‐associated invariant T cells, and severely reduced thymic output ([PMID:23522482]; [PMID:26476480]). The c.76G>A (p.Glu26Lys) allele in both mouse and human abolishes Arp2/3 regulation and T-cell migration without dominant‐negative effects, indicating loss of critical actin‐binding and signaling functions ([PMID:26108624]).

Animal and cellular models recapitulate human immunophenotypes: the Ptcd mouse strain harboring p.Glu26Lys exhibits thymic egress blockade and T-cell lymphopenia, while patient‐derived lymphocytes with the S401fs variant show defective oligomerization, cytoskeletal association and accelerated F‐actin accumulation, underscoring the importance of C-terminal domains in T-cell survival ([PMID:18836449]; [PMID:26476480]).

Integrated evidence supports a Strong gene‐disease association. Biallelic truncating and hypomorphic variants in CORO1A cause a distinctive T(–)B(+)NK(+) SCID with mucocutaneous viral susceptibility, granulomatous infections and shortened telomeres, underscoring the need for early genetic diagnosis and tailored immune reconstitution strategies. Key take‐home: CORO1A testing should be included in AR-SCID panels to guide timely hematopoietic stem cell transplantation and infection surveillance.

References

• Journal of clinical immunology • 2014 • Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy. PMID:25073507
• The Journal of allergy and clinical immunology • 2013 • Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation. PMID:23522482
• Nature immunology • 2008 • The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency. PMID:18836449
• Molecular biology of the cell • 2015 • The disease-linked Glu-26-Lys mutant version of Coronin 1A exhibits pleiotropic and pathway-specific signaling defects. PMID:26108624
• The Journal of allergy and clinical immunology • 2016 • Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association. PMID:26476480
• The Journal of allergy and clinical immunology. Global • 2024 • Novel hemizygous CORO1A variant leads to combined immunodeficiency with defective platelet calcium signaling and cell mobility. PMID:37915722

Evidence Based Scoring (AI generated)