The actin regulator coronin-1A is mutated in a thymic egress deficient mouse strain and in a T(−)B(+)NK(+) SCID patient

Mice carrying the recessive peripheral T cell deficiency (Ptcd) locus have a block in thymic egress but the mechanism responsible is undefined. Here we found that Ptcd T cells have an intrinsic migration defect, impaired lymphoid tissue trafficking and irregularly shaped protrusions. Characterization of the Ptcd locus revealed an E26K point mutation within the actin regulator coronin-1A (Coro1a) that enhanced its inhibition of the actin regulator Arp2/3 and resulted in its mislocalization from the leading edge of migrating T cells. Discovery of another Coro1a mutant during an N-ethyl-N-nitrosourea (ENU) mutagenesis screen for T cell lymphopenic mice prompted us to evaluate a T cell-deficient, B cell- and NK cell-sufficient (T(−)B(+)NK(+)) severe combined immunodeficiency (SCID) patient, whom we found had mutations in both CORO1A alleles. These findings establish a role for coronin-1A in T cell egress, identify a surface of coronin involved in Arp2/3 regulation, and reveal actin regulation as a biological process defective in human and mouse SCID.