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The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency.

Abstract
Mice carrying the recessive locus for peripheral T cell deficiency (Ptcd) have a block in thymic egress, but the mechanism responsible is undefined. Here we found that Ptcd T cells had an intrinsic migration defect, impaired lymphoid tissue trafficking and irregularly shaped protrusions. Characterization of the Ptcd locus showed a point substitution of lysine for glutamic acid at position 26 in the actin regulator coronin 1A that enhanced its inhibition of the actin regulator Arp2/3 and resulted in its mislocalization from the leading edge of migrating T cells. The discovery of another coronin 1A mutant during an N-ethyl-N-nitrosourea-mutagenesis screen for T cell-lymphopenic mice prompted us to evaluate a T cell-deficient, B cell-sufficient and natural killer cell-sufficient patient with severe combined immunodeficiency, whom we found had mutations in both CORO1A alleles. Our findings establish a function for coronin 1A in T cell egress, identify a surface of coronin involved in Arp2/3 regulation and demonstrate that actin regulation is a biological process defective in human and mouse severe combined immunodeficiency.
AuthorsLawrence R Shiow, David W Roadcap, Kenneth Paris, Susan R Watson, Irina L Grigorova, Tonya Lebet, Jinping An, Ying Xu, Craig N Jenne, Niko Föger, Ricardo U Sorensen, Christopher C Goodnow, James E Bear, Jennifer M Puck, Jason G Cyster
JournalNature immunology (Nat Immunol) Vol. 9 Issue 11 Pg. 1307-15 (Nov 2008) ISSN: 1529-2916 [Electronic] United States
PMID18836449 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Actin-Related Protein 2-3 Complex
  • Actins
  • Microfilament Proteins
  • coronin proteins
  • Glutamic Acid
  • Lysine
Topics
  • Actin-Related Protein 2-3 Complex (antagonists & inhibitors, metabolism)
  • Actins (metabolism)
  • Alleles
  • Amino Acid Substitution
  • Animals
  • Cell Movement (genetics, immunology)
  • Cell Shape
  • Female
  • Glutamic Acid (genetics)
  • Humans
  • Lysine (genetics)
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mice, Knockout
  • Microfilament Proteins (genetics, physiology)
  • Mutation
  • Severe Combined Immunodeficiency (genetics, immunology)
  • T-Lymphocytes (immunology)
  • Thymus Gland (immunology)

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