title: Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association.
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.
authors.affiliation: Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Yee
authors.affiliation: Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Massaad
authors.affiliation: Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Wayne
authors.initials: W
authors.lastname: Bainter
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, Mass.
authors.forename: Toshiro K
authors.initials: TK
authors.lastname: Ohsumi
authors.affiliation: Institute of Clinical Chemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Niko
authors.initials: N
authors.lastname: Föger
authors.affiliation: Genentech, San Francisco, Calif.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Chan
authors.affiliation: Department of Medical Genetics, Hacettepe University Medical Faculty, Ankara, Turkey.
authors.forename: Nurten A
authors.initials: NA
authors.lastname: Akarsu
authors.affiliation: Dr Sami Ulus Children's Health and Diseases Training and Research Center, Ankara, Turkey.
authors.forename: Caner
authors.initials: C
authors.lastname: Aytekin
authors.affiliation: Hacettepe University and Ihsan Doğramacı Children's Hospital, Ankara, Turkey.
authors.forename: Deniz Çagdas
authors.initials: DÇ
authors.lastname: Ayvaz
authors.affiliation: Hacettepe University and Ihsan Doğramacı Children's Hospital, Ankara, Turkey.
authors.forename: Ilhan
authors.initials: I
authors.lastname: Tezcan
authors.affiliation: Hacettepe University and Ihsan Doğramacı Children's Hospital, Ankara, Turkey.
authors.forename: Özden
authors.initials: Ö
authors.lastname: Sanal
authors.affiliation: Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass. Electronic address: Raif.Geha@childrens.harvard.edu.
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
authors.affiliation: Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass.
authors.forename: Janet
authors.initials: J
authors.lastname: Chou
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000293:Adolescent; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics; D003599:Cytoskeleton / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D006720:Homozygote; D006801:Humans; D007136:Immunoglobulins / Q000097:blood / Q000276:immunology; D018655:Lymphocyte Count; D008231:Lymphopenia; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D055503:Protein Multimerization / Q000235:genetics; D021381:Protein Transport; D035781:Siblings; D015398:Signal Transduction; D012871:Skin Diseases / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014777:Virus Diseases / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism*; D014860:Warts / Q000473:pathology
chemical_list: D000199:Actins; D007136:Immunoglobulins; D008840:Microfilament Proteins; C072061:coronin proteins
keywords: Coronin-1A; T-cell lymphopenia; immunodeficiency